Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof

Abstract

Provided are ionizable cationic lipids and lipid nanoparticles for the delivery of nucleic acids to cells (e.g., immune cells), and methods of making and using such lipids and targeted lipid nanoparticles.

Description

[0001] IONIZABLE CATIONIC LIPIDS AND LIPID NANOPARTICLES,AND METHODS OF SYNTHESIS AND USE THEREOFCROSS-REFERENCE TO RELATED APPLICATION This application claims priority to and benefit of U.S. Provisional Application No.63 / 609,852, filed December 13, 2023, the disclosure of which is hereby incorporated herein byreference in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The content of the electronic sequence listing (183952035540seqlist.xml; Size: 166,103 bytes; and Date of Creation: December 6, 2024) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION The invention provides ionizable cationic lipids and lipid nanoparticles for thedelivery of nucleic acids to immune cells (e.g., macrophages, monocytes, or dendritic cells),and methods of making and using, such lipids and targeted lipid nanoparticles.BACKGROUND In recent years, a number of therapeutic modalities have been developed thatinvolve the delivery of one or more nucleic acids to a subject. Treatment modalities include,for example, gene therapies where a gene of interest in the form of deoxyribose nucleic acid(DNA) is introduced into a cell, which is then expressed to produce a gene product, forexample, protein, for treating a disorder caused by or associated with a deficiency or absenceof the gene product. In this approach, the gene is transcribed into a messenger ribonucleic acid(mRNA), whereupon the mRNA is translated to produce the gene product. In another approach,mRNA rather than a gene of interest can be delivered to the cell. The resulting expressionproduct can ameliorate the deficiency or absence of a particular protein in a subject (forexample, a protein deficiency occurring in certain forms of cystic fibrosis or lysosomal storagedisorders), or can be used to modulate a cellular function, for example, reprogramming immunecells to initiate or otherwise modulate an immune response in the subject (for example, as atherapeutic agent for treating cancer or as a prophylactic vaccine for preventing or minimizingthe risk or severity of a microbial or viral infection). However, the delivery of mRNA to a cell for translation within the cell has been challenging for a variety of factors, such as nuclease degradation of the mRNA prior to entry into the cell and then after introduction into the cell but prior to translation. RNA may be delivered to a subject using different delivery vehicles, for example,based on cationic polymers or lipids which, together with the RNA, form nanoparticles. Thenanoparticles are intended to protect the RNA from degradation, enable delivery of the RNAto the target site and facilitate cellular uptake and processing by the target cells. For deliveryefficacy, in addition to the molecular composition, parameters like particle size, charge, or grafting with molecular moieties, such as polyethylene glycol (PEG) or ligands, play a role. Grafting with PEG is believed to reduce serum interactions, increase serum stability and increase time in circulation, which can be helpful for certain targeting approaches. Compared with DNA delivery technologies used in certain gene therapies, mRNA-based gene treatment has a number of superior features, for example, ease in manipulation, rapid and transient expression, and adaptive convertibility without mutagenesis. However, the delivery of therapeutic RNAs to cells is difficult in view of the relativeinstability and low cell permeability of RNAs. Thus, there exists a need to develop methodsand compositions to facilitate the delivery of RNAs such as mRNA to cells. SUMMARY The invention provides ionizable cationic lipids, lipid-immune cell targeting group conjugates, and lipid nanoparticle compositions comprising such ionizable cationic lipids and / or lipid-immune cell (e.g., macrophage, monocytes, or dendritic cells) targeting groupconjugates, medical kits containing such lipids and / or conjugates, and methods of making andusing, such lipids