Hepatocyte targeting molecules and methods of use thereof

Abstract

Provided herein are viral particles comprising a heterologous viral glycoprotein and a targeting moiety wherein the targeting moiety comprises a polypeptide comprising the formula T-S1 wherein T is a target binding domain that targets the viral particle to the liver, and S1 is the stem moiety. The stem portion can comprise a variant Fc domain. The stem portion can comprise a flexible polypeptide domain. The targeting moiety comprising the formula T-S1 can be incorporated into viral particles to assist in targeting such particles to specific cell types. Also provided herein are compositions comprising the viral particles and methods of using the viral particles.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 507,817, filed June 13, 2023, which is incorporated herein by reference in its entirety.

[0003] Reference sequence list submitted electronically

[0004] This application includes a sequence list, which is submitted electronically in XML format and incorporated herein by reference in its entirety. The XML copy created on May 10, 2024, is named “INH-026WO_SL.xml” and has a size of 138,150 bytes. Technical Field

[0005] The embodiments provided herein relate to hepatocyte-targeting molecules, compositions containing hepatocyte-targeting molecules, and methods of using hepatocyte-targeting molecules. Background Technology

[0006] Vesicular stomatitis virus (VSV) is an enveloped, negative-sense RNA virus belonging to the genus Vesiculovirus of the family Rhabdovirus. This virus is an arbovirus that can infect insects, cattle, horses, and pigs. The VSV genome encodes five structural proteins, among which is a single transmembrane glycoprotein (G). Glycoproteins are classic type I membrane glycoproteins with an N-terminal signal peptide, an extracellular domain of approximately 450 amino acids, a single α-helix transmembrane segment, and a small intraviral C-terminal domain. The signal peptide is cleaved in the lumen of the endoplasmic reticulum, and the native glycoprotein is present in the extracellular domain, transmembrane domain, and intraviral domain.

[0007] G plays a crucial role during the initial stages of viral infection (Albertini, AAV, Baquero, E., Ferlin, A., and Gaudin, Y. (2012). Molecular and Cellular Aspects of Rhabdovirus Entry. Viruses 4, 117-139.), which is incorporated herein by reference in its entirety. First, this glycoprotein is responsible for viral attachment to specific receptors. After binding, the viral particle enters the cell via clathrin-mediated endocytosis. In the acidic environment of the endocytic vesicles, G triggers fusion between the viral membrane and the endosomal membrane, releasing the genome into the cytosol for subsequent infection steps. The fusion was catalyzed by a large structural transition from the pre-fusion conformation to the post-fusion conformation induced by low pH, both of which are trimers (Roche, S., Bressanelli, S., Rey, FA and Gaudin, Y. (2006). Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science 313, 187-191. Roche, S., Rey, FA, Gaudin, Y. and Bressanelli, S. (2007). Structure of the prefusion form of the vesicular stomatitis virus glycoprotein g. Science 315, 843-848). Each reference is incorporated herein by reference in its entirety.

[0008] The G extracellular domain folds into three distinct domains: the fusion domain (FD), the Plek substrate homology domain (PHD), and the trimer domain (TrD). During structural transitions, FD, PHD, and TrD retain their tertiary structure. However, these domains undergo significant rearrangements in their relative orientations due to secondary changes in the refolded hinge segments (S1 to S5) during low-pH-induced conformational changes (Roche et al., 2006; Roche et al., 2007).

[0009] It has been shown that the low-density lipoprotein receptor (LDL-R) and other members of its family act as VSV receptors (Finkelshtein, D., Werman, A., Novick, D., Barak, S., and Rubinstein, M. (2013). LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus. Proceedings of the National Academy of Sciences of the United States of America 110, 7306-7311, which is incorporated herein by reference in its entirety). VSV-G can be used for pseudotypening of other viruses, and VSV-G pseudotyped lentiviruses (VSV-G-LV) exhibit the same broad tropism as VSV. However, this broad tropism can inhibit selective targeting to specific cell types. Therefore, there is a need for modified (mutant or mutant) VSV-G proteins that can be used for pseudotypening of viruses. Pseudotyped viruses lose their binding to the LDL receptor, which can then be combined with other targeting domains to target specific cell types, such as, but not limited to, liver cells. Embodiments of the present invention meet these and other needs. Summary of the Invention

[0010] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion, wherein the targeting portion comprises a polypeptide having the formula T-S1, wherein T is a target-binding domain for targeting the viral particle to the liver, and S1 is a stem portion.

[0011] In some embodiments, the stem portion S1 comprises a variant Fc protein. In some embodiments, the variant Fc protein comprises a transmembrane domain, such as, but not limited to, a CD8 or CD28 transmembrane domain. In some embodiments, the variant Fc protein comprises an effector mutation, wherein the effector mutation inhibits the interaction between the Fc protein and Fc-interacting proteins, such as FcγR, C1q, FcRβ, or FcRn.

[0012] In some implementations, the variant Fc protein is a variant IgG1 Fc protein containing one or more mutations selected from the group consisting of: L234A, L235A, N297A, P329G, I253A, H310A, and H435A.

[0013] In some embodiments, the variant IgG1 Fc protein comprises an amino acid sequence having at least 80% identity with SEQ ID NO: 91, at least 85% identity with SEQ ID NO: 91, at least 90% identity with SEQ ID NO: 91, at least 95% identity with SEQ ID NO: 91, at least 98% identity with SEQ ID NO: 91, or at least 100% identity with SEQ ID NO: 91.

[0014] In some implementations, the variant Fc protein is a variant IgG2 Fc protein containing one or more mutations selected from the group consisting of: N297A, P329G, I253A, H310A, and H435A.

[0015] In some implementations, the variant Fc protein is a variant IgG4 Fc protein containing one or more mutations selected from the group consisting of: S228P, L235E, N297A, P329G, I253A, H310A, and H435A.

[0016] In some embodiments, the targeting portion having formula T-S1 includes a stem portion S1 having formula L1-Fc-L2-X1, wherein L1 is a linker or is absent, Fc is a variant Fc protein, L2 is a linker or is absent, and X1 is a polypeptide containing a transmembrane domain, wherein the targeting portion having formula T-S1 has formula T-L1-Fc-L2-X1.

[0017] In some embodiments, the polypeptide containing the transmembrane domain (X1) comprises a peptide having the formula ECD-T M -ICD polypeptides, wherein ECD is an extracellular domain of a cell surface protein or a fragment thereof, or is absent; T M It is a transmembrane domain of a transmembrane protein; and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the viral particle envelope, or it is absent; wherein the target portion having the formula T-L1-Fc-L2-X1 has the formula T-L1-Fc-L2-ECD-T M -ICD.

[0018] In some embodiments, the stem portion S1 comprises formula L3-X1, wherein L3 is a flexible peptide linker and X1 is a polypeptide containing a transmembrane domain; wherein the targeting portion having formula T-S1 has formula T-L3-X1.

[0019] In some embodiments, the polypeptide containing the transmembrane domain (X1) comprises a peptide having the formula ECD-T M-ICD polypeptides, wherein ECD is an extracellular domain of a cell surface protein or a fragment thereof, or is absent; T M It is a transmembrane domain of a transmembrane protein; and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the viral particle envelope, or it is absent; wherein the target portion having the formula T-L3-X1 has the formula T-L3-ECD-T M -ICD.

[0020] In some embodiments, the targeting portion binds to ASGR1. In some embodiments, the targeting portion comprises a polypeptide having a heavy chain variable region comprising HCDR1 of SEQ ID NO: 30, HCDR2 of SEQ ID NO: 31, and HCDR of SEQ ID NO: 32, or a variant thereof. In some embodiments, the targeting portion comprises a polypeptide having a light chain variable region comprising LCDR1 of SEQ ID NO: 33, LCDR2 containing a GKN amino acid sequence, and LCDR of SEQ ID NO: 34, or a variant thereof. In some embodiments, the heavy chain comprises a heavy chain variable region having at least 90% sequence identity with SEQ ID NO: 35. In some embodiments, the light chain comprises a light chain variable region having at least 90% sequence identity with SEQ ID NO: 36. In some embodiments, the targeting portion binding to ASGR1 comprises a polypeptide having a sequence having at least 90% sequence identity with SEQ ID NO: 37. In some embodiments, the targeting portion that binds to ASGR1 comprises a polypeptide having a sequence having at least 90% sequence identity with SEQ ID NO: 38.

[0021] In some implementations, the heteroviral glycoprotein is the SVCV-G polypeptide as provided herein.

[0022] In some embodiments, the heteroviral glycoprotein is the VSV-G polypeptide. In some embodiments, the VSV-G polypeptide comprises substitutions at positions I182, T214, and T352 of SEQ ID NO: 2. In some embodiments, the substitution at position 182 is I182D or I182E. In some embodiments, the substitution at position 214 is T214N. In some embodiments, the substitution at position 352 is T352A.

[0023] In some embodiments, the viral particles provided herein also contain nucleic acid molecules encoding a heterologous molecule of interest. In some embodiments, the heterologous molecule of interest is as provided herein. In some embodiments, the heterologous molecule of interest is a chimeric antigen receptor (“CAR”), ATP7B, GAA, SERPINA1, OTC, GUSB, UGT1A1, PAH, BCKDHA, BCKDHB, DBT, ATP8B1, ABCB11, ABCB4, FAH, TAT, HPD, HMBS, ASS1, SLC25A13, F8, F9, AGXT, GRHPR, HOGA1, INS, glucagon-like peptide-1 (GLP-1) hormone, glucagon-like peptide-2 (GLP-2) hormone, enteroglucagon, PYY, CCK, glucagon, amylin, activin type II inhibitors, or miR-22 inhibitors.

[0024] In some implementations, the viral particles also contain at least one nucleic acid molecule encoding a gene editing system.

[0025] In some implementations, the viral particles are non-integrating lentiviral vector (NILV) particles.

[0026] In some embodiments, a method for infecting cells is provided. In some embodiments, the method includes contacting the cells with viral particles as provided herein.

[0027] In some embodiments, a method for infecting a subject's cells is provided. In some embodiments, the method includes administering to the subject a pharmaceutical composition comprising viral particles as provided herein.

[0028] In some embodiments, methods for delivering a heterologous molecule of interest into cells are provided. In some embodiments, the method includes contacting the cells with viral particles as provided herein, wherein the viral particles contain nucleic acid molecules encoding the heterologous molecule of interest.

[0029] In some embodiments, a method is provided for delivering a heterologous molecule of interest to a subject's cells. In some embodiments, the method includes administering to a subject a viral particle, as provided herein, wherein the viral particle contains a nucleic acid molecule encoding the heterologous molecule of interest.

[0030] In some embodiments, a method for treating a subject's disease or condition is provided. In some embodiments, the method includes administering to the subject a viral particle as provided herein, wherein the viral particle contains a nucleic acid molecule encoding a heterologous molecule of interest for treating the disease or condition.

[0031] In some embodiments, a method for delivering a heterologous molecule to target cells is provided. In some embodiments, the method includes contacting the cells with viral particles as provided herein, wherein the viral particles contain nucleic acid molecules encoding the heterologous molecule.

[0032] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heteroviral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heteroviral glycoprotein comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52, or SEQ ID NO: 53. In some embodiments, the target-binding domain comprises a sequence selected from SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises a variant Fc protein comprising a sequence as a variant of SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28. In some embodiments, the variant of SEQ ID NO: 26 comprises one or more mutations selected from the group consisting of L234A, L235A, N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant of SEQ ID NO: 27 comprises one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant of SEQ ID NO: 28 comprises one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant Fc protein further comprises a transmembrane domain containing a sequence selected from SEQ ID NO: 61 or SEQ ID NO: 62.

[0033] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heteroviral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heteroviral glycoprotein comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52, or SEQ ID NO: 53. In some embodiments, the target-binding domain comprises a sequence selected from SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L1-Fc-L2-X1, wherein L1 is a linker comprising a sequence selected from SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, or SEQ ID NO: 76, or is absent; Fc is a variant Fc protein comprising a sequence as a variant of SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28; L2 is a linker comprising a sequence selected from SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, or SEQ ID NO: 76, or is absent; and X1 is a polypeptide comprising a transmembrane domain. In some embodiments, the variant of SEQ ID NO: 26 comprises one or more mutations selected from the group consisting of L234A, L235A, N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant of SEQ ID NO: 27 comprises one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant of SEQ ID NO: 28 comprises one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A, and H435A. In some embodiments, the polypeptide comprising the transmembrane domain (X1) has the formula ECD-T. M -ICD, wherein ECD is an extracellular domain having a sequence selected from SEQ ID NO: 59 or SEQ ID NO: 60, or a fragment thereof, or is absent; T MIt is a transmembrane domain or a fragment thereof having the sequence of SEQ ID NO: 61 or SEQ ID NO: 62; and the ICD is an intracellular domain or a protein that facilitates the incorporation of the target portion into the envelope of a viral particle, wherein the ICD contains an env incorporation motif having the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64 or the ICD is absent.

[0034] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heteroviral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heteroviral glycoprotein comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52, or SEQ ID NO: 53. In some embodiments, the target-binding domain comprises a sequence selected from SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L1-Fc-L2-X1, wherein L1 is a linker comprising the sequence of SEQ ID NO: 55 or is absent; Fc is a variant Fc protein comprising a sequence as a variant of SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28; L2 is a linker comprising the sequence of SEQ ID NO: 55 or is absent; and X1 is a polypeptide comprising a transmembrane domain. In some embodiments, the variant of SEQ ID NO:26 comprises one or more mutations selected from the group consisting of L234A, L235A, N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant of SEQ ID NO:27 comprises one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A, and H435A. In some embodiments, the variant of SEQ ID NO:28 comprises one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A, and H435A. In some embodiments, the polypeptide comprising the transmembrane domain (X1) has the formula ECD-T. M -ICD, wherein ECD is an extracellular domain or a fragment thereof having the sequence of SEQ ID NO: 60, or is absent; T MIt is a transmembrane domain or a fragment thereof having the sequence of SEQ ID NO: 62; and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of a viral particle, wherein the ICD contains an env incorporation motif having the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64 or the ICD is absent.

[0035] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heterologous viral glycoprotein comprises a sequence selected from SEQ ID NO: 23 or SEQ ID NO: 25. In some embodiments, the target-binding domain comprises a sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L1-Fc-L2-X1, wherein L1 is a linker comprising the sequence of SEQ ID NO: 55; Fc is a variant Fc protein comprising the sequence of SEQ ID NO: 91; L2 is a linker or is absent; and X1 is a polypeptide comprising a transmembrane domain. In some embodiments, the polypeptide comprising the transmembrane domain (X1) has the formula ECD-T. M -ICD, where ECD is an extracellular domain having the sequence SEQ ID NO: 60; T M It is a transmembrane domain having the sequence of SEQ ID NO: 62; and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif having the amino acid sequence of SEQ ID NO: 63.

[0036] In some embodiments, a viral particle is provided, wherein the viral particle comprises a heterologous viral glycoprotein and a targeting portion. In some embodiments, the heterologous viral glycoprotein comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 23 or SEQ ID NO: 25, at least 95% identity with SEQ ID NO: 23 or SEQ ID NO: 25, at least 99% identity with SEQ ID NO: 23 or SEQ ID NO: 25, or at least 100% identity with SEQ ID NO: 23 or SEQ ID NO: 25. In some embodiments, the targeting portion comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 89 or SEQ ID NO: 92, at least 95% identity with SEQ ID NO: 89 or SEQ ID NO: 92, at least 99% identity with SEQ ID NO: 89 or SEQ ID NO: 92, or at least 100% identity with SEQ ID NO: 89 or SEQ ID NO: 92.

[0037] In some embodiments, a viral particle is provided, wherein the viral particle comprises a heterologous viral glycoprotein and a targeting portion. In some embodiments, the heterologous viral glycoprotein comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 52 or SEQ ID NO: 53, at least 95% identity with SEQ ID NO: 53, at least 99% identity with SEQ ID NO: 52 or SEQ ID NO: 53, or at least 100% identity with SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the targeting portion comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 89 or SEQ ID NO: 92, at least 95% identity with SEQ ID NO: 89 or SEQ ID NO: 92, at least 99% identity with SEQ ID NO: 89 or SEQ ID NO: 92, or at least 100% identity with SEQ ID NO: 89 or SEQ ID NO: 92.

[0038] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the target-binding domain comprises the amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L3-X1, wherein L3 is a flexible peptide linker comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57 or SEQ ID NO: 58, and X1 is a polypeptide linker comprising a transmembrane domain. In some embodiments, the polypeptide (X1) comprising the transmembrane domain has the formula ECD-T. M -ICD, wherein ECD is an extracellular domain containing the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 60, or a fragment thereof, or is absent, T M It is a transmembrane domain containing the amino acid sequence of SEQ ID NO: 61 or SEQ ID NO: 62, and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64, or the ICD is absent.

[0039] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heterologous viral glycoprotein comprises the sequence of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52, or SEQ ID NO: 53. In some embodiments, the target-binding domain comprises the amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L3-X1, wherein L3 is a flexible peptide linker comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58, and X1 is a polypeptide linker comprising a transmembrane domain. In some embodiments, the polypeptide (X1) comprising the transmembrane domain has the formula ECD-T. M-ICD, where ECD is an extracellular domain containing the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 60, or a fragment thereof, or is absent, T M It is a transmembrane domain containing the amino acid sequence of SEQ ID NO: 61 or SEQ ID NO: 62, and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64, or the ICD is absent.

[0040] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heterologous viral glycoprotein comprises the sequence of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52, or SEQ ID NO: 53. In some embodiments, the target-binding domain comprises the amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L3-X1, wherein L3 is a flexible peptide linker comprising the amino acid sequence of SEQ ID NO: 55, and X1 is a polypeptide linker comprising a transmembrane domain. In some embodiments, the polypeptide (X1) comprising the transmembrane domain has the formula ECD-T. M -ICD, wherein ECD is an extracellular domain containing the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 60, or a fragment thereof, or is absent, T M It is a transmembrane domain containing the amino acid sequence of SEQ ID NO: 61 or SEQ ID NO: 62, and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64, or the ICD is absent.

[0041] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heterologous viral glycoprotein comprises the sequence of SEQ ID NO: 23 or SEQ ID NO: 25. In some embodiments, the target-binding domain comprises the amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L3-X1, wherein L3 is a flexible peptide linker comprising the amino acid sequence of SEQ ID NO: 55, and X1 is a polypeptide linker comprising a transmembrane domain. In some embodiments, the polypeptide (X1) comprising the transmembrane domain has the formula ECD-T. M -ICD, where ECD is an extracellular domain containing the amino acid sequence of SEQ ID NO: 59, T M It is a transmembrane domain containing the amino acid sequence of SEQ ID NO: 61, and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64.

[0042] In some embodiments, a viral particle is provided. In some embodiments, the viral particle comprises a heterologous viral glycoprotein and a targeting portion having the formula T-S1, wherein T is a target-binding domain and S1 is a stem portion. In some embodiments, the heterologous viral glycoprotein comprises the sequence of SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the target-binding domain comprises the amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 38. In some embodiments, the stem portion S1 comprises the formula L3-X1, wherein L3 is a flexible peptide linker comprising the amino acid sequence of SEQ ID NO: 55, and X1 is a polypeptide linker comprising a transmembrane domain. In some embodiments, the polypeptide (X1) comprising the transmembrane domain has the formula ECD-T. M -ICD, where ECD is an extracellular domain containing the amino acid sequence of SEQ ID NO: 59, T M It is a transmembrane domain containing the amino acid sequence of SEQ ID NO: 61, and the ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. Attached Figure Description

[0043] Figure 1A and Figure 1B The crystal structure of VSV-G combined with LDL-R is illustrated. Figure 1A The crystal structure of VSV-G bound to CR3 of LDL-R is illustrated. Figure 1B The crystal structure of VSV-G with CR2 bonded to LDL-R is illustrated.

[0044] Figure 2A and Figure 2B The effect of adding negatively charged amino acids to the VSV-G:LDL-R binding interface on native affinity and cohesion is illustrated. Figure 2A The titration of the VSV-G construct on SupT1 cells is illustrated. Figure 2B Examples are given by Figure 2A The functional titer of each construct is calculated by titration.

[0045] Figure 3 The comparison of extracellular domains of different VSV-G proteins from different strains is illustrated.

[0046] Figure 4 The effects of various VSV-G mutations on the serum stability of viral constructs combined with CD7 binding compounds are illustrated.

[0047] Figure 5 The effects of various VSV-G mutations on the serum stability of viral constructs combined with CD7 binding compounds are illustrated.

[0048] Figure 6 The ability of various rhabdoviral G proteins, alone or in combination with CD7 conjugates, to transduce SupT1 and PBMC cells is illustrated.