and conjugates.The lipid nanoparticle compositions provided herein may further comprise a nucleicacid, such as an RNA, e.g., a messenger RNA or mRNA. The lipid nanoparticle compositionsmay be used for mRNA delivery to a cell (e.g., an immune cell, such as macrophage,monocytes, or dendritic cells) in a subject. Messenger RNA based gene therapy requiresefficient delivery of mRNA to circulating cells (e.g., immune cells, such as macrophage,monocytes, or dendritic cells) in plasma or to cells in a given tissue. The main challengesassociated with efficient mRNA delivery to attain robust levels of protein expression include: (a) ability to protect the mRNA payload against prevalent serum nucleases upon administration to a subject; (b) the ability to specifically target mRNA delivery to, and thereby maximize protein expression in the target cell (e.g., macrophage, monocytes, or dendritic cells) population; and (c) the ability to maximally deliver the mRNA payload to the cytosoliccompartment of cells (e.g., macrophage, monocytes, or dendritic cells) for translation intoproteins within the cytoplasm. The invention provides ionizable cationic lipids for producing lipid nanoparticlecompositions that facilitate the delivery of a payload (e.g., a nucleic acid, such as a DNA orRNA, such as an mRNA) disposed therein to cells, for example, mammalian cells, for examplehuman cells, for example, immune cells. The lipids are designed to enable intracellular deliveryof a nucleic acid, e.g., mRNA, to the cytosolic compartment of a target cell type and rapidlydegrade into non-toxic components. These complex functionalities are achieved by theinterplay between chemistry and geometry of the ionizable lipid head group, the hydrophobic“acyl-tail” groups and the linker connecting the head group and the acyl tail groups in theionizable cationic lipids. In one aspect, the present invention provides a compound represented by Formula(I): A compound of Formula (I):(I), or a salt thereof. In some embodiments, R1and R2are each C1-3 alkylene. In some embodiments. R3is C1-3 alkylene or a bond. In some embodiments, R1Aand R2Aare each a bond or C1-10 alkylene. In some embodiments, R3Ais a bond or C1-3 alkylene. In some embodiments, R1A1, R2A1, R3A1, and R3A2are each H. In some embodiments, R1A2and R2A2are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2. In some embodiments, R1A3and R2A3 are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2. In some embodiments, R3A3is - C(O)ORa1. In some embodiments, Ra1and Ra2are each independently C1-20 alkyl. In some embodiments, R3Bis . In some embodiments, R3B1is C4-6 alkylene. In some embodiments, R3B2and R3B3are each C1-3 alkyl. In some embodiments, R1 and R2 are each methylene. In some embodiments, R1Aand R2Aare each a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, - (CH2)8-, -(CH2)9-, or -(CH2)10-. In some embodiments, R1Aand R2Aare each a bond, -(CH2)2-, -(CH2)5-, -(CH2)7-, or -(CH2)9-. In some embodiments, R3Ais a bond, -CH2-, or -(CH2)2-. In some embodiments, R3Ais -CH2-. In some embodiments, R1A2and R2A2are each -OC(O)(C1-15 alkyl), -C(O)O(C1-15 alkyl), -OC(O)CH(C1-10 alkyl)(C1-10 alkyl), -C(O)OCH(C1-10 alkyl)(C1-10 alkyl), - (CH2)C(O)O(C1-10 alkyl), or -(CH2)OC(O)(C1-10 alkyl). In some embodiments, R1A2and R2A2are each -OC(O)(C1-10 alkyl), -C(O)O(C1-10 alkyl), -OC(O)CH(C6 alkyl)(C8 alkyl), - C(O)OCH(C2-3 alkyl)(C5-6 alkyl), or -(CH2)C(O)O(C10 alkyl). In some embodiments, R1A2and R2A2are each , , , , , , , , or . In some embodiments, R1A3 and R2A3 are each H, -OC(O)(C1-15 alkyl), or -C(O)O(C1-15 alkyl). In some embodiments, R1A3and R2A3are each H, -OC(O)(C5-10 alkyl), - C(O)O(C6-10 alkyl), or -(CH2)C(O)O(C10 alkyl). In some embodiments, R1A3and R2A3are each H, , , , , , , , , , , or . In some embodiments, R3A3is -C(O)OCH(C1-5 alkyl)(C1-10 alkyl). In some embodiments, R3A3is -C(O)OCH(C3 alkyl)(C6 alkyl). In some embodiments, R3A3is .In some embodiments, R3B1 is -(CH2)4-. In some embodiments, R3B2and R3B3are each methyl. In some embodiments, is , , or . In some embodiments, the compound is selected from Table 1. In some embodiments, the compound is lipid 40, lipid 41, lipid 42, lipid 43, lipid 46, or lipid 52. Also provided