[0049] Figure 7A and Figure 7B This demonstrates the ability of lentiviral particles carrying ASGR1 conjugates to successfully transduce ASGR1+ cells. Figure 7A Results are illustrated for ASGR1 conjugates containing SEQ ID NO: 38. Figure 7B The results of ASGR1 conjugate containing SEQ ID NO: 37 are illustrated. Detailed Implementation

[0050] This document provides viral particles comprising a heterologous viral glycoprotein and a targeting portion, wherein the targeting portion comprises a polypeptide having the formula T-S1, where T is a target-binding domain and S1 is a stem portion. In some embodiments, S1 comprises a mutant Fc polypeptide that can, for example, be linked to a transmembrane domain as provided herein. In some embodiments, S1 comprises a flexible polypeptide as provided herein. Mutant Fc polypeptides or flexible polypeptides can be incorporated into viral particles to help facilitate the targeting of viral particles to specific cell types.

[0051] Additionally, viral particles may contain VSV-G proteins that can be used, for example, to pseudotype viruses such as lentiviruses. In some embodiments, the pseudotyped virus-like particles are pseudotyped using viral glycoproteins of vesicular stomatitis New Jersey virus strain, vesicular stomatitis Indiana virus strain, vesicular stomatitis Aragos virus strain, vesicular stomatitis Malaba virus strain, or vesicular stomatitis Carajás virus strain. Examples of such proteins are provided herein.

[0052] Pseudogenized viruses containing mutant VSV-G proteins (such as those provided herein) can be used in conjunction with targeting moieties to promote the fusion of the pseudotyped virus with specific cells or tissues based on the expression of the target on those cells or tissues. As provided herein, the targeting moieties can be linked to an Fc protein, which may refer to a stem protein containing a transmembrane domain to facilitate attachment of the targeting moieties to the viral surface. In some embodiments, the Fc protein contains Fc effector mutations, such as those provided herein.

[0053] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments pertain.

[0054] As used herein, unless the context clearly indicates otherwise, the term "a" means "at least one" or "one or more".

[0055] As used herein, the term “about” means an approximate index value, and small variations will not significantly affect the practice of the disclosed embodiments. When numerical limits are used, the “about” index value may vary by ±10% and remain within the range of the disclosed embodiments unless the context otherwise specifies. Furthermore, when the phrase “about x to y” is used, the term “about” modifies both x and y unless the context otherwise specifies, and can be used interchangeably with the phrase “about x to about y”.

[0056] As used herein, the interchangeable terms “individual” or “subject” or “patient” mean any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates such as humans.

[0057] As used herein, the terms “comprise” (and any form of inclusion, such as “comprise”, “comprises”, and “comprised”), “have” (and any form of having, such as “have” and “has”), “include” (and any form of inclusion, such as “includes” and “include”), or “contains” (and any form of containing, such as “contains” and “contains”) are inclusive or open-ended and do not exclude additional, unlisted elements or method steps. Any step or composition using the transitional phrase “comprise” or “comprising” may also be described as being identical to that described by the transitional phrase “consisting of” or “consists”.

[0058] As used herein, the term “contact” means bringing two elements together in an in vitro or in vivo system. For example, “contacting” a virus or vector described herein with an individual or patient or cells includes administering a virus to an individual or patient, such as a human, and, for example, introducing a compound into a sample containing cells or a purified preparation containing cells.

[0059] As used herein, the terms “fusion” or “linkage” when referring to proteins with different domains or heterologous sequences mean that the protein domains are part of the same peptide chain and are linked to each other by peptide bonds or other covalent bonds. Domains or segments may be directly linked or fused to each other, or another domain or peptide sequence may be between two domains or sequences, and such sequences will still be considered fused or linked to each other. In some embodiments, the various domains or proteins provided herein are directly linked or fused to each other, or adapter sequences such as the glycine / serine sequences described herein link two domains together.

[0060] "Disease" is a state of health in which the animal is unable to maintain homeostasis, and in which the animal's health continues to deteriorate if the disease is not treated. In contrast, an animal's "symptom" is a state of health in which the animal is able to maintain homeostasis, but in which the animal's health is worse than it would be without the symptom. A symptom, if left untreated, does not necessarily lead to a further decline in the animal's health.

[0061] The terms "effective amount" or "therapeutic effective amount" are used interchangeably herein and refer to the amount of a compound, formulation, material, or composition as described herein that effectively achieves a particular biological outcome or provides a therapeutic or preventative benefit. Such an outcome may include, but is not limited to, the amount of immune cell activation that, when administered to a mammal, results in a detectable level of immune cell activation compared to that detected in the absence of the composition. Immune responses can be readily assessed using a wide range of methods recognized in the art. Those skilled in the art will understand that the amount of the composition administered herein varies and can be readily determined based on many factors, such as the disease or symptom being treated, the age and health and physical condition of the mammal being treated, the severity of the disease, the specific compound administered, etc.

[0062] "Encoding" refers to the inherent characteristics of a specific nucleotide sequence in a polynucleotide (such as a gene, cDNA, or mRNA) for use as a template in biological processes to synthesize other polymers and macromolecules having defined nucleotide sequences (i.e., rRNA, tRNA, and mRNA) or defined amino acid sequences, and the resulting biological characteristics. Therefore, if the transcription and translation of the mRNA corresponding to a gene produces a protein in a cell or other biological system, then the gene encodes that protein. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is typically provided in the sequence listing, and the non-coding strand, which serves as a template for transcription of the gene or cDNA, can be referred to as the protein or other product encoding that gene or cDNA.

[0063] "Expression vector" refers to a vector containing a recombinant polynucleotide that includes an expression control sequence operatively linked to a nucleotide sequence to be expressed. The expression vector contains sufficient cis-acting elements for expression; other elements for expression may be provided by a host cell or in an in vitro expression system. Expression vectors include all expression vectors known in the art, such as clomids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., Sendai virus, lentivirus, retrovirus, adenovirus, and adeno-associated virus) incorporating recombinant polynucleotides.

[0064] As used in this article, the phrase “ex vivo” in relation to transducing, transfecting or transforming cells means transducing, transfecting or transforming cells outside of a subject, i.e., removing cells from a subject prior to transducing, transfecting or transforming such cells.

[0065] As used herein, “identity” refers to the subunit sequence identity between two polymer molecules, such as two nucleic acid or amino acid molecules, or such as two polynucleotide or polypeptide molecules. Two amino acid sequences are identical when they have the same residue at the same position; for example, if each position in two polypeptide molecules is occupied by arginine, then they are identical at that position. The degree of identity, or similarity, between two amino acid or two nucleic acid sequences in an alignment is usually expressed as a percentage. Identity between two amino acid or two nucleic acid sequences is a direct function of the number of matching or identical positions; for example, if half of the positions in two sequences are identical, then the two sequences are 50% identical; if 90% of the positions (e.g., 9 out of 10) are matching or identical, then the two amino acid sequences are 90% identical.

[0066] "Substantially identical" means that the polypeptide or nucleic acid molecule exhibits at least 50% identity with a reference amino acid sequence (e.g., any one of the amino acid sequences described herein) or nucleic acid sequence (e.g., any one of the nucleic acid sequences described herein). In some embodiments, such a sequence is at least 60%, 80%, or 85%, or 90%, 95%, or even 99% identical to the sequence used for comparison at the amino acid level or nucleic acid level. Other percentages of identity with respect to specific sequences are described herein.

[0067] Sequence identity can be measured / determined using sequence analysis software, such as the sequence analysis software package from Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, including the BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs. Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conserved substitutions typically include those within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In exemplary methods for determining the degree of identity, the BLAST program can be used, where a probability score between e3 and e100 indicates closely related sequences. In some embodiments, sequence identity is determined using BLAST with default settings.

[0068] For the purposes of the embodiments provided herein, compositions comprising various proteins may, in some cases, contain amino acid sequences that have sequence identity with the amino acid sequences disclosed herein. Therefore, in some embodiments, depending on the specific sequence, the degree of sequence identity with the SEQ ID NO disclosed herein is preferably greater than 50% (e.g., 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater). Other identity percentages are also provided herein in addition to these percentages. Identity between peptides can be determined using an affine gap search with parameters gap opening penalty (12) and gap extension penalty = 1, as implemented in the MPSRCH program (Oxford Molecular).

[0069] These proteins, compared to publicly available proteins, may include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) conserved amino acid substitutions, where one amino acid is replaced by another amino acid with a related side chain. Genetically encoded amino acids are generally classified into four families: (1) acidic, i.e., aspartic acid and glutamic acid; (2) basic, i.e., lysine, arginine, and histidine; (3) nonpolar, i.e., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan; and (4) uncharged polar, i.e., glycine, asparagine, glutamine, cysteine, serine, threonine, and tyrosine. Phenylalanine, tryptophan, and tyrosine are sometimes collectively classified as aromatic amino acids. Generally, substitution of a single amino acid within these families does not significantly affect biological activity. Proteins may have one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) single amino acid deletions relative to publicly available protein sequences. In addition to the publicly available protein sequence, the protein may also contain one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) insertions (e.g., each of 1, 2, 3, 4, or 5 amino acids).

[0070] As used in this article, the phrase “in vivo” in relation to transducing, transfecting, or transforming cells means transducing, transfecting, or transforming such cells in a subject without removing the cells from the subject prior to transducing, transfecting, or transforming them.

[0071] "Separated" means altered or removed from its natural state. For example, nucleic acids or peptides that are naturally present in living organisms are not "separated," but the same nucleic acids or peptides that are partially or completely separated from their natural counterparts are "separated." Separated nucleic acids or proteins can exist in a substantially purified form or in non-natural environments, such as, for example, host cells.

[0072] As used herein, “lentivirus” refers to a genus of the family Retroviridae capable of infecting non-dividing cells. Non-limiting examples of lentiviruses are HIV, SIV, and FIV. Vectors or virus-like particles derived from lentiviruses can be used to transduce cells and deliver genes or other molecules, enabling their expression in cells either in vitro (ex vivo) or in vivo.

[0073] As used herein, the term "modified" refers to an altered state or structure of a molecule or cell as presented herein. Molecules can be modified in many ways, including chemically, structurally, and functionally, such as through mutation, substitution, insertion, or deletion (e.g., internal deletion truncation). Cells can be modified by introducing nucleic acids or expressing heterologous proteins.

[0074] As used herein, the term "modulation" means mediating an increase or decrease in a subject's response level compared to the response level of a subject in the absence of treatment or the compound, and / or compared to the response level of other subjects who are otherwise identical but untreated. This term includes interfering with and / or influencing natural signals or responses, thereby mediating a beneficial therapeutic response in a subject (such as a human).

[0075] Unless otherwise specified, "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate to each other and encode the same amino acid sequence. Phrases encoding protein or RNA may also contain introns, to the extent that nucleotide sequences encoding proteins may contain introns in some forms.

[0076] The term "oligonucleotide" usually refers to short polynucleotides. It should be understood that when a nucleotide sequence is represented by a DNA sequence (i.e., A, T, C, G), this also provides the corresponding RNA sequence (i.e., A, U, C, G) in which "U" replaces "T".

[0077] "Parenteral" administration of the composition includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection or infusion.

[0078] As used herein, the term "polynucleotide" is defined as a nucleotide chain. Furthermore, nucleic acids are polymers of nucleotides. Therefore, as used herein, the terms "nucleic acid" and "polynucleotide" are interchangeable. As used herein, polynucleotides include, but are not limited to, all nucleic acid sequences obtained by any method available in the art, including, but not limited to, recombinant methods, i.e., cloning nucleic acid sequences from recombinant libraries or cell genomes using cloning techniques and PCR, as well as synthetic methods.

[0079] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to compounds consisting of multiple amino acid residues covalently linked by peptide bonds. As used herein, the term refers to both short chains (which are also commonly referred to in the art as, for example, peptides, oligopeptides, and oligomers) and long chains (which are commonly referred to in the art as proteins, of which there are many types). “Polypeptide” includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, and so on. Polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0080] Unless otherwise explicitly stated, the terms “heteroviral structural protein” and “heteroviral glycoprotein” as used herein are synonymous and interchangeable. Therefore, unless otherwise explicitly stated, any implementation that refers to “heteroviral structural protein” should be understood to mean “heteroviral glycoprotein”, and vice versa.

[0081] As used herein, the term "pseudotyped" or "pseudotyped viral particle" refers to a viral particle carrying a glycoprotein derived from another enveloped virus or a viral vector encoding an envelope glycoprotein from a virus different from its parent virus. Therefore, the host range of a vector particle can be expanded or altered depending on the type of cell surface receptor used by the glycoprotein. For example, viruses can be pseudotyped using VSV-G mutant proteins as described herein.

[0082] As used herein with respect to antibodies, the term "specifically binding" refers to an antibody that recognizes a specific antigen but substantially does not recognize or bind to other molecules in the sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. However, this cross-species reactivity itself does not alter the antibody's specific classification. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, this cross-reactivity itself does not alter the antibody's specific classification. In some cases, the term "specifically binding" or "specifically binding" may be used in relation to the interaction of an antibody, protein, or peptide with a second chemical substance to mean that the interaction depends on the presence of a specific structure on the chemical substance (e.g., an antigenic determinant or epitope); for example, the antibody recognizes and binds to a specific protein structure, rather than a protein in general. If an antibody is specific for epitope "A," then in a reaction containing labeled "A" and an antibody, the presence of a molecule containing epitope A (or free, unlabeled A) will reduce the amount of labeled A that binds to the antibody. In some implementations, the targeting portions of viral particles containing mutant VSV-G proteins or other viral structural proteins used for pseudotypening of viruses, as described herein, can bind specifically to their targets.

[0083] The term "subject" includes living organisms, including those that can elicit an immune response (e.g., mammals). As used herein, a "subject" or "patient" can be a human or a non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, non-human primates, cats, and rodents. In some embodiments, the subject is a human.

[0084] As used in this article, the term "therapeutic" refers to treatment and / or prevention. Therapeutic effects are achieved by suppressing, alleviating, or eradicating a disease state.

[0085] As used herein, the terms “transfected,” “transformed,” or “transduced” refer to the process of transferring or introducing exogenous nucleic acids into cells. “Transfected,” “transformed,” or “transduced” cells are cells that have been transfected, transformed, or transduced with exogenous nucleic acids. Cells include primary subject cells and their progeny. In some embodiments, transfection, transformation, or transduction occurs in vivo.

[0086] As used in this article, “treatment” means reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by the subject.

[0087] A "vector" is a composition of material containing isolated nucleic acids encoding proteins or peptides. Many vectors are known in the art, including but not limited to linear polynucleotides, plasmids, DNA, and RNA. Examples of viral vectors include, but are not limited to, Sendai virus vectors, adenovirus vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, etc.

[0088] "Carriers" or "delivery mediators" include viral particles, viruses, polylysine compounds, and liposomes that facilitate the transfer of nucleic acids into cells. Carriers or delivery mediators can also be used to deliver proteins or peptides into cells.

[0089] Scope: Throughout this disclosure, various aspects of the embodiments may be presented in a scope format. It should be understood that the scope format is for convenience and brevity only and should not be construed as an inflexible limitation. Therefore, the scope description should be considered as having specifically disclosed all possible sub-scopes and the individual values ​​within those scopes. For example, a scope such as 1 to 6 should be considered as having specifically disclosed sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and the individual numbers within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the scope. Unless otherwise expressly stated to the contrary, the disclosed scope also includes the endpoints of the scope.

[0090] Viral particles containing heterologous viral glycoproteins and targeting components

[0091] In some embodiments, a viral particle comprising a heterologous viral glycoprotein and a targeting portion is provided. In some embodiments, the targeting portion comprises a polypeptide having the formula T-S1, where T is a target-binding domain for targeting the viral particle to the liver, and S1 is a stem portion. In some embodiments, S1 comprises a variant Fc protein, wherein the variant Fc protein comprises a transmembrane domain, such as, but not limited to, a CD8 or CD28 transmembrane domain. Thus, in some embodiments, the stem portion S1 comprises an N-terminal to C-terminal orientation (transmembrane domain) of the variant Fc. In some embodiments, the variant Fc protein comprises an effector mutation, wherein the effector mutation inhibits the interaction between the Fc protein and Fc-interacting proteins, such as FcγR, C1q, FcRβ, or FcRn.

[0092] In some embodiments, the S1 stem portion is attached to the surface of the viral particle via a transmembrane domain. In some embodiments, the variant Fc protein is a variant of the IgG1 Fc, IgG2 Fc, or IgG4 Fc protein. In some embodiments, the variant Fc protein comprises a variant of the sequence SEQ ID NO: 26 (IgG1 Fc), SEQ ID NO: 27 (IgG2 Fc), or SEQ ID NO: 28 (IgG4 Fc).

[0093] In some embodiments, the variant Fc protein is the variant IgG1 Fc protein (SEQ ID NO: 26). In some embodiments, the variant IgG1 Fc protein comprises one or more mutations corresponding to those mutations selected from the group consisting of: L234A, L235A, N297A, P329G, I253A, H310A, and H435A of SEQ ID NO: 26 according to the Kabat EU number index, as described in Edelman, GM et al., “The covalent structure of anentire gammaG immunoglobulin molecule.” Proceedings of the National Academy of Sciences of the United States of America, Vol. 63, 1 (1969): 78-85. doi:10.1073 / pnas.63.1.78, which is incorporated herein by reference in its entirety. The mutations L234A, L235A, N297A, P329G, I253A, H310A, and H435A of SEQ ID NO: 26 may or may not be present, and the mutations may be combined in any combination. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to L234A and L235A of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to N297A of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to P329G of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to L234A, L235A, N297A, and P329G of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to I253A of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to H310A of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to H435A of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to I253A, H310A, and H435A of SEQ ID NO: 26. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to L234A, L235A, N297A, P329G, I253A, H310A, and H435A of SEQ ID NO: 26.

[0094] In some embodiments, the variant Fc protein comprising the variant IgG1 Fc protein comprises a truncated IgG1 Fc sequence. Truncating may include the deletion of any number of amino acids from the N-terminus, C-terminus, or both of the IgG1 Fc sequence. In some embodiments, the variant Fc protein comprising the variant IgG1 Fc protein comprises a truncated SEQ ID NO: 26. Truncating may include the deletion of any number of amino acids from the N-terminus, C-terminus, or both of SEQ ID NO: 26. In some embodiments, truncating includes the deletion of amino acids from the N-terminus of SEQ ID NO: 26. In some embodiments, truncating includes the deletion of amino acids from both the N-terminus and C-terminus of SEQ ID NO: 26. In some embodiments, the truncated SEQ ID NO: 26 comprises the amino acid sequence of SEQ ID NO: 90:

[0095] EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 90)

[0096] In some embodiments, the variant IgG1 Fc protein contains one or more mutations relative to SEQ ID NO: 90, selected from the group consisting of: L19A, L20A, N82A, P114G, I38A, H95A, and H220A. It should be understood that positions L19, L20, N82, P114, I38, H95, and H220 refer only to SEQ ID NO: 90. Those skilled in the art will readily recognize that positions L234, L235, N297, P329, I253, H310, and H435, numbered according to Kabat's EU numbering system, correspond to positions L19, L20, N82, P114, I38, H95, and H220 of SEQ ID NO: 90, respectively. The mutations L19A, L20A, N82A, P114G, I38A, H95A, and H220A of SEQ ID NO: 90 may be present or absent, and the mutations may be combined in any combination. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to L19A and L20A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to N82A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc contains a mutation corresponding to P114G of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc contains mutations corresponding to L19A, L20A, N82A, and P114G of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to I38A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to H95A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to H220A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to I38A, H95A, and H220A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains mutations corresponding to L19A, L20A, N82A, P114G, I38A, H95A, and H220A of SEQ ID NO: 90. In some embodiments, the variant IgG1 Fc protein contains a mutation corresponding to each of L18A, L19A, N82A, P114G, I38A, H95A, and H220A of SEQ ID NO: 90.Exemplary variants of IgG1 protein comprising each of L18A, L19A, N82A, P114G, I38A, H95A, and H220A are shown in the amino acid sequence of SEQ ID NO: 91 below.

[0097] EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK (SEQ ID NO: 91)

[0098] In some embodiments, the variant Fc protein is the variant IgG2 Fc protein (SEQ ID NO: 27). In some embodiments, the variant IgG2 Fc protein contains one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A, and H435A according to the Kabat EU number index, because those positions correspond to SEQ ID NO: 27. Any of the mutations N297A, P329G, I253A, H310A, and H435A in SEQ ID NO: 27 may or may not be present, and the mutations may be combined in any combination. In some embodiments, the variant IgG2 Fc protein contains a mutation corresponding to N297A of SEQ ID NO: 27. In some embodiments, the variant IgG2 Fc protein contains a mutation corresponding to P329G of SEQ ID NO: 27. In some embodiments, the variant IgG2 Fc protein contains mutations corresponding to both N297A and P329G of SEQ ID NO: 27. In some embodiments, the variant IgG2 Fc protein contains the mutation corresponding to I253A of SEQ ID NO: 27. In some embodiments, the variant IgG2 Fc protein contains the mutation corresponding to H310A of SEQ ID NO: 27. In some embodiments, the variant IgG2 Fc protein contains the mutation corresponding to H435A of SEQ ID NO: 27. In some embodiments, the variant IgG2 Fc protein contains mutations corresponding to I253A, H310A, and H435A of SEQ ID NO: 27.