herein is a lipid nanoparticle (LNP). In some embodiments, the LNP comprises a lipid blend for targeted delivery of a nucleic acid into an immune cell. In someembodiemnts, the lipid blend comprises a lipid-immune cell targeting group conjugatecomprising the compound of Formula (II): [Lipid] – [optional linker] – [immune cell targetinggroup]. In some embodiments, the lipid blend comprises an ionizable cationic lipid such as anyof the lipids described herein. In some embodiments, the lipid blend comprises a nucleic acid,wherein the nucleic acid is encapsulated in the LNP. In some embodiments, the ionizablecationic lipid is selected from the lipids described herein.In some embodiments, the immune cell targeting group comprises an antibody that binds a macrophage antigen, a monocyte antigen, and / or a dendritic antigen. In some embodiments, the macrophage comprises an M1 macrophage, an M2 macrophage, or both.In some embodiments, the macrophage comprises an M2a macrophage, an M2b macrophage, an M2c macrophage, or any combination thereof. In some embodiments, the macrophage antigen comprises CDIIB, CD68, CD80, CD86, TRL-2, TRL-4, iNOS, MHC-II, CD163, CD206, CD209, FIZZ1, or Ym1 / 2, or any combination thereof. In some embodiments, the macrophage antigen comprises CD206. In some embodiments, the immune cell targeting group is covalently coupled to alipid in the lipid blend via a polyethylene glycol (PEG) containing linker. In someembodiments, the lipid covalently coupled to the immune cell targeting group via a PEGcontaining linker is distearoylglycerol (DSG), distearoyl-phosphatidylethanolamine (DSPE), dimyrstoyl-phosphatidylethanolamine (DMPE), distearoyl-glycero-phosphoglycerol (DSPG), dimyristoyl-glycerol (DMG), dipalmitoyl-phosphatidylethanolamine (DPPE), dipalmitoyl-glycerol (DPG), or ceramide. In some embodiments, the PEG is PEG 2000 or PEG 3400. Insome embodiments, the lipid-immune cell targeting group conjugate is present in the lipid blend in a range of 0.001 to 0.5 mole percent (e.g., 0.002-0.2 mole percent). In some embodiments, the lipid blend further comprises one or more of a structural lipid (e.g., a sterol), a neutral phospholipid, and a free PEG-lipid. In some embodiments, the ionizable cationic lipid is present in the lipid blend in arange of 30-70 (e.g., 40-60) mole percent. In some embodiments, the sterol is present in thelipid blend in a range of 20-70 (e.g., 30-50) mole percent. In some embodiments, the sterol ischolesterol. In some embodiments, the neutral phospholipid is selected from the groupconsisting of phosphatidylcholine, phosphatidylethanolamine, distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and sphingomyelin. In some embodiments, the neutral phospholipidis present in the lipid blend in a range of 5-15 mole percent.In some embodiments, the free PEG-lipid is selected from the group consisting ofPEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, and PEG-modifieddialkylglycerols. For example, a PEG lipid may be PEG- dioleoylgylcerol (PEG-DOG), PEG-dimyristoyl-glycerol (PEG-DMG), PEG-dipalmitoyl-glycerol (PEG-DPG), PEG-dilinoleoyl- glycero-phosphatidyl ethanolamine (PEG-DLPE), PEG-dimyrstoyl-phosphatidylethanolamine(PEG-DMPE), PEG-dipalmitoyl- phosphatidylethanolamine (PEG-DPPE), PEG-distearoylglycerol (PEG-DSG), PEG-diacylglycerol (PEG-DAG, e.g., PEG-DMG, PEG-DPG, and PEG-DSG), PEG-ceramide, PEG-distearoyl-glycero-phosphoglycerol (PEG-DSPG), PEG-dioleoyl-glycero-phosphoethanolamine (PEG-DOPE), 2-[(polyethylene glycol)-2000]- N,N-ditetradecylacetamide, or a PEG-distearoyl-phosphatidylethanolamine (PEG-DSPE)lipid. In some embodiments, the free PEG-lipid comprises a diacylphosphatidylethanolaminecomprising Dipalmitoyl (C16) chain or Distearoyl (C18) chain, and optionally the free PEG-lipid comprises PEG-DPG and PEG-DMG. In some embodiments, the free PEG-lipid is presentin the lipid blend in a range of 1-4 mole percent. In some embodiments, the free PEG-lipidcomprises the same or a different lipid as the lipid in the lipid-immune cell targeting group conjugate. In some embodiments, the LNP has a mean diameter in the range of 50-200 nm. Insome embodiments, the LNP has a mean diameter of about 100 nm. In some