[0099] In some embodiments, the variant Fc protein comprising the variant IgG2 Fc protein comprises a truncated IgG2 Fc sequence. Truncating may include the deletion of any number of amino acids from the N-terminus, C-terminus, or both of the IgG2 Fc sequence. In some embodiments, the variant Fc protein comprising the variant IgG2 Fc protein comprises a truncated SEQ ID NO: 27. Truncating may include the deletion of any number of amino acids from the N-terminus, C-terminus, or both of SEQ ID NO: 27. In some embodiments, truncating includes the deletion of amino acids from the N-terminus of SEQ ID NO: 27. In some embodiments, truncating includes the deletion of amino acids from both the N-terminus and C-terminus of SEQ ID NO: 27.

[0100] In some embodiments, the variant Fc protein is the variant IgG4 Fc protein (SEQ ID NO: 28). In some embodiments, the variant IgG4 Fc protein contains one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A, and H435A according to the Kabat EU number index, because those positions correspond to SEQ ID NO: 28. Any of the mutations S228P, L235E, N297A, P329G, I253A, H310A, and H435A in SEQ ID NO: 28 may or may not be present, and the mutations may be combined in any combination. In some embodiments, the variant IgG4 Fc protein contains the mutation corresponding to S228P of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains the mutation corresponding to L235E of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains a mutation corresponding to N297A of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains a mutation corresponding to P329G of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains mutations corresponding to S228P, L235E, N297A, and P329G of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains a mutation corresponding to I253A of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains a mutation corresponding to H310A of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains a mutation corresponding to H435A of SEQ ID NO: 28. In some embodiments, the variant IgG4 Fc protein contains mutations corresponding to I253A, H310A, and H435A of SEQ ID NO: 28.

[0101] In some embodiments, the variant Fc protein comprising the variant IgG4 Fc protein comprises a truncated IgG4 Fc sequence. Truncating may include the deletion of any number of amino acids from the N-terminus, C-terminus, or both of the IgG4 Fc sequence. In some embodiments, the variant Fc protein comprising the variant IgG4 Fc protein comprises a truncated SEQ ID NO: 28. Truncating may include the deletion of any number of amino acids from the N-terminus, C-terminus, or both of SEQ ID NO: 28. In some embodiments, truncating includes the deletion of amino acids from the N-terminus of SEQ ID NO: 28. In some embodiments, truncating includes the deletion of amino acids from both the N-terminus and C-terminus of SEQ ID NO: 28.

[0102] In some embodiments, the stem portion S1 comprising the variant Fc protein is given by the formula L1-Fc-L2-X1, where L1 is a linker or is absent; Fc is the variant Fc protein; L2 is a linker or is absent; and X1 is a polypeptide comprising a transmembrane domain. Therefore, the targeting portion comprising the formula T-S1 can also be given by the formula T-L1-Fc-L2-X1, where: T is a targeting-binding domain for targeting viral particles to the liver; L1 is a linker or is absent; Fc is the variant Fc protein; L2 is a linker or is absent; and X1 is a polypeptide comprising a transmembrane domain. Therefore, it should be understood that in some embodiments, the stem portion S1 can be given by the formula L1-Fc-L2-X1. In some embodiments, the target-binding domain T is as provided herein. In some embodiments, the variant Fc protein is as provided herein.

[0103] In some embodiments, L1 and L2 are each independently a peptide linker. In some embodiments, the peptide linker includes (GGGGA). n (SEQ ID NO: 54), (GGGGS) n (SEQ ID NO: 55), (EAAAK) n (SEQ ID NO: 73), A(EAAAK) n A (SEQ ID NO: 74), (XP) n(SEQ ID NO: 75) (where X is Ala, Lys, or Glu), GSAGSAAGSGEF (SEQ ID NO: 56), KESGSVSSEQLAQFRSLD (SEQ ID NO: 57), EGKSSGSGSESKST (SEQ ID NO: 58), AEAAAKEAAAKA (SEQ ID NO: 76) or combinations thereof, wherein each n is independently 1-5. In some embodiments, each n is independently 1. In some embodiments, each n is independently 2. In some embodiments, each n is independently 3. In some embodiments, each n is independently 4. In some embodiments, each n is independently 5. In some embodiments, each n is independently greater than 5. In some embodiments, L1 is not present. In some embodiments, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 1-5. In some implementations, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 1. In some implementations, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 2. In some implementations, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 3. In some implementations, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 4. In some implementations, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 5. In some implementations, L1 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently greater than 5. In some embodiments, L2 is absent. In some embodiments, L2 is (GGGGA).n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 1-5. In some implementations, L2 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 1. In some implementations, L2 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 2. In some implementations, L2 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 3. In some implementations, L2 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently 4. In some implementations, L2 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO:55), where each n is independently 5. In some implementations, L2 is (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n (SEQ ID NO: 55), where each n is independently greater than 5.

[0104] In some implementations, X1 includes a formula ECD-T M -ICD polypeptides, wherein ECD is an extracellular domain of a cell surface protein or a fragment thereof, or is absent; T M It is a transmembrane domain of a transmembrane protein; and the ICD is an intracellular domain of a protein or a protein that promotes the incorporation of the targeting portion into the viral particle envelope, or it may not exist. Therefore, in some embodiments, the targeting portion comprising formula T-S1, which may also be given by formula T-L1-Fc-L2-X1, may also be given by formula T-L1-Fc-L2-ECD-T. M -ICD is given, where T is the target-binding domain that directs viral particles to the liver; L1 is the linker or is absent; Fc is the variant Fc protein; L2 is the linker or is absent; ECD is the extracellular domain of a cell surface protein or a fragment thereof, or is absent; T MIt is a transmembrane domain of a transmembrane protein; and the ICD is an intracellular domain of a protein or a protein that promotes the incorporation of the target portion into the viral particle envelope, or it may not exist. Therefore, it should be understood that in some embodiments, the stem portion S1 may be composed of the formula L1-Fc-L2-ECD-T M -ICD provides this information.

[0105] In some embodiments, the stem portion S1 does not contain a variant Fc region. In some embodiments, the stem portion S1 is given by formula L3-X1, where L3 is a flexible peptide linker and X1 is a polypeptide containing a transmembrane domain as provided herein. Therefore, in some embodiments, the targeting portion containing formula T-S1 may also be given by formula T-L3-X1, where T is a target-binding domain for targeting viral particles to the liver, L3 is a flexible peptide linker, and X1 is a polypeptide containing a transmembrane domain as provided herein. Therefore, it should be understood that in some embodiments, the stem portion S1 may be given by formula L3-X1. In some embodiments, the S1 stem portion is attached to the surface of the viral particle via a transmembrane domain.

[0106] In some embodiments, the flexible peptide linker L3 can be any flexible peptide linker. In some embodiments, L3 is selected from the group consisting of flexible linkers, including but not limited to (GGGGA). n (SEQ ID NO: 54), (GGGGS) n (SEQ ID NO: 55), GSAGSAAGSGEF (SEQ ID NO: 56), KESGSVSSEQLAQFRSLD (SEQ ID NO: 57), EGKSSGSGSESSKST (SEQ ID NO: 58), or any combination thereof, wherein each n is independently an integer selected from 1 to 4. In some embodiments, each n is independently an integer selected from 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, or 1 to 10. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, each n is independently greater than 10. In some embodiments, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 1. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 2. In some implementations, L3 is (GGGGA). n(SEQ ID NO:54) and n is 3. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 4. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 5. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 6. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 7. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 8. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 9. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 10. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is greater than 10. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 1. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 2. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 3. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 4. In some implementations, L3 is (GGGGS). n (SEQ ID NO:55) and n is 5. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 6. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 7. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 8. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 9. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 10. In some implementations, L3 is (GGGGS).n (SEQ ID NO: 55) and n is greater than 10. In some embodiments, L3 is GSAGSAAGSGEF (SEQ ID NO: 56). In some embodiments, L3 is KESGSVSSEQLAQFRSLD (SEQ ID NO: 57). In some embodiments, L3 is EGKSSGSGSESKST (SEQ ID NO: 58).

[0107] In some embodiments, the flexible peptide linker L3 can be any flexible peptide linker. In some embodiments, L3 is selected from the group consisting of flexible linkers, including but not limited to (GGGGA). n (SEQ ID NO: 54), (GGGGS) n (SEQ ID NO: 55), GSAGSAAGSGEF (SEQ ID NO: 56), KESGSVSSEQLAQFRSLD (SEQ ID NO: 57), EGKSSGSGSESSKST (SEQ ID NO: 58), or any combination thereof, wherein each n is independently an integer selected from 1 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 1. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 2. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 3. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 4. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 1. In some implementations, L3 is (GGGGS). n (SEQ ID NO:55) and n is 2. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 3. In some implementations, L3 is (GGGGS). n(SEQ ID NO: 55) and n is 4. In some embodiments, L3 is GSAGSAAGSGEF (SEQ ID NO: 56). In some embodiments, L3 is KESGSVSSEQLAQFRSLD (SEQ ID NO: 57). In some embodiments, L3 is EGKSSGSGSESKST (SEQ ID NO: 58).

[0108] In some implementations, L3 is selected from the group consisting of flexible joints, including but not limited to (GGGGA). n (SEQ ID NO:54), (GGGGS) n (SEQ ID NO: 55), GSAGSAAGSGEF (SEQ ID NO: 56), KESGSVSSEQLAQFRSLD (SEQ ID NO: 57), EGKSSGSGSESSKST (SEQ ID NO: 58), or any combination thereof, wherein each n is independently an integer selected from 1, 2, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 4. In some embodiments, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 1. In some implementations, L3 is (GGGGA). n (SEQ ID NO: 54) and n is 2. In some implementations, L3 is (GGGGA). n (SEQ ID NO:54) and n is 4. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 1. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 2. In some implementations, L3 is (GGGGS). n (SEQ ID NO: 55) and n is 4. In some embodiments, L3 is GSAGSAAGSGEF (SEQ ID NO: 56). In some embodiments, L3 is KESGSVSSEQLAQFRSLD (SEQ ID NO: 57). In some embodiments, L3 is EGKSSGSGSESKST (SEQ ID NO: 58).

[0109] In some implementations, X1 includes a formula ECD-T M -ICD polypeptides, wherein ECD is an extracellular domain of a cell surface protein or a fragment thereof, or is absent; T MIt is a transmembrane domain of a transmembrane protein; and the ICD is an intracellular domain of a protein or a protein that promotes the incorporation of the targeting portion into the viral particle envelope, or it is absent. Therefore, in some embodiments, the targeting portion comprising formula T-S1, which may also be given by formula T-L3-X1, may also be given by formula T-L3-ECD-T. M -ICD is given, where T is the target-binding domain that directs viral particles to the liver, L3 is the flexible peptide linker, and ECD is the extracellular domain of a cell surface protein or a fragment thereof, or it may not be present; T M It is a transmembrane domain of a transmembrane protein; and the ICD is an intracellular domain of a protein or a protein that promotes the incorporation of the target portion into the viral particle envelope, or it may not exist. Therefore, it should be understood that in some embodiments, the stem portion S1 may be derived from formula L3-ECD-T. M -ICD provides this information.

[0110] In some embodiments, the ECD is absent. In some embodiments, the ECD can be any suitable extracellular domain or a fragment thereof. In some embodiments, the ECD originates from a different protein than the transmembrane domain. The ECD domain can be the entire ECD domain or a fragment thereof. In some embodiments, the ECD domain is a CD8 or CD28 ECD domain or a fragment thereof. In some embodiments, the ECD domain is a CD8 ECD domain or a fragment thereof. In some embodiments, the CD8 ECD domain comprises a polypeptide of FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 59). In some embodiments, the CD8 ECD domain consists of or is substantially composed of a polypeptide of FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 59). In some embodiments, the ECD domain comprises a polypeptide of 25-45 amino acids in length. In some embodiments, the ECD comprises at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the peptide of FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 59). In some embodiments, the ECD domain is a CD28 ECD domain or a fragment thereof. In some embodiments, the CD28 ECD domain comprises a polypeptide of KIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 60). In some embodiments, the CD28 ECD domain is composed of or substantially composed of the polypeptide of KIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 60). In some embodiments, the ECD domain comprises a polypeptide of 25-45 amino acids in length. In some embodiments, the ECD contains at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the peptide of KIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO:60).

[0111] In some implementations, T M It can be any suitable transmembrane domain or fragment thereof. In some embodiments, T MThe structural domain is CD8 or CD28 T M A domain or a fragment thereof. In some implementations, T M The structural domain is CD8 T M A domain or a fragment thereof. In some implementations, CD8 T M The domain contains a polypeptide of IYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 61). In some embodiments, CD8 T M The domain is composed of or substantially composed of a polypeptide of IYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 61). In some embodiments, T M The polypeptide contains at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the peptide identical to that of IYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 61). In some embodiments, T M The structural domain is CD28T M A domain or a fragment thereof. In some implementations, CD28 T M The domain comprises a polypeptide of the form FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 62). In some embodiments, CD28 T M The domain is composed of or substantially composed of a polypeptide of the form FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 62). In some embodiments, T M The polypeptide contains at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the same peptide as FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 62).

[0112] In some implementations, T M The domain originates from the same protein as ECD. In some implementations, T M The domain originates from a protein different from ECD. In some implementations, T M The structural domain is CD8 or CD28 T M A structural domain or a fragment thereof, and the ECD structural domain is a CD8 or CD28 ECD structural domain or a fragment thereof. In some embodiments, T MThe peptide with the structural domain is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to that of IYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 61), and the ECD structural domain is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to that of FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 59). In some embodiments, T M The peptide with the structural domain is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to that of IYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 61), and the ECD structural domain is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to that of KIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 60). In some embodiments, T M The peptide with the structural domain is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to that of FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 62), and the ECD structural domain is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to that of FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 59). In some embodiments, T M The peptides of FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 62) have at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in terms of their structural domains, and the peptides of KIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 60) have at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in terms of their ECD domains.

[0113] In some embodiments, the transmembrane domain is linked to the intracellular domain (ICD) of a cellular transmembrane protein or a fragment thereof. In some embodiments, the ICD is absent. In some embodiments, the ICD originates from a protein that is the same as or different from the TM domain. In some embodiments, the ICD contains an Env incorporation motif. An Env incorporation motif is a molecule, such as a polypeptide, that can facilitate protein incorporation into the viral envelope. A non-limiting example of an Env incorporation motif is a polypeptide containing the amino acid sequence NRVRQGYS (SEQ ID NO: 63). This is a non-limiting example, and other peptide sequences, such as, but not limited to, GGTETSQVAPA (SEQ ID NO: 64), can be used. In some embodiments, the Env incorporation motif contains the amino acid sequence of SEQ ID NO: 63, SEQ ID NO: 64, or a combination thereof. In some embodiments, the Env incorporation motif contains the amino acid sequence of SEQ ID NO: 63. In some embodiments, the Env incorporation motif contains the amino acid sequence of SEQ ID NO: 64.

[0114] In some embodiments, the target-binding domain "T" is any polypeptide or polynucleotide that can be used to bind to a desired target. In some embodiments, the desired target is a liver cell. In some embodiments, the liver cell is a hepatocyte. In some embodiments, T is any polypeptide, polynucleotide, or fragment thereof that binds to an ASGPR, including its subunits such as ASGR1 or ASGR2. In some embodiments, the targeting portion "T" binds to an ASGPR. In some embodiments, the target-binding domain "T" binds to the ASGR1 subunit of an ASGPR. In some embodiments, the target-binding domain "T" binds to the ASGR2 subunit of an ASGPR. In some embodiments, the target-binding domain "T" binds to both the ASGR1 and ASGR2 subunits of an ASGPR, such as through conserved epitopes on ASGR1 and ASGR2 or through epitopes spanning ASGR1 and ASGR2. In some embodiments, the target-binding domain "T" is an antibody. It should be understood that, in the context of this disclosure, "antibody" refers not only to a "complete" antibody comprising two identical heavy chains, two identical light chains, and two antigen-binding fragments, but also to any isotype of antibody, antibody fragment (including but not limited to Fab, Fv, scFv, and Fd fragments), chimeric antibody, humanized antibody, single-chain antibody (scAb), single-domain antibody (dAb), single-domain heavy chain antibody, single-domain light chain antibody, bispecific antibody, multispecific antibody, and fusion protein comprising the antigen-binding portion of an antibody and a non-antibody protein. In some embodiments, the antibody is selected from the group including scFv, Fab, VHH, single-domain antibody, etc. In some embodiments, the antibody is scFv. In some embodiments, the antibody is Fab. In some embodiments, the antibody is VHH. In some embodiments, the antibody is a single-domain antibody.

[0115] In some embodiments, the viral particles provided herein are pseudotyped viral particles. In some embodiments, viral particles are pseudotyped using viral glycoproteins of viruses from the Paramyxoviridae family. In some embodiments, pseudotyped virus-like particles are pseudotyped using viral glycoproteins of the morbillivirus genus (such as Measlesvirus). In some embodiments, pseudotyped virus-like particles are pseudotyped using viral glycoproteins of Measlesvirus. In some embodiments, pseudotyped virus-like particles are pseudotyped using viral glycoproteins of Henipavirus (such as Nipah virus, Cedar virus, or Hendra virus). In some embodiments, pseudotyped virus-like particles are pseudotyped using viral glycoproteins of Nipah virus. In some embodiments, pseudotyped virus-like particles are pseudotyped using viral glycoproteins of Nipah virus. In some embodiments, peptides or antibodies as provided herein are linked to envelope glycoproteins G or H of viruses from the Paramyxoviridae family via a linker. In some implementations, the viruses of the Paramyxoviridae family are those of the Measlesvirus genus, such as measles virus. In other implementations, the viruses of the Paramyxoviridae family are Hennipa viruses, such as Nipah virus, Cedar virus, or Hendra virus.

[0116] As provided herein, viruses can be pseudotyped using the VSV-G protein (wild type or a mutant thereof). Without being bound by any particular theory, a mutant VSV-G protein containing a mutation at position 182, which can be used to pseudotype viruses (e.g., lentiviruses) when the virus contains a target region, can be used to pseudotype the virus and transduce cells. This mutation inhibits or reduces the affinity of VSV-G for its natural co-receptor LDL-R. In some embodiments, the provided mutant VSV-G protein can be used to transduce target cells and deliver heterologous molecules to target cells.

[0117] In some embodiments, a VSV-G protein comprising a mutation at position 198 compared to SEQ ID NO: 1 or a mutation at position 182 compared to SEQ ID NO: 2 is provided. SEQ ID NO: 1 is the full-length protein, and SEQ ID NO: 2 is the extracellular domain of the VSV-G protein. The 16-mer signal peptide of MKCLLYLAFLFIGVNC (SEQ ID NO: 65) as shown at the N-terminus of SEQ ID NO: 1 is cleaved, leaving the protein of SEQ ID NO: 2. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 2, it should be understood that the mutation also occurs in the context of SEQ ID NO: 1 containing the leader sequence, and will therefore be a position number 16 positions higher than that described in SEQ ID NO: 2. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the I182D mutation compared to SEQ ID NO: 2. In some implementations, the mutation is the I182E mutation compared to SEQ ID NO: 2.

[0118] In some embodiments, a VSV-G protein comprising a mutation at position 198 compared to SEQ ID NO: 10 or a mutation at position 182 compared to SEQ ID NO: 11 is provided. SEQ ID NO: 10 is the full-length protein, and SEQ ID NO: 11 is the extracellular domain of the VSV-G protein. The 16-mer signal peptide of MLSYLIFALVVSPILG (SEQ ID NO: 66) as shown at the N-terminus of SEQ ID NO: 10 is cleaved, leaving the protein of SEQ ID NO: 11. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 11, it should be understood that the mutation also occurs in the context of SEQ ID NO: 10 containing the leader sequence, and will therefore be a position number 16 positions higher than that described in SEQ ID NO: 11. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the T182D mutation compared to SEQ ID NO: 11. In some implementations, the mutation is the T182E mutation compared to SEQ ID NO: 11.

[0119] In some embodiments, a VSV-G protein comprising a mutation at position 198 compared to SEQ ID NO: 12 or a mutation at position 182 compared to SEQ ID NO: 13 is provided. SEQ ID NO: 12 is the full-length protein, and SEQ ID NO: 13 is the extracellular domain of the VSV-G protein. The 16-mer signal peptide MLRLFLFCFLALGAHS (SEQ ID NO: 67) shown at the N-terminus of SEQ ID NO: 12 is cleaved, leaving the protein of SEQ ID NO: 13. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 13, it should be understood that the mutation also occurs in the context of SEQ ID NO: 12 containing the leader sequence, and will therefore be a position number 16 positions higher than that described in SEQ ID NO: 13. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the A182D mutation compared to SEQ ID NO: 13. In some implementations, the mutation is the A182E mutation compared to SEQ ID NO: 13.

[0120] In some embodiments, a VSV-G protein comprising a mutation at position 203 compared to SEQ ID NO: 14 or a mutation at position 182 compared to SEQ ID NO: 15 is provided. SEQ ID NO: 14 is the full-length protein, and SEQ ID NO: 15 is the extracellular domain of the VSV-G protein. The 21-mer signal peptide of MKMKMVIAGLILCIGILPAIG (SEQ ID NO: 68) as shown at the N-terminus of SEQ ID NO: 14 is cleaved, leaving the protein of SEQ ID NO: 15. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 15, it should be understood that the mutation also occurs in the context of SEQ ID NO: 14 containing the leader sequence, and will therefore be a position number 21 more than the position described in SEQ ID NO: 15. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the V182D mutation compared to SEQ ID NO: 15. In some implementations, the mutation is the V182E mutation compared to SEQ ID NO: 15.

[0121] In some embodiments, a VSV-G protein comprising a mutation at position 199 compared to SEQ ID NO: 16 or a mutation at position 182 compared to SEQ ID NO: 17 is provided. SEQ ID NO: 16 is the full-length protein, and SEQ ID NO: 17 is the extracellular domain of the VSV-G protein. The 17-mer signal peptide of MTPAFILCMLLAGSSWA (SEQ ID NO: 69), as shown at the N-terminus of SEQ ID NO: 16, is cleaved, leaving the protein of SEQ ID NO: 17. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 17, it should be understood that the mutation also occurs in the context of SEQ ID NO: 16 containing the leader sequence, and will therefore be a position number 17 more than the position described in SEQ ID NO: 17. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the V182D mutation compared to SEQ ID NO: 17. In some implementations, the mutation is the V182E mutation compared to SEQ ID NO: 17.

[0122] In some embodiments, a VSV-G protein comprising a mutation at position 199 compared to SEQ ID NO: 18 or a mutation at position 182 compared to SEQ ID NO: 19 is provided. SEQ ID NO: 18 is the full-length protein, and SEQ ID NO: 19 is the extracellular domain of the VSV-G protein. The 17-mer signal peptide MNFLLLTFIVLPLCSHA (SEQ ID NO: 70) shown at the N-terminus of SEQ ID NO: 18 is cleaved, leaving the protein of SEQ ID NO: 19. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 19, it should be understood that the mutation also occurs in the context of SEQ ID NO: 18 containing the leader sequence, and will therefore be a position number 17 positions higher than that described in SEQ ID NO: 19. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the V182D mutation compared to SEQ ID NO: 19. In some implementations, the mutation is the V182E mutation compared to SEQ ID NO: 19.

[0123] In some embodiments, a VSV-G protein comprising a mutation at position 199 compared to SEQ ID NO: 20 or a mutation at position 182 compared to SEQ ID NO: 21 is provided. SEQ ID NO: 20 is the full-length protein, and SEQ ID NO: 21 is the extracellular domain of the VSV-G protein. The 17-mer signal peptide of MLVLYLLLSLLALGAQC (SEQ ID NO: 71), as shown at the N-terminus of SEQ ID NO: 20, is cleaved, leaving the protein of SEQ ID NO: 21. Therefore, although the mutation may be mentioned in the context of SEQ ID NO: 21, it should be understood that the mutation also occurs in the context of SEQ ID NO: 20 containing the leader sequence, and will therefore be a position number 17 positions higher than that described in SEQ ID NO: 21. In some embodiments, the mutation inhibits or reduces the binding of the VSV-G protein to the LDL receptor (LDL-R). In some embodiments, the mutation is the I182D mutation compared to SEQ ID NO: 21. In some implementations, the mutation is the I182E mutation compared to SEQ ID NO: 21.

[0124] As used herein, when a peptide is considered to have a mutation compared to a reference sequence, this comparison is based on alignment performed using software such as BlastP, ClustalW, or ClustalOmega with default parameters. For example, position 182 can be found in SEQ ID NO: 2, and is also related to... Figure 3 Compare with other strains shown. Figure 3 Clustal alignments of the wild-type sequences of the extracellular domain of the VSV-G protein from various strains are shown. Bold and underlined residues are those aligned to position 182 of SEQ ID NO: 2 for each strain. SEQ ID NO: 2 refers to the extracellular domain of the VSV-G protein from the Indiana strain. SEQ ID NO: 11 refers to the extracellular domain of the VSV-G protein from the New Jersey strain. SEQ ID NO: 13 refers to the extracellular domain of the VSV-G protein from the Malabar strain. SEQ ID NO: 15 refers to the extracellular domain of the VSV-G protein from the Carajá strain. SEQ ID NO: 17 refers to the extracellular domain of the VSV-G protein from the Alagoa strain. SEQ ID NO: 19 refers to the extracellular domain of the VSV-G protein from the Cocal strain. SEQ ID NO: 21 refers to the extracellular domain of the VSV-G protein from the Morton strain. Therefore, residues that are compared with residue 182 of SEQ ID NO: 2 can also be mutated as provided herein.

[0125] In some embodiments, the mutation at position 182 compared to SEQ ID NO: 2 is not alanine. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 2 is not valine.

[0126] In some embodiments, the mutation at position 182 compared to SEQ ID NO: 2 is I182S, I182H, I182T, I182Q, or I182N. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 11 is T182S, T182H, T182Q, or T182N. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 13 is A182S, A182H, A182T, A182Q, or A182N. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 15 is V182S, V182H, V182T, V182Q, or V182N. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 17 is V182S, V182H, V182T, V182Q, or V182N. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 19 is V182S, V182H, V182T, V182Q, or V182N. In some embodiments, the mutation at position 182 compared to SEQ ID NO: 21 is I182S, I182H, I182T, I182Q, or I182N. In some embodiments, the mutation at position 182 is not a hydrophobic residue. In some embodiments, the mutation at position 182 is a charged residue. In some embodiments, the mutation at position 182 is a negatively charged residue.

[0127] Although the mutation may be described with reference to SEQ ID NO: 1 or SEQ ID NO: 2 (which is the VSV-G protein from the Indiana strain), the mutation can also be used in other strains of the VSV-G protein. For example, the mutation can be made in the New Jersey strain of VSV-G, the Malaba strain of VSV-G, the Carajás strain of VSV-G, the Alagoa strain of VSV-G, the Cocal strain of VSV-G, or the Morton strain of VSV-G. In some embodiments, the sequence of each strain is as provided herein. Examples of these strains can be found, for example, in U.S. Patent Application Publication No. 20200216502, which is incorporated herein by reference. For example, the wild-type full-length or extracellular domains of the New Jersey strain of VSV-G are SEQ ID NO:10 and SEQ ID NO:11, respectively; the wild-type full-length or extracellular domains of the Malaba strain of VSV-G are SEQ ID NO:12 and SEQ ID NO:13, respectively; the wild-type full-length or extracellular domains of the Carajás strain of VSV-G are SEQ ID NO:14 and SEQ ID NO:15, respectively; the wild-type full-length or extracellular domains of the Alagoa strain of VSV-G are SEQ ID NO:16 and SEQ ID NO:17, respectively; the wild-type full-length or extracellular domains of the Cocal strain of VSV-G are SEQ ID NO:18 and SEQ ID NO:19, respectively; or the wild-type full-length or extracellular domains of the Morton strain of VSV-G are SEQ ID NO:20 and SEQ ID NO:21, respectively.

[0128] The VSV-G protein containing the mutation at position 182 compared to SEQ ID NO: 2 may also contain other mutations, such as those described in U.S. Patent Application Publication No. 20200216502, the entire contents of which are incorporated herein by reference. For example, the VSV-G protein may contain mutations at positions corresponding to positions 8, 47, 209, and / or 354 of SEQ ID NO: 2.

[0129] In some embodiments, the substitution at position 8 is made by any amino acid other than Y that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution at position 209 is made by any amino acid other than H that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution at position 47 is made by any amino acid other than K or R that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution at position 354 is made by any amino acid other than K or R that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2.

[0130] In some embodiments, the replacement is located at position 47 or at position 354, or at both positions 47 and 354, and is replaced by A, G, F, or Q. In some embodiments, the replacement is A or Q.

[0131] In some implementations, the substitution at position 8 is alanine, i.e., H8A.

[0132] In some implementations, the substitution at position 47 is Q or N, i.e., K47Q or K47N.

[0133] In some embodiments, the protein contains a mutation (substitution) at position 10. In some embodiments, the substitution / mutation is Q10A, Q10R, or Q10K.

[0134] In some embodiments, the protein containing a mutation at position 182 compared to SEQ ID NO: 2 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2 (or SEQ ID NO: 1 if a full-length protein is used). In some embodiments, the polypeptide contains an I182D or I182E mutation. In some embodiments, the VSV-G protein contains an I182S, I182H, I182T, I182Q, or I182N mutation.

[0135] In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 11 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 11 (or SEQ ID NO: 10 if a full-length protein is used). In some embodiments, the polypeptide contains a T182D or T182E mutation. In some embodiments, the VSV-G protein contains a T182S, T182H, T182Q, or T182N mutation.

[0136] In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 13 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 13 (or SEQ ID NO: 12 if a full-length protein is used). In some embodiments, the polypeptide contains an A182D or A182E mutation. In some embodiments, the VSV-G protein contains an A182S, A182H, A182T, A182Q, or A182N mutation.

[0137] In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 15 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 15 (or SEQ ID NO: 14 if a full-length protein is used). In some embodiments, the polypeptide contains a V182D or V182E mutation. In some embodiments, the VSV-G protein contains a V182S, V182H, V182T, V182Q, or V182N mutation.

[0138] In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 17 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 17 (or SEQ ID NO: 16 if a full-length protein is used). In some embodiments, the polypeptide contains a V182D or V182E mutation. In some embodiments, the VSV-G protein contains a V182S, V182H, V182T, V182Q, or V182N mutation.

[0139] In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 19 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 19 (or SEQ ID NO: 18 if a full-length protein is used). In some embodiments, the polypeptide contains a V182D or V182E mutation. In some embodiments, the VSV-G protein contains a V182S, V182H, V182T, V182Q, or V182N mutation.

[0140] In some embodiments, the protein containing a mutation at position 182 compared to SEQ ID NO: 21 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 21 (or SEQ ID NO: 20 if a full-length protein is used). In some embodiments, the polypeptide contains an I182D or I182E mutation. In some embodiments, the VSV-G protein contains an I182S, I182H, I182T, I182Q, or I182N mutation.

[0141] viral glycoproteins

[0142] The mutant VSV-G protein can be used, for example, for pseudotypening viruses (such as, but not limited to, lentiviruses). Therefore, in some embodiments, viral particles comprising the mutant VSV-G protein as provided herein are provided. In some embodiments, the viral particle comprises the VSV-G protein containing a mutation at position 198 compared to SEQ ID NO: 1. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 2 contains a mutation at position 182 and is at least, or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2 (or SEQ ID NO: 1 if a full-length protein is used). In some embodiments, the peptide contains an I182D or I182E mutation compared to SEQ ID NO: 2. In some embodiments, the VSV-G protein contains an I182S, I182H, I182T, I182Q, or I182N mutation.

[0143] In some embodiments, the viral particle comprises a VSV-G protein containing a mutation at position 198 compared to SEQ ID NO: 10. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 11 contains a mutation at position 182 and is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 11 (or SEQ ID NO: 10 if a full-length protein is used). In some embodiments, the polypeptide comprises a T182D or T182E mutation compared to SEQ ID NO: 11. In some implementations, the VSV-G protein contains T182S, T182H, T182Q, or T182N mutations.

[0144] In some embodiments, the viral particle comprises a VSV-G protein containing a mutation at position 198 compared to SEQ ID NO: 12. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 13 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 13 (or SEQ ID NO: 12 if a full-length protein is used). In some embodiments, the polypeptide comprises an A182D or A182E mutation compared to SEQ ID NO: 13. In some implementations, the VSV-G protein contains mutations of A182S, A182H, A182T, A182Q, or A182N.

[0145] In some embodiments, the viral particle comprises a VSV-G protein containing a mutation at position 203 compared to SEQ ID NO: 14. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 15 contains a mutation at position 182 and is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 15. In some embodiments, the polypeptide comprises a V182D or V182E mutation compared to SEQ ID NO: 15. In some implementations, the VSV-G protein contains mutations of V182S, V182H, V182T, V182Q, or V182N.

[0146] In some embodiments, the viral particle comprises a VSV-G protein containing a mutation at position 199 compared to SEQ ID NO: 16. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 17 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 17. In some embodiments, the polypeptide comprises a V182D or V182E mutation compared to SEQ ID NO: 17. In some implementations, the VSV-G protein contains mutations of V182S, V182H, V182T, V182Q, or V182N.

[0147] In some embodiments, the viral particle comprises a VSV-G protein containing a mutation at position 199 compared to SEQ ID NO: 18. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 19 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 19 (or SEQ ID NO: 18 if a full-length protein is used). In some embodiments, the polypeptide comprises a V182D or V182E mutation compared to SEQ ID NO: 19. In some implementations, the VSV-G protein contains mutations of V182S, V182H, V182T, V182Q, or V182N.

[0148] In some embodiments, the viral particle comprises a VSV-G protein containing a mutation at position 199 compared to SEQ ID NO: 20. In some embodiments, a protein containing a mutation at position 182 compared to SEQ ID NO: 21 contains a mutation at position 182 and is at least or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 21. In some embodiments, the polypeptide comprises an I182D or I182E mutation compared to SEQ ID NO: 21. In some implementations, the VSV-G protein contains I182S, I182H, I182T, I182Q, or I182N mutations.

[0149] In some embodiments, the VSV-G protein further comprises a mutation at the position corresponding to position 214 and / or 352 of SEQ ID NO: 2. In some embodiments, the residue corresponding to position 214 of SEQ ID NO: 2 is T214. In some embodiments, the residue corresponding to position 352 of SEQ ID NO: 2 is T352. In some embodiments, the VSV-G protein comprises a mutation corresponding to the T214N mutation compared to SEQ ID NO: 2. In some embodiments, the VSV-G protein comprises a mutation corresponding to the T352A mutation compared to SEQ ID NO: 2. In some embodiments, the VSV-G protein comprises both T214N and T352A mutations compared to SEQ ID NO: 2. These mutations may be combined with any other mutations as provided herein. In some embodiments, the T214N and / or T352A mutations are combined with the I182E or I182D mutation. In some embodiments, the VSV-G protein comprises the amino acid sequences of SEQ ID NO: 22 and SEQ ID NO: 23, which combine I182D or I182E with the T214N and T352A mutations, respectively. These sequences are further illustrated below using leader sequences that are removed during protein processing.

[0150] VSV-G protein mutations I196D, T230N, and T368A (with leader sequence and adjusted numbering)

[0151] MKCLLYLAFLFIGVNCKFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLDSMDITFFSEDGELSSLGKEGTGFRSNYFAYENGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTAERELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK(SEQ ID NO:24)

[0152] VSV-G protein mutations: I182D, T214N, and T352A (without leader sequence)

[0153] KFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLDSMDITFFSEDGELSSLGKEGTGFRSNYFAYENGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTAERELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK(SEQ ID NO: 22)

[0154] VSV-G protein with I196E, T230N, and T368A mutations (with leader sequence and adjusted numbering)

[0155] MKCLLYLAFLFIGVNCKFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLESMDITFFSEDGELSSLGKEGTGFRSNYFAYENGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTAERELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK(SEQ ID NO:25)

[0156] VSV-G protein with I182E, T214N, and T352A mutations (without leader sequence)

[0157] KFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEA VIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLESMDITFFSEDGELSSLGKEGTGFRSNYFAYENGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAAR FPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTAERELWDDWAPYEDVEIGPNGVL RTSSGYKFPLYMIGGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK (SEQ ID NO: 23)

[0158] Other strains of the VSV-G protein described herein may also contain mutations corresponding to T214N and / or T352A in SEQ ID NO: 2 and are shown in SEQ ID NO: 22 and SEQ ID NO: 23.

[0159] In some embodiments, the composition comprises mutations as described in Hwang et al., Gene Ther, Aug 2013; 20(8):807-15. (Epub, Jan 31, 2013), which is incorporated herein by reference in its entirety. For example, mutations may be at positions 230, 368, 66, and / or 162 corresponding to SEQ ID NO: 1. These positions would be 16 fewer than those in SEQ ID NO: 2 when the leader sequence is removed. In some embodiments, mutations at those positions are, for example, T230N, T368A, K66T, S162T, or any combination thereof. In some embodiments, the VSV-G protein comprises the T230N and T368A mutations. In some embodiments, the VSV-G polypeptide comprises K66T, S162T, T230N, and T368A. These positions are those corresponding to the positions in the full-length protein (SEQ ID NO: 1). In some embodiments, the VSV-G protein comprises the T230N mutation, the T368A mutation, the K66T mutation, the S162T mutation, or any combination thereof. In some embodiments, in addition to the mutation corresponding to position 182 of SEQ ID NO: 2, the VSV-G protein also comprises one or more mutations, such as those described in U.S. Patent Application Publication No. 20200216502, the entire contents of which are incorporated herein by reference. For example, the VSV-G protein may also comprise mutations at positions corresponding to positions 8, 47, 209, and / or 354 of SEQ ID NO: 2.

[0160] In some embodiments, the substitution at position 8 is made by any amino acid other than Y that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution at position 209 is made by any amino acid other than H that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution at position 47 is made by any amino acid other than K or R that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution at position 354 is made by any amino acid other than K or R that is different from the amino acid indicated at that position in sequence SEQ ID NO: 2. In some embodiments, the substitution is located at position 47 or position 354, or at both positions 47 and 354, and is substituted by A, G, F, or Q. In some embodiments, the substitution is A or Q. In some embodiments, the substitution at position 8 is alanine, i.e., H8A. In some embodiments, the substitution at position 47 is Q or N, i.e., K47Q or K47N. In some embodiments, the protein contains a mutation (substitution) at position 10. In some embodiments, the substitution / mutation is Q10A, Q10R, or Q10K.

[0161] In addition, in some implementations, other viral structural proteins can be used to pseudotype the virus instead of the VSV-G protein or its mutants.

[0162] For example, viral particles can be pseudotyped using the carp viremia virus G (SVCV-G) protein, and cells can be transduced when the virus contains a targeting portion. In some embodiments, the provided carp viremia virus G protein can be used to transduce target cells and deliver heterologous molecules to target cells. In some embodiments, a carp viremia virus G protein comprising SEQ ID NO: 52 is provided. SEQ ID NO: 52 is the full-length protein, and SEQ ID NO: 53 is the extracellular domain of the carp viremia virus G protein with the N-terminal signal peptide removed. Therefore, in some embodiments, the protein comprises the amino acid sequence of SEQ ID NO: 53. The carp viremia virus G protein can be used, for example, to pseudotype viruses (such as, but not limited to, lentiviruses). Therefore, in some embodiments, viral particles comprising the carp viremia virus G protein as provided herein are provided. In some embodiments, the viral particle contains a carp spring viremia virus G protein containing at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the same sequence as SEQ ID NO: 52 or SEQ ID NO: 53.