embodiments, theLNP has a polydispersity index in a range from 0.01 to 0.1. In some embodiments, the LNPhas a zeta potential of from about +0 mV to about +10 mV at pH 5.5, or from about -5 mV to about 0 mV at pH 7.4. In some embodiments, the nucleic acid is DNA or RNA. In some embodiments, theRNA is an mRNA. In some embodiments, the mRNA encodes a receptor, a growth factor, ahormone, a cytokine, an antibody, an antigen, an enzyme, or a vaccine. In some embodiments,the mRNA encodes a polypeptide capable of regulating immune response in the immune cell. In some embodiments, the mRNA encodes a polypeptide capable of reprogramming theimmune cell. In some embodiments, the mRNA encodes polypeptide capable ofreprogramming an M2 macrophage to an M1 macrophage.In some embodiments, the immune cell targeting group comprises an antibody, and the antibody is a Fab or an immunoglobulin single variable domain (e.g., a VHH, such as aNanobody®). Nanobody® is a registered trademark of Ablynx N.V. In some embodiments, theimmune cell targeting group comprises a Fab, F(ab’)2, Fab’-SH, Fv, or scFv fragment. In someembodiments, the immune cell targeting group comprises a Fab that is engineered to knock outthe natural interchain disulfide bond at the C-terminus. In some embodiments, the Fabcomprises a heavy chain fragment that comprises C233S substitution, and a light chainfragment that comprises C214S substitution, numbering according to Kabat. In someembodiments, the immune cell targeting group comprises a Fab that has a non-naturalinterchain disulfide bond (e.g., an engineered, buried interchain disulfide bond). In someembodiments, the Fab comprises F174C substitution in the heavy chain fragment, and S176Csubstitution in the light chain fragment, numbering according to Kabat. In some embodiments,the immune cell targeting group comprises a Fab that comprises a cysteine at the C-terminusof the heavy or light chain fragment. In some embodiments, the Fab further comprises one ormore amino acids between the heavy chain fragment of the Fab and the C-terminal cysteine. In some embodiments, the immune cell targeting group comprises animmunoglobulin single variable domain. In some embodiments, the immunoglobulin singlevariable domain comprises a cysteine at the C-terminus. In some embodiments, theimmunoglobulin single variable domain comprises a VHH domain and further comprises a spacer comprising one or more amino acids between the VHH domain and the C-terminalcysteine. In some embodiments, the immune cell targeting group comprises two or more VHHdomains. In some embodiments, the two or more VHH domains are linked by an amino acidlinker. In some embodiments, the immune cell targeting group comprises a first VHH domainlinked to an antibody CH1 domain and a second VHH domain linked to an antibody light chain constant domain, and wherein the antibody CH1 domain and the antibody light chain constantdomain are linked by one or more disulfide bonds. In some embodiments, the immune celltargeting group comprises a VHH domain linked to an antibody CH1 domain, and wherein theantibody CH1 domain is linked to an antibody light chain constant domain by one or moredisulfide bonds. In some embodiments, the CH1 domain comprises F174C and C233Ssubstitutions, and the light chain constant domain comprises S176C and C214S substitutions, numbering according to Kabat. In some embodiments, the LNP is for delivering a nucleic acid into an immune cell, and wherein the LNP binds a first macrophage antigen, and also binds a second macrophage antigen. In some embodiments, the LNP comprises two conjugates, wherein the first conjugate comprises an antibody that binds the first macrophage antigen, and the second conjugate comprises an antibody that binds the second macrophage antigen. In some embodiments, the LNP comprises one conjugate, and the conjugate comprises a bispecific antibody that binds both the first macrophage antigen and the second macrophage antigen. In some embodiments, the bispecific antibody is an immunoglobulin single variable domain or Fab-ScFv. In some embodiments, the LNP binds to a first antigen on the surface of the first type of immune cell, and also binds to a second antigen on the surface