[0163] The sequence of carp spring viremia virus-G (SEQ ID NO: 52 - with leader sequence)

[0164] MSIISYIAFLLLIDSNLGIPIFVPSGRNISWQPVIQPFDYQCPIHGNLPNTMGLSATKLTIKSPSVFSTDKVSGWICHAAEWKTTCDYRWYGPQYITHSIHPISPTIDECRRIIQRIASGTDEDLGFPPQSCGWASVTTVSNTNYRVVPHSVHLEPYGGHWIDHEFNGGECREKVCEMKGNHSIWITEETVQHECAKHIEEVEGIMYGNVPRGDVMYANNFIIDRHHRVYRFGGSCQMKFCNKDGIKFARGDWVEKTAGTLTTIHDNVPKCVDGTLVSGHRPGLDLIDTVFNLENVVEYTLCEGTKRKINKQEKLTSVDLSYLAPRIGGFGSVFRVRNGTLERGSTTYIRIEVEGPIVDSLNGTDPRTNASRVFWDDWELDGNIYQGFNGVYKGKDGKIHIPLNMIESGIIDDELQHAFQADIIPHPHYDDDEIREDDIFFDNTGENGNPVDAVVEWVSGWGTSLKFFGMTLVALILIFLLIRCCVACTYLMKRSKRPATESHEMRSLV

[0165] Sequence of carp spring viremia virus-G (SEQ ID NO: 53 - without leader sequence) :

[0166] IPIFVPSGRNISWQPVIQPFDYQCPIHGNLPNTMGLSATKLTIKSPSVFSTDKVSGWICHAAEWKTTCDYRWYGPQYITHSIHPISPTIDECRRIIQRIASGTDEDLGFPPQSCGWASVTTVSNTNYRVVPHSVHLEPYGGHWIDHEFNGGECREKVCEMKGNHSIWITEETVQHECAKHIEEVEGIMYGNVPRGDVMYANNFIIDRHHRVYRFGGSCQMKFCNKDGIKFARGDWVEKTAGTLTTIHDNVPKCVDGTLVSGHRPGLDLIDTVFNLENVVEYTLCEGTKRKINKQEKLTSVDLSYLAPRIGGFGSVFRVRNGTLERGSTTYIRIEVEGPIVDSLNGTDPRTNASRVFWDDWELDGNIYQGFNGVYKGKDGKIHIPLNMIESGIIDDELQHAFQADIIPHPHYDDDEIREDDIFFDNTGENGNPVDAVVEWVSGWGTSLKFFGMTLVALILIFLLIRCCVACTYLMKRSKRPATESHEMRSLV

[0167] Targeted portion

[0168] In some embodiments, the viral particle includes a targeting portion having the formula T-S1, where T is a target-binding domain for targeting the viral particle to the liver and S1 is a stem portion. The targeting portion can be used to target viral particles containing mutant VSV-G or SVCV-G proteins to liver cells expressing a target to which the targeting portion binds. In some embodiments, the target-binding domain is an antibody, scFv antibody, antigen-binding domain, an ankyrin repeat sequence (e.g., DARPIN), a VHH domain antibody, a nanobody, a single-domain antibody, an FN3 domain, or any combination thereof. The target-binding domain can be attached to the viral surface via a stem portion S1 containing a variant Fc protein (e.g., L1-Fc-L2-X1) as provided herein or via a stem portion S1 containing a flexible polypeptide (e.g., L3-X1) as provided herein. In some embodiments, the targeting portion attaches (fused to or linked to) the envelope glycoprotein G or H of a virus belonging to the Paramyxoviridae family, such as measlesvirus, or Hennipa virus, such as Nipah virus, cedar virus, or Hendra virus. In some embodiments, the targeting portion may attach (fused to or linked to) the glycoprotein of a virus belonging to the Rhabdoviridae family, such as vesicular stomatitis virus (VSDV), vesicular stomatitis virus (VSDV), vesicular stomatitis virus (VSDV), vesicular stomatitis virus (VSDV), vesicular stomatitis virus (VSDV), vesicular stomatitis virus (VSDV), parainfluenza virus, fall armyworm rhabdovirus isolate Sf G, Drosophila sigmavirus 10A, Wuhan insect virus 7, perch virus, or carp spring viremia virus. In some embodiments, the VSV protein is a mutant protein, such as those described herein. In some implementations, the target portion is attached to the glycoprotein of viruses of the Filoviridae family (such as Ebola virus) or viruses of the Arenaviridae family (such as Machupo virus).

[0169] In some implementations, the target-binding domain is scFv. In some implementations, the target-binding domain is a single-domain antibody. In some implementations, the target-binding domain is VHH.

[0170] In some embodiments, the targeting portion binds to the desialyl glycoprotein receptor (ASGPR). The ASGPR comprises two subunits, desialyl glycoprotein receptor 1 (ASGR1) and desialyl glycoprotein receptor 2 (ASGR2). Therefore, in some embodiments, the targeting portion binds to ASGR1, ASGR2, or a combination thereof. In some embodiments, the targeting portion binds to ASGR1. In some embodiments, the targeting portion binds to ASGR2. In some embodiments, the targeting portion binds to both ASGR1 and ASGR2. When binding to both ASGR1 and ASGR2, the targeting portion can recognize and bind to regions between ASGR1 and ASGR2 that have conserved epitope similarities. Alternatively, the targeting portion can recognize epitopes spanning both subunits. The ASGPR consists of an extracellular carbohydrate recognition domain (CRD), a transmembrane domain, a stem region connecting the CRD and the transmembrane domain, and a cytoplasmic domain. The targeting portion can bind to any accessible region on the ASGPR. In some embodiments, the targeting portion binds to the CRD of the ASGPR. In some embodiments, the targeting portion binds to the stem region of the ASGPR. Each subunit constituting the ASGPR (ASGR1 and ASGR2) also has the same composition of CRD, stem region, transmembrane domain, and cytoplasmic domain. Therefore, in some embodiments, the targeting portion binds to the CRD of ASGR1. In some embodiments, the targeting portion binds to the CRD of ASGR2. In some embodiments, the targeting portion binds to the CRDs of both ASGR1 and ASGR2. In some embodiments, the targeting portion binds to the stem region of ASGR1. In some embodiments, the targeting portion binds to the stem region of ASGR2. In some embodiments, the targeting portion binds to the stem regions of both ASGR1 and ASGR2.

[0171] In some embodiments, the targeting portion binds to a target present on cells, such as hepatocytes. In some embodiments, the cells are hepatocytes. In some embodiments, the cells are ASGR1+ hepatocytes. In some embodiments, the cells are ASGR2+ hepatocytes.

[0172] ASGR-binding peptide

[0173] In some implementations, the target moiety (e.g., a peptide) binds to ASGR1.

[0174] In some embodiments, the peptide binding to ASGR1 is an antibody that binds to non-human primate ASGR1. In some embodiments, the peptide binding to ASGR1 is an antibody that binds to human ASGR1. The sequence of human ASGR1 (UniProtP07306-1) is as follows (SEQ ID NO: 29):

[0175] MTKEYQDLQHLDNEESDHHQLRKGPPPPQPLLQRLCSGPRLLLLSLGLSLLLLVVVCVIGSQNSQLQEELRGLRETFSNFTASTEAQVKGLSTQGGNVGRKMKSLESQLEKQQKDLSEDHSSLLLHVKQFVSDLRSLSCQMAALQGNG SERTCCPVNWVEHERSCYWFSRSGKAWADADNYCRLEDAHLVVVTSWEEQKFVQHHIGPVNTWMGLHDQNGPWKWVDGTDYETGFKNWRPEQPDDWYGHGLGGGEDCAHFTDDGRWNDDVCQRPYRWVCETELDKASQEPPLL(SEQID NO: 29).

[0176] In some embodiments, peptide-bound ASGR1 is expressed on the cell surface. In some embodiments, the cells are liver cells. In some embodiments, the liver cells are ASGR1+ hepatocytes.

[0177] In some embodiments, the antibody comprises an Fc region. The Fc region may be linked to either the heavy or light chain of the antibody. In some embodiments, the Fc region is an IgG Fc. In some embodiments, the IgG is selected from IgG1, IgG2, IgG3, or IgG4. In some embodiments, the IgG fc is an IgG1 Fc. In some embodiments, the antibody comprises a constant Fc region as shown herein, such as SEQ ID NO: 26, 27, or 28, or a mutant or variant thereof as provided herein.

[0178] In some embodiments, this document provides a peptide (e.g., an ASGR1-binding peptide). In some embodiments, this document provides an antibody (e.g., an anti-ASGR1 antibody). In some embodiments, the antibody is a recombinant antibody that binds to ASGR1. In some embodiments, the ASGR1 protein is the human ASGR1 protein. In some embodiments, the ASGR1 protein is a non-human ASGR1 protein (e.g., mouse, rat, pig, dog, non-human primate). As used herein, the term "recombinant antibody" refers to an antibody that is not naturally occurring. In some embodiments, the term "recombinant antibody" refers to an antibody that has not been isolated from a human subject.

[0179] In some implementations, the target moiety (e.g., a peptide) binds to ASGR2.

[0180] In some embodiments, the peptide binding to ASGR2 is an antibody that binds to non-human primate ASGR2. In some embodiments, the peptide binding to ASGR2 is an antibody that binds to human ASGR2. The sequence of human ASGR2 (UniProtP07307-1) is as follows (SEQ ID NO: 131):

[0181] MAKDFQDIQQLSSEENDHPFHQGEGPGTRRLNPRRGNPFLKGPPPAQPLAQRLCSMVCFSLLALSFNILLLVVICVTGSQSEGHGGAQLQAELRSLKEAFSNFSSSTLTEVQAISTHGGSVGDKITSLGAKLEKQQQDLKADHDALLFHLKHFPVDL RFVACQMELLHSNGSQRTCCPVNWVEHQGSCYWFSHSGKAWAEAEKYCQLENAHLVVINSWEEQKFIVQHTNPFNTWIGLTDSDGSWKWVDGTDYRHNYKNWAVTQPDNWHGHELGGSEDCVEVQPDGRWNDDFCLQVYRWVCEKRRNATGEVA (SEQ ID NO: 131).

[0182] In some embodiments, peptide-bound ASGR2 is expressed on the cell surface. In some embodiments, the cells are liver cells. In some embodiments, the liver cells are ASGR2+ hepatocytes.

[0183] In some embodiments, the antibody comprises an Fc region. The Fc region may be linked to either the heavy or light chain of the antibody. In some embodiments, the Fc region is an IgG Fc. In some embodiments, the IgG is selected from IgG1, IgG2, IgG3, or IgG4. In some embodiments, the IgG fc is an IgG1 Fc. In some embodiments, the antibody comprises a constant Fc region as shown herein, such as SEQ ID NO: 26, 27, or 28, or a mutant or variant thereof as provided herein.

[0184] In some embodiments, this document provides a peptide (e.g., an ASGR2-binding peptide). In some embodiments, this document provides an antibody (e.g., an anti-ASGR2 antibody). In some embodiments, the antibody is a recombinant antibody that binds to ASGR2. In some embodiments, the ASGR2 protein is the human ASGR2 protein. In some embodiments, the ASGR2 protein is a non-human ASGR2 protein (e.g., mouse, rat, pig, dog, non-human primate). As used herein, the term "recombinant antibody" refers to an antibody that is not naturally occurring. In some embodiments, the term "recombinant antibody" refers to an antibody that has not been isolated from a human subject.

[0185] In some embodiments, the targeting portion (e.g., a peptide) binds to ASGR1. In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antibody fragment binds to ASGR1. In some embodiments, the ASGR1-binding antibody or its antigen-binding fragment is described in the following literature: U.S. Patent Sequence No. 9,771,427, U.S. Patent Sequence No. 10,975,151, and U.S. Patent Publication No. 202110324085A1; Bon, Charlotte et al., “Capacity limits of asialoglycoprotein receptor-mediated liver targeting.” mAbs, Vol. 9, 8(2017): 1360-1369. doi:10.1080 / 19420862.2017.1373924; Trahtenherts, Alla, and Itai Benhar. “An internalizing antibody specific for the human asialoglycoprotein receptor.” Hybridoma (2005), Vol. 28, 4(2009): 225-33. doi:10.1089 / hyb.2009.0019; Coulstock, Edward et al., “Liver-targeting of interferon-alpha with tissue-specific domain antibodies.” PloS one, Vol. 8, 2 (2013): e57263. doi:10.1371 / journal.pone.0057263; and Born, Rita. “Benefit and application of antibodies against the H1 carbohydrate recognition domain of the human hepaticasialoglycoprotein receptor.” 2005. University of Basel. Doctoral Thesis. Doi: 10.5451 / unibas-004136448; each of these references is incorporated herein by reference in its entirety. In some embodiments, the antibody binding to ASGR1 or its antigen-binding fragment comprises a peptide selected from the table below, which exemplifies CDRs based on Kabat numbers.

[0186]

[0187] Although the table above presents exemplary CDRs in IMGT numbering format, it should be understood that other numbering systems can also be used. For example, antibodies or their antigen-binding fragments may contain peptides in the Chothia, AbM, or Kabat numbering systems, or any other applicable numbering system. Exemplary sequences in the Chothia, AbM, and Kabat numbering systems are presented in the table below:

[0188]

[0189]

[0190]

[0191] Therefore, it should be understood that although the following implementation may refer only to the sequences provided in the IMGT numbering system, the implementation also covers the corresponding combinations or descriptions of the Chothia, AbM and Kabat numbering sequences as provided herein.

[0192] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to non-human primate ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to human ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence selected from SEQ ID NO: 33, the amino acid sequence GKN, or SEQ ID NO: 35. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 33. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having GKN. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 34. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having a sequence selected from SEQ ID NO: 30-32. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 30. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 31. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 32. The CDRs mentioned throughout the embodiments of this specification may be interchanged with CDRs characterized in different formats (such as Chothia, AbM, or Kabat).

[0193] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 33, LCDR2 has the sequence of GKN, and LCDR3 has the sequence of SEQ ID NO: 34.

[0194] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 30, HCDR2 has the sequence of SEQ ID NO: 31, and HCDR3 has the sequence of SEQ ID NO: 32.

[0195] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises: (i) a light chain having any of the aforementioned combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any of the aforementioned combinations of HCDR1, HCDR2, and HCDR3 sequences.

[0196] Different CDR motifs can be combined in any combination (including those not described in the table above). For example, the following embodiments are provided as non-limiting examples of such combinations.

[0197] In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 33; the light chain CDR2 has the amino acid sequence of GKN; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 34; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 30; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 31; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 32; or a variant of any of the foregoing.

[0198] Although the preceding paragraph may refer to CDRs according to the IMGT system, equivalent CDR sequences from the names Chothia, Kabat, or AbM can be used.

[0199] In some embodiments, the light chain variable region CDR1 is replaced by any of the other light chain CDR1 sequences. In some embodiments, the light chain variable region CDR2 is replaced by any of the other light chain CDR2 sequences. In some embodiments, the light chain variable region CDR3 is replaced by any of the other light chain CDR3 sequences. In some embodiments, the heavy chain variable region CDR1 is replaced by any of the other heavy chain CDR1 sequences. In some embodiments, the heavy chain variable region CDR2 is replaced by any of the other heavy chain CDR2 sequences. In some embodiments, the heavy chain variable region CDR3 is replaced by any of the other heavy chain CDR3 sequences.

[0200] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to non-human primate ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to human ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence selected from SEQ ID NO: 42, amino acid sequence SA, or SEQ ID NO: 43. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 42. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SA. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 43. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having a sequence selected from SEQ ID NO: 39-41. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 39. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 40. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 41.

[0201] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 42, LCDR2 has the sequence of SA, and LCDR3 has the sequence of SEQ ID NO: 43.

[0202] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 39, HCDR2 has the sequence of SEQ ID NO: 40, and HCDR3 has the sequence of SEQ ID NO: 41.

[0203] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises: (i) a light chain having any of the aforementioned combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any of the aforementioned combinations of HCDR1, HCDR2, and HCDR3 sequences.

[0204] Different CDR motifs can be combined in any combination (including those not described in the table above). For example, the following embodiments are provided as non-limiting examples of such combinations.

[0205] In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 42; the light chain CDR2 has the amino acid sequence of SA; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 43; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 39; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 40; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 41; or a variant of any of the foregoing.

[0206] In some embodiments, the light chain variable region CDR1 is replaced by any of the other light chain CDR1 sequences. In some embodiments, the light chain variable region CDR2 is replaced by any of the other light chain CDR2 sequences. In some embodiments, the light chain variable region CDR3 is replaced by any of the other light chain CDR3 sequences. In some embodiments, the heavy chain variable region CDR1 is replaced by any of the other heavy chain CDR1 sequences. In some embodiments, the heavy chain variable region CDR2 is replaced by any of the other heavy chain CDR2 sequences. In some embodiments, the heavy chain variable region CDR3 is replaced by any of the other heavy chain CDR3 sequences.

[0207] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to non-human primate ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to human ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence selected from SEQ ID NO: 49, amino acid sequence KN, or SEQ ID NO: 50. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 49. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having KN. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 50. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having a sequence selected from SEQ ID NO: 46-48. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 46. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 47. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 48.

[0208] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 49, LCDR2 has the KN sequence, and LCDR3 has the sequence of SEQ ID NO: 50.

[0209] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 46, HCDR2 has the sequence of SEQ ID NO: 47, and HCDR3 has the sequence of SEQ ID NO: 48.

[0210] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises: (i) a light chain having any of the aforementioned combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any of the aforementioned combinations of HCDR1, HCDR2, and HCDR3 sequences.

[0211] Different CDR motifs can be combined in any combination (including those not described in the table above). For example, the following embodiments are provided as non-limiting examples of such combinations.

[0212] In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 49; the light chain CDR2 has the amino acid sequence of KN; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 50; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 46; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 47; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 48; or a variant of any of the foregoing.

[0213] In some embodiments, the light chain variable region CDR1 is replaced by any of the other light chain CDR1 sequences. In some embodiments, the light chain variable region CDR2 is replaced by any of the other light chain CDR2 sequences. In some embodiments, the light chain variable region CDR3 is replaced by any of the other light chain CDR3 sequences. In some embodiments, the heavy chain variable region CDR1 is replaced by any of the other heavy chain CDR1 sequences. In some embodiments, the heavy chain variable region CDR2 is replaced by any of the other heavy chain CDR2 sequences. In some embodiments, the heavy chain variable region CDR3 is replaced by any of the other heavy chain CDR3 sequences.

[0214] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to non-human primate ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain or light chain CDR as provided in the table above and binds to human ASGR1. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence selected from SEQ ID NO: 83, amino acid sequence LV, or SEQ ID NO: 84. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 83. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having LV. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a light chain CDR having a sequence having SEQ ID NO: 84. In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having a sequence selected from SEQ ID NO: 80-82. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 80. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 81. In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain CDR having the sequence of SEQ ID NO: 82.

[0215] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a light chain variable region having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 83, LCDR2 has the sequence of LV, and LCDR3 has the sequence of SEQ ID NO: 84.

[0216] In some embodiments, the peptide, antibody, or antibody-binding fragment thereof comprises a heavy chain variable region having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO: 80, HCDR2 has the sequence of SEQ ID NO: 81, and HCDR3 has the sequence of SEQ ID NO: 82.

[0217] In some embodiments, the polypeptide, antibody, or antibody-binding fragment thereof comprises: (i) a light chain having any of the aforementioned combinations of LCDR1, LCDR2, and LCDR3 sequences; and (ii) a heavy chain having any of the aforementioned combinations of HCDR1, HCDR2, and HCDR3 sequences.

[0218] Different CDR motifs can be combined in any combination (including those not described in the table above). For example, the following embodiments are provided as non-limiting examples of such combinations.

[0219] In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 has the amino acid sequence of LV; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 84; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82; or a variant of any of the foregoing.

[0220] In some embodiments, the light chain variable region CDR1 is replaced by any of the other light chain CDR1 sequences. In some embodiments, the light chain variable region CDR2 is replaced by any of the other light chain CDR2 sequences. In some embodiments, the light chain variable region CDR3 is replaced by any of the other light chain CDR3 sequences. In some embodiments, the heavy chain variable region CDR1 is replaced by any of the other heavy chain CDR1 sequences. In some embodiments, the heavy chain variable region CDR2 is replaced by any of the other heavy chain CDR2 sequences. In some embodiments, the heavy chain variable region CDR3 is replaced by any of the other heavy chain CDR3 sequences.

[0221] In some embodiments, the polypeptide comprises a heavy chain variable region peptide or a variant thereof having one of the following sequences:

[0222] SEQ IDNO: AB ID number sequence 35 ASGR14F3 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFSSRRWYLEYWGQGTLVTVSS 44 ASGR18D7 QVQLQQSAAELARPGASVKMSCKASGYTFTSYPMHWVKQRPGQGLEWIAYISPSSGYTKYNQKFTDKTTLTADKSSSTTAYMQLSSLTSDDSAVYYCARKGGYLDYWGQGTTLTVSS 51 ASGR1B11 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSAITTGGGSPNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRTAGYFDYWGQGALVTVSS 85 ASGR1C11 QVQLQQSGAELVKPGASVKLSCKTSGYTFTSYWIQWVKQRPGQGLGWIGEIFPGTGTSYYNENFKGKATLTIDTSSSTAYMQPSSLTSEDSAVYFCARTNNYRSYALDYWGQGTNYRS

[0223] In some embodiments, the polypeptide comprises a light chain variable region peptide having one of the following sequences or a variant thereof:

[0224] SEQ IDNO: AB ID number sequence 36 ASGR14F3 SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSLERIGYLSYVFGGGTKLTVL 45 ASGR18D7 DIVMTQSQKFMSTSVGDRVSVTCKASQNVDTNVAWFQQKPGQYPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPFTFGAGTKLELKRA 77 ASGR1B11 DIVLTQPPSASGTPGQRVTISCTGSSSGIGNAYVSWYQQLPGKAPKLLIYKNGQRPSGVSDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKVTVL 86 ASGR1C11 DIVMTQSPASLAVSLGQRATISYRASKSVSTSGYSYMHWNQQKPGQPPRLLIYLVSNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQIRGGAYTFGGGTKLEIKR

[0225] In some embodiments, the peptide, antibody, or antigen-binding fragment thereof comprises V of SEQ ID NO: 35, SEQ ID NO: 44, SEQ ID NO: 51, or SEQ ID NO: 85. H Peptide. In some implementations, V H The peptide contains the amino acid sequence of SEQ ID NO:35. In some embodiments, V HThe peptide contains the amino acid sequence of SEQ ID NO: 44. In some embodiments, V H The peptide contains the amino acid sequence of SEQ ID NO: 51. In some embodiments, V H The peptide comprises the amino acid sequence of SEQ ID NO:85. In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises V of SEQ ID NO:36, SEQ ID NO:45, SEQ ID NO:77, or SEQ ID NO:86. L Peptide. In some implementations, V L The peptide contains the amino acid sequence of SEQ ID NO: 36. In some embodiments, V L The peptide contains the amino acid sequence of SEQ ID NO: 45. In some embodiments, V L The peptide contains the amino acid sequence of SEQ ID NO: 77. In some embodiments, V L The peptide comprises the amino acid sequence of SEQ ID NO: 86. In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 35 or a variant thereof; and V L The peptide contains the sequence of SEQ ID NO: 36 or a variant thereof. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 44 or a variant thereof; and V L The peptide contains the sequence of SEQ ID NO: 45 or a variant thereof. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 51 or a variant thereof; and V L The peptide contains the sequence of SEQ ID NO: 77 or a variant thereof. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 85 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 86 or a variant thereof. In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 36 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 37 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to the non-human primate ASGR1. In some embodiments, V HThe peptide contains the sequence of SEQ ID NO: 44 or a variant thereof; and V L The peptide contains the sequence of SEQ ID NO: 51 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to the non-human primate ASGR1. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 51 or a variant thereof; and V L The peptide contains the sequence of SEQ ID NO:77 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to the non-human primate ASGR1. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 85 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 86 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to the non-human primate ASGR1. In some embodiments, the polypeptide, antibody, or antigen-binding fragment thereof comprises V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 36 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 37 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to human ASGR1. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 44 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 45 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to human ASGR1. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 51 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 77 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to human ASGR1. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 85 or a variant thereof; and V L The peptide comprises the sequence of SEQ ID NO: 86 or a variant thereof, and the polypeptide, antibody, or antigen-binding fragment thereof binds to human ASGR1. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 36; and V L The peptide contains the sequence of SEQ ID NO: 37. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 44; and V L The peptide contains the sequence of SEQ ID NO: 45. In some embodiments, VH The peptide contains the sequence of SEQ ID NO: 51; and V L The peptide contains the sequence of SEQ ID NO: 77. In some embodiments, V H The peptide contains the sequence of SEQ ID NO: 85; and V L The peptide contains the sequence of SEQ ID NO: 86.

[0226] V H and V L The sequence can be of any form, including but not limited to the scFv form, where V H and V L The region connects to the peptide linker. Examples of peptide linkers that can be used to connect the various peptides described herein include, but are not limited to: (GGGGS) n (SEQ ID NO: 55), where each n is independently 1-5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, the variable region is not connected to the peptide linker. In some embodiments, the polypeptide comprises SEQ ID NO: 36 and SEQ ID NO: 37. In some embodiments, the polypeptide comprises SEQ ID NO: 44 and SEQ ID NO: 45. In some embodiments, the polypeptide comprises SEQ ID NO: 51 and SEQ ID NO: 77. In some embodiments, the polypeptide comprises SEQ ID NO: 85 and SEQ ID NO: 86.

[0227] As provided in this article, peptides, antibodies, or their antigen-binding fragments can be sequence variants.

[0228] The sequences of peptides or antibodies can be modified to generate human IgG antibodies. Transformations of the sequences provided herein can be modified to generate other types of antibodies. CDRs can also be linked with other antibodies, proteins, or molecules to generate antibody fragments that bind to ASGR1.

[0229] In some embodiments, the peptides or antibodies provided herein are targeting portions on the surface of engineered viral particles. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as the peptides or antibodies provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 37.

[0230] SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSLERIGYLSYVFGGGTKLTVLGGGGSGGGGSGGGGS EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFSSRRWYLEYWGQGTLVTVSS (SEQ ID NO: 37)

[0231] Or substantially similar to SEQ ID NO: 37, or an active fragment of SEQ ID NO: 37. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 37. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 37. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 37. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 37. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 37 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0232] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38.

[0233] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFSSRRWYLEYWGQGTLVTVSSGGGG SGGGGSGGGGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSLERIGYLSYVFGGGTKLTVL (SEQ ID NO: 38)

[0234] Alternatively, it may be substantially similar to SEQ ID NO: 38, or an active fragment of SEQ ID NO: 38. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 38. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 38. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 38. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 38. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 38 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0235] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129.

[0236] DIVMTQSQKFMSTSVGDRVSVTCKASQNVDTNVAWFQQKPGQYPKVLIYSASYRYSGVPDRFTGSGSGTTDFTLTISNVQSEDLAEYFCQQYNSYPFTFGAGTKLELKRAGGGGSGGGGSGGG GSQVQLQQSAAELARPGASVKMSCKASGYTFTSYPMHWVKQRPGQGLEWIAYISPSSGYTKYNQKFTDKTTLTADKSSSTTAYMQLSSLTSDDSAVYYCARKGGYLDYWGQGTTLTVSS (SEQ ID NO: 129)

[0237] Alternatively, it may be substantially similar to SEQ ID NO: 129, or an active fragment of SEQ ID NO: 129. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 129. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 129. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 129. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 129. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 129 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0238] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130.

[0239] QVQLQQSAAELARPGASVKMSCKASGYTFTSYPMHWVKQRPGQGLEWIAYISPSSGYTKYNQKFTDKTTLTADKSSSTTAYMQLSSLTSDDSAVYYCARKGGYLDYWGQGTTLTVSSGGGGSG GGGSGGGGSDIVMTQSQKFMSTSVGDRVSVTCKASQNVDTNVAWFQQKPGQYPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPFTFGAGTKLELKRA (SEQ ID NO: 130)

[0240] Or substantially similar to SEQ ID NO: 130, or an active fragment of SEQ ID NO: 130. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 130. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 130. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 130. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 130. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 130 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0241] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78.

[0242] DIVLTQPPSASGTPGQRVTISCTGSSSGIGNAYVSWYQQLPGKAPKLLIYKNGQRPSGVSDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKVTVLGGGGSGGGGSGGG GSEVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSAITTGGGSPNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRTAGYFDYWGQGALVTVSS (SEQ ID NO: 78)

[0243] Alternatively, it may be substantially similar to SEQ ID NO: 78, or an active fragment of SEQ ID NO: 78. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 78. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 78. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 78. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 78. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 78 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0244] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79.

[0245] EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSAITTGGGSPNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRTAGYFDYWGQGALVTVSSGGGGS GGGGSGGGGSDIVLTQPPSASGTPGQRVTISCTGSSSGIGNAYVSWYQQLPGKAPKLLIYKNGQRPSGVSDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKVTVL (SEQ ID NO: 79)

[0246] Or substantially similar to SEQ ID NO: 79, or an active fragment of SEQ ID NO: 79. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 79. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 79. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 79. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 79. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 79 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0247] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87.

[0248] DIVMTQSPASLAVSLGQRATISYRASKSVSTSGYSYMHWNQQKPGQPPRLLIYLVSNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQXXGGAYTFGGGTKLEIKRGGGGSGGGGSGG GGSQVQLQQSGAELVKPGASVKLSCKTSGYTFTSYWIQWVKQRPGQGLGWIGEIFPGTGTSYYNENFKGKATLTIDTSSSTAYMQPSSLTSEDSAVYFCARTNNYRSYALDYWGQGTNYRS (SEQ ID NO: 87)

[0249] Alternatively, it may be substantially similar to SEQ ID NO: 87, or an active fragment of SEQ ID NO: 87. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 87. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 87. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 87. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 87. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 87 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0250] In some embodiments, the peptide or antibody, as provided herein, is a targeting portion on the surface of an engineered viral particle. In some embodiments, the engineered viral particle is a pseudotyped virus-like particle. In some embodiments, the targeting portion allows binding to target cells. In some embodiments, the targeting portion is an ASGR1 binding portion, such as a peptide or antibody as provided herein. In some embodiments, the target-binding domain (“T”) comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 88.

[0251] QVQLQQSGAELVKPGASVKLSCKTSGYTFTSYWIQWVKQRPGQGLGWIGEIFPGTGTSYYNENFKGKATLTIDTSSSTAYMQPSSLTSEDSAVYFCARTNNYRSYALDYWGQGTNYRSGGGGSG GGGSGGGGSDIVMTQSPASLAVSLGQRATISYRASKSVSTSGYSYMHWNQQKPGQPPRLLIYLVSNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQXXGGAYTFGGGTKLEIKR (SEQ ID NO: 88)

[0252] Or substantially similar to SEQ ID NO: 88, or an active fragment of SEQ ID NO: 88. In some embodiments, the target-binding domain (“T”) comprises at least 90% identical to the sequence of SEQ ID NO: 88. In some embodiments, the target-binding domain (“T”) comprises at least 95% identical to the sequence of SEQ ID NO: 88. In some embodiments, the target-binding domain (“T”) comprises at least 99% identical to the sequence of SEQ ID NO: 88. In some embodiments, the target-binding domain (“T”) comprises the sequence shown in SEQ ID NO: 88. In some embodiments, the target-binding domain (“T”) shown in SEQ ID NO: 88 is an antibody or an antigen-binding fragment thereof. In some embodiments, the target-binding domain (“T”) is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0253] Targeting portion containing Fc domain

[0254] In some implementation schemes, V H and V LThe polypeptide is linked to a stem portion S1 containing the Fc region. In some embodiments, the Fc region is as provided herein. In some embodiments, the Fc region is a variant Fc region as provided herein. Non-restrictive mutations in the Fc region are provided herein. In some embodiments, the variant Fc region contains a sequence as a variant of SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28 as provided herein. In some embodiments, the variant of SEQ ID NO:26 contains one or more mutations selected from the group consisting of L234A, L235A, N297A, P329G, I253A, H310A, and H435A as provided herein. In some embodiments, the variant of SEQ ID NO:27 contains one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A, and H435A as provided herein. In some embodiments, the variant of SEQ ID NO: 28 comprises one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A, and H435A as provided herein. As provided herein, the heavy chain may be linked to the Fc region. In some embodiments, the Fc region also comprises (e.g., linked to) a transmembrane domain. In some embodiments, the Fc region also comprising the transmembrane domain has the formula L1-Fc-L2-X1, where L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising the transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. Examples of ECDs include, but are not limited to, the CD8 and / or CD28 extracellular domains as described herein. T M Examples include, but are not limited to, CD8 and / or CD28 transmembrane domains as provided herein. In some embodiments, X1 includes T M Furthermore, ECD and ICD are not present. In some implementations, X1 includes ECD and T. M And ICD does not exist. In some implementations, X1 includes T. M And ICD, but ECD is not present. In some implementations, X1 includes ECD, T MAnd ICD. In any of the following embodiments, it should be understood that ECD, ICD, or both may optionally be absent. Thus, X1 comprises CD8 and / or CD28 ECD, CD8 and / or CD28 T. M Implementations of ICDs containing Env-doped motifs are understood to include the following X1 members: i) CD8 and / or CD28 ECD, CD8 and / or CD28 T M and ICDs containing Env-doped motifs; ii) CD8 and / or CD28 T M and ICDs containing Env-doped motifs, where ECDs are absent; iii) CD8 and / or CD28 ECDs and CD8 and / or CD28 T M iv) where ICD is absent; and iv) CD8 and / or CD28 T M Where neither ECD nor ICD exists. Similarly, where X1 contains CD8 and / or CD28 T. M Implementations of ICDs containing Env-doped motifs are understood to include the following X1 members: i) CD8 and / or CD28 T M and ICDs containing Env-doped motifs; and ii) CD8 and / or CD28 T M Where ICD is absent. Similarly, where X1 contains CD8 and / or CD28 ECD and CD8 and / or CD28 T. M The implementation scheme is understood to include the following X1 members: i) CD8 and / or CD28 ECD and CD8 and / or CD28 T M ; and ii) CD8 and / or CD28 T M The ECD is not present. It should also be understood that the foregoing explanation does not address specific ECDs or Ts. M This is also correct in the implementation scheme of the ICD. For example, where X1 includes an ECD, CD8, and / or CD28 T. M The implementation scheme of ICD will be understood to include the following X1 members: i) ECD, CD8 and / or CD28 T M and ICD; ii) ECD and CD8 and / or CD28 T M iii) CD8 and / or CD28 T M and ICD, where ECD is absent; and iv) CD8 and / or CD28 T M Where ECD and ICD are absent. Similarly, where X1 contains CD8 and / or CD28 T. M The implementation scheme of ICD is understood to include the following X1 members: i) CD8 and / or CD28T Mand ICD; and ii) CD8 and / or CD28 T M Where ICD is absent. Similarly, where X1 contains ECD and CD8 and / or CD28T. M The implementation scheme is understood to include the following X1 members: i) ECD and CD8 and / or CD28 T M ; and ii) CD8 and / or CD28T M Where the ECD does not exist. Unless otherwise stated, the foregoing examples and explanations apply to any of the following implementations.

[0255] In some implementations, X1 includes CD8 and / or CD28 ECD, T M And ICD. In some implementations, X1 includes an ECD, CD8, and / or CD28 T. M and ICD. In some implementations, X1 includes CD8 and / or CD28 ECD, CD8 and / or CD28 TCD. M and ICD. In some implementations, X1 includes ECD, T M and ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, X1 contains CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, X1 comprises ECD, CD8, and / or CD28 T. M And ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, X1 comprises CD8 and / or CD28 ECD, CD8 and / or CD28 TCD. M and ICD, wherein the ICD contains env-incorporated motifs as provided herein.

[0256] In some implementation schemes, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing the Fc region as described herein. In some embodiments, the V region described herein... H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region comprising a transmembrane domain as described herein. In some embodiments, the Fc region comprising the transmembrane domain also has the formula L1-Fc-L2-X1, where L1 is a linker as described herein or is absent, Fc is a variant Fc region as described herein, L2 is a linker as described herein or is absent, and X1 is a polypeptide comprising the transmembrane domain as described herein. As provided herein, X1 may comprise a portion having the formula ECD-T M-ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the V provided herein... H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M and ICD. In some implementations, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28T. M and ICD. In some implementations, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M and ICD. In some implementations, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M and ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M and ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, the V provided herein H and V L The polypeptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. Mand ICD, wherein the ICD contains env-incorporated motifs as provided herein. In some embodiments, the env-incorporated motifs provided herein are linked to the stem portion (S1) containing the Fc region (L1-Fc-L2-X1). H and V L The peptide anchors to the surface of viral particles (such as those described in this article), and the Fc region contains ECD, T... M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0257] In some implementations, V having a sequence such as SEQ ID NO: 35 H Peptide and V having the sequence shown in SEQ ID NO: 36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 35 H peptides and V having the sequence shown in SEQ ID NO:36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 35 H Peptide and V having the sequence shown in SEQ ID NO: 36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 35 H Peptide and V having the sequence shown in SEQ ID NO: 36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 35 H Peptide and V having the sequence shown in SEQ ID NO: 36 LThe peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 35. H peptides and V having the sequence shown in SEQ ID NO:36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 35. H Peptide and V having the sequence shown in SEQ ID NO: 36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 35. H Peptide and V having the sequence shown in SEQ ID NO: 36 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a V motif having the sequence shown in SEQ ID NO: 35 is attached to the stem portion (S1) containing the Fc region (L1-Fc-L2-X1). H Peptide and V having the sequence shown in SEQ ID NO: 36 L The peptide anchors to the surface of viral particles (such as those described in this article), and the Fc region contains ECD, T... M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0258] In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO:36. L The peptide is linked to a stem portion (S1) containing the Fc region as described herein. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L The peptide is linked to a stem portion (S1) comprising an Fc region containing a transmembrane domain as provided herein. In some embodiments, the Fc region, which also includes a transmembrane domain, has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L Peptide linked to a compound containing ECD, T MAnd the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L The peptide is linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing CD8 and / or CD28 ECD, TM, and ICD. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. H A peptide; and a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36, linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing ECD, CD8, and / or CD28™ and ICD. In some embodiments, a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. HPeptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L Peptide linked to a compound containing ECD, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to the sequence of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L Peptide linked to ECD containing CD8 and / or CD28, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L Peptide linked to a T-cell containing ECD, CD8 and / or CD28 M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to the sequence of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. LPeptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 35. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36. L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, and anchored to the surface of viral particles (such as those provided herein). In some embodiments, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0259] In some implementations, V is provided H Peptides and Vitamins L peptides are polypeptides, in which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO:35; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 36.

[0260] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 35; and V LThe peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 36; the condition is V. H Peptides and Vitamins L The peptide comprises a light chain CDR having the sequence of SEQ ID NO: 33 and the amino acid sequence of GKN, and the sequence of SEQ ID NO: 34; and / or a heavy chain CDR having the sequences of SEQ ID NO: 30-32. In some embodiments, the polypeptide comprises V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 35; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 36; the condition is V. H Peptides and Vitamins L The peptide comprises a light chain CDR1 having the sequence of SEQ ID NO: 33; a light chain CDR2 having the sequence of GKN; a light chain CDR3 having the sequence of SEQ ID NO: 34; and / or a heavy chain CDR1 having the sequence of SEQ ID NO: 30; a heavy chain CDR2 having the sequence of SEQ ID NO: 31; and a heavy chain CDR3 having the sequence of SEQ ID NO: 32. In some embodiments, V H or V L The CDRs in the chain are shown in the combinations provided in this article.

[0261] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 35; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 36; the condition is V. LThe peptide comprises LCDR1 having the sequence of SEQ ID NO: 33; LCDR2 having the sequence of GKN; and LCDR3 having the sequence of SEQ ID NO: 34; V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 30; HCDR2 having the sequence of SEQ ID NO: 31; and HCDR3 having the sequence of SEQ ID NO: 32.

[0262] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 35; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 36; the condition is V. L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 33, wherein LCDR1 contains at most one conserved amino acid substitution; LCDR2 having the sequence of GKN, wherein LCDR2 contains at most one conserved amino acid substitution; and LCDR3 having the sequence of SEQ ID NO: 34, wherein LCDR3 contains at most one conserved amino acid substitution. And V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 30, wherein HCDR1 contains at most one conserved amino acid substitution; HCDR2 having the sequence of SEQ ID NO: 31, wherein HCDR2 contains at most one conserved amino acid substitution; and HCDR3 having the sequence of SEQ ID NO: 32, wherein HCDR3 contains at most one conserved amino acid substitution.

[0263] In some implementations, V having a sequence such as SEQ ID NO: 44 H Peptide and V having the sequence shown in SEQ ID NO: 45 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 44 H peptides and V having the sequence shown in SEQ ID NO:45 LThe peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 44 H Peptide and V having the sequence shown in SEQ ID NO: 45 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 44 H Peptide and V having the sequence shown in SEQ ID NO: 45 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 44 H Peptide and V having the sequence shown in SEQ ID NO: 45 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 44. H peptides and V having the sequence shown in SEQ ID NO:45 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 44. H Peptide and V having the sequence shown in SEQ ID NO: 45 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 44. H Peptide and V having the sequence shown in SEQ ID NO: 45 LThe peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M and ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V motif having the sequence shown in SEQ ID NO: 44 is linked to the stem portion (S1) containing the Fc region (L1-Fc-L2-X1). H Peptide and V having the sequence shown in SEQ ID NO: 45 L The peptide anchors to the surface of viral particles (such as those described in this article), and the Fc region contains ECD, T... M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0264] In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO:45. L The peptide is linked to a stem portion (S1) containing the Fc region as described herein. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. LThe peptide is linked to a stem portion (S1) comprising an Fc region containing a transmembrane domain as provided herein. In some embodiments, the Fc region, which also includes a transmembrane domain, has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L The peptide is linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing CD8 and / or CD28 ECD, TM, and ICD. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. HA peptide; and a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45, linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing ECD, CD8, and / or CD28™ and ICD. In some embodiments, a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to a compound containing ECD, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to ECD containing CD8 and / or CD28, T MThe stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to a T-cell containing ECD, CD8 and / or CD28 M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 44. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 45. L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, and anchored to the surface of viral particles (such as those provided herein). In some embodiments, L1, Fc, L2, ECD, T MThe identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0265] In some implementations, V is provided H Peptides and Vitamins L peptides are polypeptides, in which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO:44; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 45.

[0266] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 44; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 45; condition V H Peptides and Vitamins L The peptide comprises a light chain CDR having the sequence of SEQ ID NO: 42 and the amino acid sequence of SA, and the sequence of SEQ ID NO: 43; and / or a heavy chain CDR having the sequences of SEQ ID NO: 39-41. In some embodiments, the polypeptide comprises V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 44; and V LThe peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 45; condition V H Peptides and Vitamins L The peptide comprises a light chain CDR1 having the sequence of SEQ ID NO: 42; a light chain CDR2 having the sequence of SA; a light chain CDR3 having the sequence of SEQ ID NO: 43; and / or a heavy chain CDR1 having the sequence of SEQ ID NO: 39; a heavy chain CDR2 having the sequence of SEQ ID NO: 40; and a heavy chain CDR3 having the sequence of SEQ ID NO: 41. In some embodiments, V H or V L The CDRs in the chain are shown in the combinations provided in this article.

[0267] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 44; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 45; condition V L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 42; LCDR2 having the sequence of SA; and LCDR3 having the sequence of SEQ ID NO: 43; V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 39; HCDR2 having the sequence of SEQ ID NO: 40; and HCDR3 having the sequence of SEQ ID NO: 41.

[0268] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 44; and V LThe peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 45; condition V L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 42, wherein LCDR1 contains at most one conserved amino acid substitution; LCDR2 having the sequence of SA, wherein LCDR2 contains at most one conserved amino acid substitution; and LCDR3 having the sequence of SEQ ID NO: 43, wherein LCDR3 contains at most one conserved amino acid substitution. And V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 39, wherein HCDR1 contains at most one conserved amino acid substitution; HCDR2 having the sequence of SEQ ID NO: 40, wherein HCDR2 contains at most one conserved amino acid substitution; and HCDR3 having the sequence of SEQ ID NO: 41, wherein HCDR3 contains at most one conserved amino acid substitution.

[0269] In some implementations, V having a sequence as shown in SEQ ID NO: 51 H Peptide and V having the sequence shown in SEQ ID NO: 77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 51 H peptides and V having the sequence shown in SEQ ID NO:77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 51 H Peptide and V having the sequence shown in SEQ ID NO: 77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 51 H Peptide and V having the sequence shown in SEQ ID NO: 77 LThe peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, V having a sequence as shown in SEQ ID NO: 51 H Peptide and V having the sequence shown in SEQ ID NO: 77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 51. H peptides and V having the sequence shown in SEQ ID NO:77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 51. H Peptide and V having the sequence shown in SEQ ID NO: 77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 51. H Peptide and V having the sequence shown in SEQ ID NO: 77 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the V motif having the sequence shown in SEQ ID NO: 51 is linked to the stem portion (S1) containing the Fc region (L1-Fc-L2-X1). H Peptide and V having the sequence shown in SEQ ID NO: 77 L The peptide anchors to the surface of viral particles (such as those described in this article), and the Fc region contains ECD, T... M And ICD. In some implementations, L1, Fc, L2, ECD, T MThe identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0270] In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO:77. L The peptide is linked to a stem portion (S1) containing the Fc region as described herein. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L The peptide is linked to a stem portion (S1) comprising an Fc region containing a transmembrane domain as provided herein. In some embodiments, the Fc region, which also includes a transmembrane domain, has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 51. HPeptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L The peptide is linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing CD8 and / or CD28 ECD, TM, and ICD. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H A peptide; and a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77, linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing ECD, CD8, and / or CD28™ and ICD. In some embodiments, a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T MAnd the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to a compound containing ECD, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to ECD containing CD8 and / or CD28, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to a T-cell containing ECD, CD8 and / or CD28 MThe stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 51. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77. L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, and anchored to the surface of viral particles (such as those provided herein). In some embodiments, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0271] In some implementations, V is provided H Peptides and Vitamins L peptides are polypeptides, in which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO:51; and V LThe peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 77.

[0272] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 51; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 77; the condition is V. H Peptides and Vitamins L The peptide comprises a light chain CDR having the amino acid sequence of SEQ ID NO: 49 and KN, and the sequence of SEQ ID NO: 50; and / or a heavy chain CDR having the sequences of SEQ ID NO: 46-48. In some embodiments, the polypeptide comprises V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 51; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 77; the condition is V. H Peptides and Vitamins L The peptide comprises a light chain CDR1 having the sequence of SEQ ID NO: 49; a light chain CDR2 having the sequence KN; a light chain CDR3 having the sequence of SEQ ID NO: 50; and / or a heavy chain CDR1 having the sequence of SEQ ID NO: 46; a heavy chain CDR2 having the sequence of SEQ ID NO: 47; and a heavy chain CDR3 having the sequence of SEQ ID NO: 48. In some embodiments, V H or V L The CDRs in the chain are shown in the combinations provided in this article.

[0273] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 51; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 77; the condition is V. L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 49; LCDR2 having the sequence KN; and LCDR3 having the sequence of SEQ ID NO: 50; V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 46; HCDR2 having the sequence of SEQ ID NO: 47; and HCDR3 having the sequence of SEQ ID NO: 48.

[0274] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 51; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 77; the condition is V. L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 49, wherein LCDR1 contains at most one conserved amino acid substitution; LCDR2 having the sequence of KN, wherein LCDR2 contains at most one conserved amino acid substitution; and LCDR3 having the sequence of SEQ ID NO: 50, wherein LCDR3 contains at most one conserved amino acid substitution. And V HThe peptide comprises HCDR1 having the sequence of SEQ ID NO: 46, wherein HCDR1 contains at most one conserved amino acid substitution; HCDR2 having the sequence of SEQ ID NO: 47, wherein HCDR2 contains at most one conserved amino acid substitution; and HCDR3 having the sequence of SEQ ID NO: 48, wherein HCDR3 contains at most one conserved amino acid substitution.

[0275] In some implementations, V having a sequence such as SEQ ID NO: 85 H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD. In some embodiments, V having a sequence such as SEQ ID NO: 85 H peptides and V having the sequence shown in SEQ ID NO:86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD. In some embodiments, V having a sequence such as SEQ ID NO: 85 H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD. In some embodiments, V having a sequence such as SEQ ID NO: 85 H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M and ICD. In some embodiments, V having a sequence such as SEQ ID NO: 85 H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1), which includes ECD and T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 85. Hpeptides and V having the sequence shown in SEQ ID NO:86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes CD8 and / or CD28 ECD, T M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 85. H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, CD8, and / or CD28 T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, V has a sequence as shown in SEQ ID NO: 85. H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide is linked to a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T. M and ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a V motif having the sequence shown in SEQ ID NO: 85 is attached to the stem portion (S1) containing the Fc region (L1-Fc-L2-X1). H Peptide and V having the sequence shown in SEQ ID NO: 86 L The peptide anchors to the surface of viral particles (such as those described in this article), and the Fc region contains ECD, T... M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0276] In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO:86.L The peptide is linked to a stem portion (S1) containing the Fc region as described herein. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L The peptide is linked to a stem portion (S1) comprising an Fc region containing a transmembrane domain as provided herein. In some embodiments, the Fc region, which also includes a transmembrane domain, has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, V comprises a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. LThe peptide is linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing CD8 and / or CD28 ECD, TM, and ICD. In some embodiments, a V-shaped portion comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H A peptide; and a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86, linked to a stem portion (S1) comprising an Fc region (L1-Fc-L2-X1) containing ECD, CD8, and / or CD28™ and ICD. In some embodiments, a VL peptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD. In some embodiments, V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L Peptide linked to a compound containing ECD, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. HPeptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L Peptide linked to ECD containing CD8 and / or CD28, T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L Peptide linked to a T-cell containing ECD, CD8 and / or CD28 M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86. L Peptide linked to ECD containing CD8 and / or CD28, CD8 and / or CD28 T M The stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, wherein the ICD contains the env incorporation motif as provided herein. In some embodiments, the V contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 85. H Peptide; and V containing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86.L Peptide linked to a compound containing ECD, T M And the stem portion (S1) of the Fc region (L1-Fc-L2-X1) of the ICD, and anchored to the surface of viral particles (such as those provided herein). In some embodiments, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, V H and V L The peptides bind to liver cells (such as those described in this article).

[0277] In some implementations, V is provided H Peptides and Vitamins L peptides are polypeptides, in which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO:85; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence identical to that of SEQ ID NO: 86.

[0278] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 85; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 86; the condition is V. H Peptides and Vitamins L The peptide comprises a light chain CDR having the sequence of SEQ ID NO: 83 and the amino acid sequence of LV, and the sequence of SEQ ID NO: 84; and / or a heavy chain CDR having the sequences of SEQ ID NO: 80-82. In some embodiments, the polypeptide comprises V H Peptides and Vitamins L peptides, of which V HThe peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 85; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 86; the condition is V. H Peptides and Vitamins L The peptide comprises a light chain CDR1 having the sequence of SEQ ID NO: 83; a light chain CDR2 having the sequence of SEQ ID NO: 84; a light chain CDR3 having the sequence of SEQ ID NO: 84; and / or a heavy chain CDR1 having the sequence of SEQ ID NO: 80; a heavy chain CDR2 having the sequence of SEQ ID NO: 81; and a heavy chain CDR3 having the sequence of SEQ ID NO: 82. In some embodiments, V H or V L The CDRs in the chain are shown in the combinations provided in this article.

[0279] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 85; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 86; the condition is V. L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 83; LCDR2 having the sequence of LV; and LCDR3 having the sequence of SEQ ID NO: 84; V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 80; HCDR2 having the sequence of SEQ ID NO: 81; and HCDR3 having the sequence of SEQ ID NO: 82.

[0280] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V HThe peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 85; and V L The peptide contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequence to the sequence of SEQ ID NO: 86; the condition is V. L The peptide comprises LCDR1 having the sequence of SEQ ID NO: 83, wherein LCDR1 contains at most one conserved amino acid substitution; LCDR2 having the sequence of LV, wherein LCDR2 contains at most one conserved amino acid substitution; and LCDR3 having the sequence of SEQ ID NO: 84, wherein LCDR3 contains at most one conserved amino acid substitution. And V H The peptide comprises HCDR1 having the sequence of SEQ ID NO: 80, wherein HCDR1 contains at most one conserved amino acid substitution; HCDR2 having the sequence of SEQ ID NO: 81, wherein HCDR2 contains at most one conserved amino acid substitution; and HCDR3 having the sequence of SEQ ID NO: 82, wherein HCDR3 contains at most one conserved amino acid substitution.

[0281] In some implementations, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 35, and V L The peptide contains the sequence of SEQ ID NO: 36. In some embodiments, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 44, and V L The peptide contains the sequence of SEQ ID NO: 45. In some embodiments, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 51, and V L The peptide contains the sequence of SEQ ID NO: 77. In some embodiments, the polypeptide contains V H Peptides and Vitamins L peptides, of which V H The peptide contains the sequence of SEQ ID NO: 85, and V L The peptide contains the sequence of SEQ ID NO: 86.

[0282] In some embodiments, the peptides provided herein bind to non-human primate ASGR1. In some embodiments, the peptides provided herein bind to human ASGR1.

[0283] As provided in this article, the different polypeptides (V) described herein H or V L This can be linked to a peptide linker or not to form a continuous sequence. In some embodiments, the peptide linker comprises (GGGGS). n The sequence (SEQ ID NO: 55), wherein each n is independently 1-5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. The linked peptide form can be derived from formula V. H -ZV L or V L -ZV H This indicates that Z represents a peptide linker. In some embodiments, Z is (GGGGS). n (SEQ ID NO: 55), where each n is independently 1-5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0284] In some implementations, it includes formula V L -ZV H The peptide representing the linked peptide comprises a heavy chain variable region, as shown in SEQ ID NO: 35, linked to a light chain variable region, as shown in SEQ ID NO: 36, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a heavy chain variable region, as shown in SEQ ID NO: 35, linked to a light chain variable region, as shown in SEQ ID NO: 36, via a peptide linker. H Connected V L The polypeptide has the sequence shown below.

[0285] SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSLERIGYLSYVFGGGTKLTVLGGGGSGGGGSGGGGS EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFSSRRWYLEYWGQGTLVTVSS (SEQ ID NO: 37).

[0286] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 37. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 37. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 37. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 37. In some embodiments, the polypeptide shown in SEQ ID NO: 37 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0287] In some implementations, it includes formula V H -ZV L The peptide representing the linked peptide comprises a light chain variable region, as shown in SEQ ID NO: 36, linked to a heavy chain variable region, as shown in SEQ ID NO: 35, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a light chain variable region, as shown in SEQ ID NO: 36, linked to a heavy chain variable region, as shown in SEQ ID NO: 35, via a peptide linker. L Connected V H The polypeptide has the sequence shown below.

[0288] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFSSRRWYLEYWGQGTLVTVSSGGGG SGGGGSGGGGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSLERIGYLSYVFGGGTKLTVL (SEQ ID NO: 38).

[0289] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 38. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 38. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 38. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 38. In some embodiments, the polypeptide shown in SEQ ID NO: 38 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0290] In some implementations, it includes formula V L -ZV H The peptide representing the linked peptide comprises a heavy chain variable region, as shown in SEQ ID NO: 44, linked to a light chain variable region, as shown in SEQ ID NO: 45, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a heavy chain variable region, as shown in SEQ ID NO: 44, linked to a light chain variable region, as shown in SEQ ID NO: 45, via a peptide linker. H Connected V L The polypeptide has the sequence shown below.

[0291] DIVMTQSQKFMSTSVGDRVSVTCKASQNVDTNVAWFQQKPGQYPKVLIYSASYRYSGVPDRFTGSGSGTTDFTLTISNVQSEDLAEYFCQQYNSYPFTFGAGTKLELKRAGGGGSGGGGSGGG GSQVQLQQSAAELARPGASVKMSCKASGYTFTSYPMHWVKQRPGQGLEWIAYISPSSGYTKYNQKFTDKTTLTADKSSSTTAYMQLSSLTSDDSAVYYCARKGGYLDYWGQGTTLTVSS (SEQ ID NO: 129).

[0292] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 129. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 129. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 129. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 129. In some embodiments, the polypeptide shown in SEQ ID NO: 129 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0293] In some implementations, it includes formula V H -ZV L The peptide representing the linked peptide comprises a light chain variable region, as shown in SEQ ID NO: 45, linked to a heavy chain variable region, as shown in SEQ ID NO: 44, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a light chain variable region, as shown in SEQ ID NO: 45, linked to a heavy chain variable region, as shown in SEQ ID NO: 44, via a peptide linker. L Connected V H The polypeptide has the sequence shown below.

[0294] QVQLQQSAAELARPGASVKMSCKASGYTFTSYPMHWVKQRPGQGLEWIAYISPSSGYTKYNQKFTDKTTLTADKSSSTTAYMQLSSLTSDDSAVYYCARKGGYLDYWGQGTTLTVSSGGGGSG GGGSGGGGSDIVMTQSQKFMSTSVGDRVSVTCKASQNVDTNVAWFQQKPGQYPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPFTFGAGTKLELKRA (SEQ ID NO: 130).

[0295] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 130. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 130. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 130. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 130. In some embodiments, the polypeptide shown in SEQ ID NO: 130 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0296] In some implementations, it includes formula V L -ZV H The peptide representing the linked peptide comprises a heavy chain variable region, as shown in SEQ ID NO: 51, linked via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72) to a light chain variable region, as shown in SEQ ID NO: 77. In some embodiments, it comprises a heavy chain variable region, as shown in SEQ ID NO: 51, linked via a peptide linker to a V-linker. H Connected V L The polypeptide has the sequence shown below.

[0297] DIVLTQPPSASGTPGQRVTISCTGSSSGIGNAYVSWYQQLPGKAPKLLIYKNGQRPSGVSDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKVTVLGGGGSGGGGSGGG GSEVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSAITTGGGSPNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRTAGYFDYWGQGALVTVSS (SEQ ID NO: 78).

[0298] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 78. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 78. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 78. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 78. In some embodiments, the polypeptide shown in SEQ ID NO: 78 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0299] In some implementations, it includes formula V H -ZV L The peptide representing the linked peptide comprises a light chain variable region, as shown in SEQ ID NO: 77, linked to a heavy chain variable region, as shown in SEQ ID NO: 51, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a light chain variable region, as shown in SEQ ID NO: 51, linked to a V-linker via a peptide linker. L Connected V H The polypeptide has the sequence shown below.

[0300] EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSAITTGGGSPNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRTAGYFDYWGQGALVTVSSGGGGS GGGGSGGGGSDIVLTQPPSASGTPGQRVTISCTGSSSGIGNAYVSWYQQLPGKAPKLLIYKNGQRPSGVSDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKVTVL (SEQ ID NO: 79).

[0301] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 79. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 79. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 79. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 79. In some embodiments, the polypeptide shown in SEQ ID NO: 79 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0302] In some implementations, it includes formula V L -ZV H The peptide representing the linked peptide comprises a heavy chain variable region, as shown in SEQ ID NO: 85, linked to a light chain variable region, as shown in SEQ ID NO: 86, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a heavy chain variable region, as shown in SEQ ID NO: 85, linked to a light chain variable region, as shown in SEQ ID NO: 86, via a peptide linker. H Connected V L The polypeptide has the sequence shown below.

[0303] DIVMTQSPASLAVSLGQRATISYRASKSVSTSGYSYMHWNQQKPGQPPRLLIYLVSNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQXXGGAYTFGGGTKLEIKRGGGGSGGGGSGG GGSQVQLQQSGAELVKPGASVKLSCKTSGYTFTSYWIQWVKQRPGQGLGWIGEIFPGTGTSYYNENFKGKATLTIDTSSSTAYMQPSSLTSEDSAVYFCARTNNYRSYALDYWGQGTNYRS (SEQ ID NO: 87).

[0304] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 87. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 87. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 87. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 87. In some embodiments, the polypeptide shown in SEQ ID NO: 87 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0305] In some implementations, it includes formula V H -ZV L The peptide representing the linked peptide comprises a light chain variable region, as shown in SEQ ID NO: 86, linked to a heavy chain variable region, as shown in SEQ ID NO: 85, via a linker sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 72). In some embodiments, it comprises a light chain variable region, as shown in SEQ ID NO: 86, linked to a heavy chain variable region, as shown in SEQ ID NO: 85, via a peptide linker. L Connected V H The polypeptide has the sequence shown below.

[0306] QVQLQQSGAELVKPGASVKLSCKTSGYTFTSYWIQWVKQRPGQGLGWIGEIFPGTGTSYYNENFKGKATLTIDTSSSTAYMQPSSLTSEDSAVYFCARTNNYRSYALDYWGQGTNYRSGGGGSG GGGSGGGGSDIVMTQSPASLAVSLGQRATISYRASKSVSTSGYSYMHWNQQKPGQPPRLLIYLVSNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQXXGGAYTFGGGTKLEIKR (SEQ ID NO: 88).

[0307] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88. In some embodiments, the polypeptide comprises at least 90% identical to the sequence of SEQ ID NO: 88. In some embodiments, the polypeptide comprises at least 95% identical to the sequence of SEQ ID NO: 88. In some embodiments, the polypeptide comprises at least 99% identical to the sequence of SEQ ID NO: 88. In some embodiments, the polypeptide comprises the sequence shown in SEQ ID NO: 88. In some embodiments, the polypeptide shown in SEQ ID NO: 88 is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an anti-ASGR1 antibody. In some embodiments, the anti-ASGR1 antibody binds to non-human primate ASGR1. In some embodiments, the anti-ASGR1 antibody binds to human ASGR1.

[0308] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 37 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:37 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0309] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And an ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 38 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:38 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0310] In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and a stem portion (S1) containing an Fc region, the Fc region further comprising a transmembrane domain, such as those provided herein. In some embodiments, the Fc region further comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a polypeptide having the formula ECD-TM -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 37 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising a sequence having the sequence shown in SEQ ID NO: 37 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising an ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0311] In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and a stem portion (S1) containing an Fc region, the Fc region further comprising a transmembrane domain, such as those provided herein. In some embodiments, the Fc region further comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a portion having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 38 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising a sequence having the sequence shown in SEQ ID NO: 38 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising an ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0312] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region, which further comprises a transmembrane domain, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 129 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:129 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0313] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 130 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:130 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0314] In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and a stem portion (S1) containing an Fc region, the Fc region further comprising a transmembrane domain, such as those provided herein. In some embodiments, the Fc region further comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide containing a transmembrane domain as provided herein. As provided herein, X1 may comprise a polypeptide having the formula ECD-TM -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO:129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 129 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising a sequence having the sequence shown in SEQ ID NO: 129 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising an ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0315] In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and a stem portion (S1) containing an Fc region, said Fc region further comprising a transmembrane domain, such as those provided herein. In some embodiments, the Fc region further comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide containing a transmembrane domain as provided herein. As provided herein, X1 may comprise a polypeptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO:130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 130 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising a sequence having the sequence shown in SEQ ID NO: 130 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising an ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0316] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) which includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 78 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:78 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0317] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 79 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:79 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0318] In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and a stem portion (S1) containing an Fc region, the Fc region further comprising a transmembrane domain, such as those provided herein. In some embodiments, the Fc region further comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a polypeptide having the formula ECD-TM -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) containing ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 78 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising a sequence having the sequence shown in SEQ ID NO: 78 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising an ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0319] In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and a stem portion (S1) containing an Fc region, the Fc region further comprising a transmembrane domain, such as those provided herein. In some embodiments, the Fc region further comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a polypeptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) containing ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises a sequence having the sequence shown in SEQ ID NO: 79 and includes a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising a sequence having the sequence shown in SEQ ID NO: 79 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising an ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0320] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) which includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And an ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 87 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T MAnd ICD, wherein the ICD contains an env-incorporated motif as provided herein. In some embodiments, a polypeptide comprising at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:87 and comprising a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) is anchored to the surface of a viral particle (such as those provided herein), the Fc region comprising ECD, T M And ICD. In some implementations, L1, Fc, L2, ECD, T M The identity of the ICD is as provided herein. In some implementations, the peptide binds to liver cells, such as those described herein.

[0321] In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (such as those provided herein). In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region, which further comprises transmembrane domains, such as those provided herein. In some embodiments, the Fc region comprising a transmembrane domain has the formula L1-Fc-L2-X1, wherein L1 is a linker as provided herein or is absent, Fc is a variant Fc region as provided herein, L2 is a linker as provided herein or is absent, and X1 is a polypeptide comprising a transmembrane domain as provided herein. As provided herein, X1 may comprise a peptide having the formula ECD-T M -ICD polypeptide, wherein ECD is an extracellular domain or a fragment thereof as provided herein, or is absent, T M It is a transmembrane domain as described herein, and the ICD is an intracellular domain as described herein or is absent. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) that includes ECD, T MAnd ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising ECD, CD8, and / or CD28 T. M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:88 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, CD8 and / or CD28 T M And ICD. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) which includes ECD, T M And ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (L1-Fc-L2-X1) comprising CD8 and / or CD28 ECD, T MAnd ICD, wherein the ICD contains an env incorporation motif as provided herein. In some embodiments, the polypeptide comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 88 and comprises a stem portion (S1) containing an Fc region (L1...

Claims

1. A viral particle comprising a heterologous viral glycoprotein and a targeting portion, wherein the targeting portion comprises a polypeptide having the formula T-S1, wherein T is a target-binding domain for targeting the viral particle to the liver, and S1 is a stem portion. T is combined with ASGR1, ASGR2, or a combination thereof.

2. The viral particle of claim 1, wherein the stem portion S1 comprises a variant Fc protein, wherein the variant Fc protein comprises a transmembrane domain and an effector mutation, wherein the effector mutation inhibits the interaction between the Fc protein and Fc-interacting proteins such as FcγR, C1q, FcRβ, or FcRn.

3. The viral particle of claim 2, wherein the variant Fc protein comprises a variant of the sequence of SEQ ID NO: 26, SEQ ID NO: 27 or SEQ ID NO:

28.

4. The viral particle of claim 2, wherein the variant Fc protein comprises an amino acid sequence having at least 80% identity with SEQ ID NO: 91, at least 85% identity with SEQ ID NO: 91, at least 90% identity with SEQ ID NO: 91, at least 95% identity with SEQ ID NO: 91, at least 98% identity with SEQ ID NO: 91, or at least 100% identity with SEQ ID NO:

91.

5. The viral particle of claim 1, wherein the target-binding domain (T) binds to ASGR2.

6. The viral particle of claim 1, wherein the target-binding domain (T) binds to ASGR1.

7. The viral particle of claim 6, wherein the target-binding domain (T) comprises a polypeptide, the polypeptide comprising: (i) a heavy chain comprising a heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 30; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 31; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 32, or a variant thereof; and (ii) a light chain comprising a light chain variable region, the light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 33; the light chain CDR2 sequence has the amino acid sequence of GKN; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 34; or a variant thereof.

8. The viral particle of claim 7, wherein the polypeptide comprises a heavy chain and a light chain, the heavy chain and light chain comprising: a heavy chain variable region of the heavy chain having at least 90% sequence identity with SEQ ID NO: 35, and a light chain variable region of the light chain having at least 90% sequence identity with SEQ ID NO: 36, wherein the polypeptide comprises the following sequences: HCDR1 as shown in SEQ ID NO: 30; HCDR2 as shown in SEQ ID NO: 31; HCDR3 as shown in SEQ ID NO: 32; LCDR1 as shown in SEQ ID NO: 33; LCDR2 of GKN; and LCDR3 as shown in SEQ ID NO:

34.

9. The viral particle of claim 7, wherein the light chain and the heavy chain comprise: a heavy chain variable region comprising SEQ ID NO: 35, and a light chain variable region comprising SEQ ID NO:

36.

10. The viral particle of claim 7, wherein the target-binding domain (T) binding to ASGR1 comprises a polypeptide, the polypeptide comprising a sequence having at least 90% sequence identity with SEQ ID NO: 37 or SEQ ID NO: 38, at least 95% sequence identity with SEQ ID NO: 37 or SEQ ID NO: 38, at least 99% sequence identity with SEQ ID NO: 37 or SEQ ID NO: 38, or a sequence as shown in SEQ ID NO: 37 or SEQ ID NO:

38.

11. The viral particle of claim 6, wherein the target-binding domain (T) comprises a polypeptide, the polypeptide comprising: (i) a heavy chain comprising a heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 39; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 40; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 41, or a variant thereof; and (ii) a light chain comprising a light chain variable region, the light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 42; the light chain CDR2 sequence has the amino acid sequence of SA; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 43; or a variant thereof.

12. The viral particle of claim 11, wherein the polypeptide comprises a heavy chain and a light chain, the heavy chain and light chain comprising: a heavy chain variable region of the heavy chain having at least 90% sequence identity with SEQ ID NO: 44, and a light chain variable region of the light chain having at least 90% sequence identity with SEQ ID NO: 45, wherein the polypeptide comprises the following sequences: HCDR1 as shown in SEQ ID NO: 39; HCDR2 as shown in SEQ ID NO: 40; HCDR3 as shown in SEQ ID NO: 41; LCDR1 as shown in SEQ ID NO: 42; LCDR2 of SA; and LCDR3 as shown in SEQ ID NO:

43.

13. The viral particle of claim 11, wherein the light chain and the heavy chain comprise: a heavy chain variable region comprising SEQ ID NO: 44, and a light chain variable region comprising SEQ ID NO:

45.

14. The viral particle of claim 11, wherein the target-binding domain (T) binding to ASGR1 comprises a polypeptide, the polypeptide comprising a sequence having at least 90% sequence identity with SEQ ID NO: 129 or SEQ ID NO: 130, at least 95% sequence identity with SEQ ID NO: 129 or SEQ ID NO: 130, at least 99% sequence identity with SEQ ID NO: 129 or SEQ ID NO: 130, or a sequence as shown in SEQ ID NO: 129 or SEQ ID NO:

130.

15. The viral particle of claim 6, wherein the target-binding domain (T) comprises a polypeptide, the polypeptide comprising: (i) a heavy chain comprising a heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 46; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 47; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 48, or a variant thereof; and (ii) a light chain comprising a light chain variable region, the light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 49; the light chain CDR2 sequence has the amino acid sequence of KN; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 50; or a variant thereof.

16. The viral particle of claim 15, wherein the polypeptide comprises a heavy chain and a light chain, the heavy chain and light chain comprising: a heavy chain variable region of the heavy chain having at least 90% sequence identity with SEQ ID NO: 51, and a light chain variable region of the light chain having at least 90% sequence identity with SEQ ID NO: 77, wherein the polypeptide comprises the following sequences: HCDR1 as shown in SEQ ID NO: 46; HCDR2 as shown in SEQ ID NO: 47; HCDR3 as shown in SEQ ID NO: 48; LCDR1 as shown in SEQ ID NO: 49; LCDR2 of KN; and LCDR3 as shown in SEQ ID NO:

50.

17. The viral particle of claim 15, wherein the light chain and the heavy chain comprise: a heavy chain variable region comprising SEQ ID NO: 51, and a light chain variable region comprising SEQ ID NO:

77.

18. The viral particle of claim 15, wherein the target-binding domain (T) binding to ASGR1 comprises a polypeptide, the polypeptide comprising a sequence having at least 90% sequence identity with SEQ ID NO: 78 or SEQ ID NO: 79, at least 95% sequence identity with SEQ ID NO: 79, at least 99% sequence identity with SEQ ID NO: 78 or SEQ ID NO: 79, or a sequence as shown in SEQ ID NO: 78 or SEQ ID NO:

79.

19. The viral particle of claim 6, wherein the target-binding domain (T) comprises a polypeptide, the polypeptide comprising: (i) a heavy chain comprising a heavy chain variable region, the heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82, or a variant thereof; and (ii) a light chain comprising a light chain variable region, the light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 84; or a variant thereof.

20. The viral particle of claim 19, wherein the polypeptide comprises a heavy chain and a light chain, the heavy chain and light chain comprising: a heavy chain variable region of the heavy chain having at least 90% sequence identity with SEQ ID NO: 85, and a light chain variable region of the light chain having at least 90% sequence identity with SEQ ID NO: 86, wherein the polypeptide comprises the following sequences: HCDR1 as shown in SEQ ID NO: 80; HCDR2 as shown in SEQ ID NO: 81; HCDR3 as shown in SEQ ID NO: 82; LCDR1 as shown in SEQ ID NO: 83; LCDR2 of LV; and LCDR3 as shown in SEQ ID NO:

84.

21. The viral particle of claim 19, wherein the light chain and the heavy chain comprise: a heavy chain variable region comprising SEQ ID NO: 85, and a light chain variable region comprising SEQ ID NO:

86.

22. The viral particle of claim 19, wherein the target-binding domain (T) binding to ASGR1 comprises a polypeptide, the polypeptide comprising a sequence having at least 90% sequence identity with SEQ ID NO: 87 or SEQ ID NO: 88, at least 95% sequence identity with SEQ ID NO: 87 or SEQ ID NO: 88, at least 99% sequence identity with SEQ ID NO: 87 or SEQ ID NO: 88, or a sequence as shown in SEQ ID NO: 87 or SEQ ID NO:

88.

23. The viral particle of claim 1, wherein the target-binding domain (T) is an antibody or an antigen-binding fragment thereof, such as an scFv antibody.

24. The viral particle according to any one of claims 1 to 23, wherein the targeting portion having the formula T-S1 comprises a stem portion S1 having the formula L1-Fc-L2-X1, wherein: L1 is a connector or does not exist; Fc is a variant of the Fc protein; L2 is a connector or does not exist; and X1 is a polypeptide containing the transmembrane domain. The target portion having the formula T-S1 has the formula T-L1-Fc-L2-X1.

25. The viral particle of claim 24, wherein L1 and L2 each independently lack or contain a polypeptide linker of the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 or SEQ ID NO:

76.

26. The viral particle of claim 24, wherein L1 and L2 each independently comprise (GGGGA). n (SEQ ID NO: 54) or (GGGGS) n The amino acid sequence of (SEQ ID NO: 55), and Each n is independently between 1 and 5.

27. The virus particle of claim 24, wherein X1 comprises having the formula ECD-T M -ICD polypeptide, wherein: ECD is the extracellular domain or a fragment thereof of a cell surface protein, or it may not exist. T M It is a transmembrane domain of a transmembrane protein; and ICD is an intracellular domain or a protein that promotes the incorporation of the target portion into the viral particle's envelope, or it may be absent. The target portion having the formula T-L1-Fc-L2-X1 has the formula T-L1-Fc-L2-ECD-T M -ICD.

28. The virus particle of claim 27, wherein the ECD comprises the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO:

60.

29. The virus particle of claim 27, wherein the T M The amino acid sequence containing SEQ ID NO: 61 or SEQ ID NO:

62.

30. The virus particle of claim 27, wherein the ICD comprises an Env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO:

64.

31. The viral particle according to any one of claims 1 to 30, wherein the heterologous viral glycoprotein is a VSV-G polypeptide.

32. The virus particle of claim 31, wherein the VSV-G polypeptide comprises the sequence of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24 or SEQ ID NO:

25.

33. The viral particle according to any one of claims 1 to 32, wherein the viral particle further comprises a nucleic acid molecule encoding a heterologous molecule of interest.

34. The viral particle of claim 33, wherein the heterologous molecule of interest is a chimeric antigen receptor ("CAR"), ATP7B, GAA, SERPINA1, OTC, GUSB, UGT1A1, PAH, BCKDHA, BCKDHB, DBT, ATP8B1, ABCB11, ABCB4, FAH, TAT, HPD, HMBS, ASS1, SLC25A13, F8, F9, AGXT, GRHPR, HOGA1, INS, glucagon-like peptide-1 (GLP-1) hormone, glucagon-like peptide-2 (GLP-2) hormone, enteroglucagon, PYY, CCK, glucagon, amylin, activin type II inhibitor, or miR-22 inhibitor.

35. The viral particle according to any one of claims 1 to 34, wherein the viral particle further comprises at least one nucleic acid molecule encoding a gene editing system.

36. The viral particle of claim 35, wherein the gene editing system is a CRISPR-Cas system, a zinc finger nuclease system, TALEN, a large-scale nuclease, or a gene product regulating nucleic acid molecule.

37. A method of infecting a cell, the method comprising contacting the cell with viral particles according to any one of claims 1 to 36.

38. A method of infecting the cells of a subject, the method comprising administering to the subject a pharmaceutical composition comprising viral particles according to any one of claims 1 to 36.

39. A method for delivering a heterologous molecule of interest to a cell, the method comprising contacting the cell with a viral particle according to any one of claims 1 to 36, wherein the viral particle contains a nucleic acid molecule encoding the heterologous molecule of interest.

40. A method of delivering a heterologous molecule of interest to the cells of a subject, the method comprising administering to the subject a viral particle according to any one of claims 1 to 36, wherein the viral particle contains a nucleic acid molecule encoding the heterologous molecule of interest.

41. A method for editing a target nucleic acid molecule in a cell, the method comprising contacting the cell with a viral particle according to any one of claims 35 to 36, wherein the nucleic acid molecule encoding the gene editing system is expressed in the cell and the target nucleic acid molecule is edited in the cell.

42. The method according to any one of claims 37 to 41, wherein the cell is a liver cell, optionally a hepatocyte.

43. A method of treating a disease or condition in a subject, the method comprising administering to the subject a viral particle according to any one of claims 1 to 36, wherein the viral particle comprises a nucleic acid molecule encoding the heterologous molecule of interest for treating the disease or condition.

44. The method of claim 43, wherein the disease or condition is Wilson's disease, glycogen storage disease (e.g., von Gilke's disease, Pompe disease, etc.), α-1 antitrypsin (AAT) deficiency, ornithine transcarbamoylase (OTC) deficiency, mucopolysaccharidosis VII, Krieger-Najjar syndrome type 1, phenylketonuria, maple syrup diabetes mellitus, progressive familial intrahepatic cholestasis, tyrosinemia, acute intermittent porphyria, citrullinemia type 1, type 1 diabetes, hemophilia A, hemophilia B, hemoglobinopathies, obesity, oxalate deposition syndrome, type II diabetes, gestational diabetes, malignant vegetations, or extrahepatic tumors.

45. A viral particle comprising a heterologous viral glycoprotein and a targeting portion, the targeting portion comprising a polypeptide having the formula T-S1. Where T is the target-binding domain and S1 is the stem portion. The heteroviral glycoprotein comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52 or SEQ ID NO: 53; The target-binding domain comprises a sequence selected from SEQ ID NO: 37 or SEQ ID NO: 38; The stem portion S1 comprises the formula L1-Fc-L2-X1, wherein: L1 is a connector that contains a sequence selected from SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75 or SEQ ID NO: 76, or it is absent; Fc is a variant Fc protein containing sequences that are variants of SEQ ID NO: 26, SEQ ID NO: 27 or SEQ ID NO: 28; The variant of SEQ ID NO: 26 contains one or more mutations selected from the group consisting of L234A, L235A, N297A, P329G, I253A, H310A and H435A; The variant of SEQ ID NO: 27 contains one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A and H435A; The variant of SEQ ID NO: 28 contains one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A and H435A; L2 is a connector that contains a sequence selected from SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, or SEQ ID NO: 76, or it is absent; and X1 is a formula ECD-T M -ICDs are polypeptides containing transmembrane domains, wherein: ECD is an extracellular domain having a sequence selected from SEQ ID NO: 59 or SEQ ID NO: 60, or a fragment thereof, or it is absent; T M It is a transmembrane domain or a fragment thereof having a sequence of SEQ ID NO: 61 or SEQ ID NO: 62; and An ICD is an intracellular domain or a protein that facilitates the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64, or the ICD is absent.

46. ​​A viral particle comprising a heterologous viral glycoprotein and a targeting portion, the targeting portion comprising a polypeptide having the formula T-S1. Where T is the target-binding domain and S1 is the stem portion. The heteroviral glycoprotein comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 52 or SEQ ID NO: 53; The target-binding domain comprises a sequence selected from SEQ ID NO: 37 or SEQ ID NO: 38; The stem portion S1 comprises the formula L1-Fc-L2-X1, wherein: L1 is a connector containing the sequence of SEQ ID NO: 55 or it does not exist; Fc is a variant Fc protein containing sequences that are variants of SEQ ID NO: 26, SEQ ID NO: 27 or SEQ ID NO: 28; The variant of SEQ ID NO: 26 contains one or more mutations selected from the group consisting of L234A, L235A, N297A, P329G, I253A, H310A and H435A; The variant of SEQ ID NO: 27 contains one or more mutations selected from the group consisting of N297A, P329G, I253A, H310A and H435A; The variant of SEQ ID NO: 28 contains one or more mutations selected from the group consisting of S228P, L235E, N297A, P329G, I253A, H310A and H435A; L2 is a connector containing the sequence of SEQ ID NO: 55 or it is absent; and X1 is a formula ECD-T M -ICDs are polypeptides containing transmembrane domains, wherein: ECD is an extracellular domain or a fragment thereof having the sequence SEQ ID NO: 60, or it may not exist; T M It is a transmembrane domain or a fragment thereof having the sequence of SEQ ID NO: 62; and An ICD is an intracellular domain or a protein that facilitates the incorporation of the target portion into the envelope of the viral particle, wherein the ICD contains an env incorporation motif containing the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64, or the ICD is absent.

47. A viral particle comprising a heterologous viral glycoprotein and a targeting portion, wherein: The heteroviral glycoprotein comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 23 or SEQ ID NO: 25, at least 95% identity with SEQ ID NO: 23 or SEQ ID NO: 25, at least 99% identity with SEQ ID NO: 23 or SEQ ID NO: 25, or at least 100% identity with SEQ ID NO: 23 or SEQ ID NO: 25; and The target portion comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 89 or SEQ ID NO: 92, at least 95% identity with SEQ ID NO: 89 or SEQ ID NO: 92, at least 99% identity with SEQ ID NO: 89 or SEQ ID NO: 92, or at least 100% identity with SEQ ID NO: 89 or SEQ ID NO:

92.

48. The viral particle according to any one of claims 45 to 47, wherein the viral particle further comprises a nucleic acid molecule encoding a heterologous molecule of interest.

49. The viral particle of claim 48, wherein the heterologous molecule of interest is CAR, ATP7B, GAA, SERPINA1, OTC, GUSB, UGT1A1, PAH, BCKDHA, BCKDHB, DBT, ATP8B1, ABCB11, ABCB4, FAH, TAT, HPD, HMBS, ASS1, SLC25A13, F8, F9, AGXT, GRHPR, HOGA1, INS, glucagon-like peptide-1 (GLP-1) hormone, glucagon-like peptide-2 (GLP-2) hormone, enteroglucagon, PYY, CCK, glucagon, amylin, activin type II inhibitor, or miR-22 inhibitor.

50. The viral particle according to any one of claims 45 to 49, wherein the viral particle further comprises at least one nucleic acid molecule encoding a gene editing system.

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