of the second type of immune cell. In some embodiments, the first type of immune cell is a first macrophage, and the second type of immune cell is a second macrophage, a T-cell, or an NK cell. In some embodiments, the LNP comprises two conjugates, and the first conjugate comprises a first antibody that binds to the first antigen of the first type of immune cell, and the second conjugate comprises a second antibody that binds to the second antigen of the second type of immune cell. In some embodiments, the LNP comprises one conjugate, and the conjugate comprises a bispecific antibody, and the bispecific antibody binds to both the first antigen on the first type of immune cell, and the second antigen on the second type of immune cells. In some embodiments, the bispecific antibody is an immunoglobulin single variable domain or a Fab-ScFv. In someembodiments, the LNP is for delivering a nucleic acid into an immune cell, and wherein theimmune cell targeting group comprises a single antibody that binds to CD206. In some embodiments, the LNP is for delivering a nucleic acid into both a macrophage and a T-cell or both a macrophage and an NK cell, wherein the immune cell targeting group binds to both (i) CD206 and (ii) one of CD3, CD7, CD8, and CD56. In one aspect, provided is an LNP comprising a lipid blend for targeted delivery ofa nucleic acid into a macrophage, the lipid blend comprising: a lipid-macrophage targetinggroup conjugate comprising the compound of Formula (II-m): [Lipid] – [optional linker] –[macrophage targeting group]; and a nucleic acid, wherein the nucleic acid is encapsulated inthe LNP. In some embodiments, the macrophage is an M2 macrophage. In someembodiments, the macrophage targeting group binds CD206. In some embodiments, thenucleic acid is mRNA, and the mRNA encodes polypeptide capable of reprogramming an M2macrophage to an M1 macrophage. In some embodiments, the LNP further comprises anionizable cationic lipid. In some embodiments, the ionizable cationic lipid is selected from thelipids described herein. In some aspect, provided is a method of targeting the delivery of a nucleic acid toan immune cell of a subject. In some embodiments, the method comprises contacting theimmune cell with the LNP described herein, wherein the LNP comprises the nucleic acid. In some aspect, provided is a method of expressing a polypeptide of interest in atargeted immune cell of a subject. In some embodiments, the method comprises contacting theimmune cell with the LNP described herein, wherein the LNP comprises a nucleic acid encoding the polypeptide. In some aspect, provided is a method of modulating cellular function of a targetimmune cell of a subject. In some embodiments, the method comprises administering to thesubject the LNP described herein, wherein the LNP comprises a nucleic acid modulates the cellular function of the immune cell. In some aspect, provided is a method of treating, ameliorating, or preventing a symptom of a disorder or disease in a subject in need thereof. In some embodiments, the methodcomprises administering to the subject an LNP described herein for delivering a nucleic acidinto an immune cell of the subject, wherein the LNP comprises the nucleic acid. In some embodiments, the disorder is an immune disorder, an inflammatory disorder, or cancer. In some embodiments, the nucleic acid encodes an antigen for use in a therapeutic or prophylactic vaccine for treating or preventing cancer. In some embodiments, the antibody is a human or humanized antibody. In some embodiments, the free PEG-lipid comprises a diacylphosphatidylethanolamines comprising dimyristoyl (C14) chain, Dipalmitoyl (C16) chain or Distearoyl (C18) chain. In some embodiments, the free PEG-lipid is present in the lipid blend in a range of 0.5-2.5 mole percent. In some embodiments, the RNA is an mRNA, tRNA, siRNA, gRNA, or microRNA. In some embodiments, the Fab comprises a heavy chain variable domain linked to an antibody CH1 domain and a light chain variable domain linked to an antibody light chain constant domain, wherein the CH1 domain and the light chain constant domain are linked by one or more interchain disulfide bonds, and wherein the immune cell targeting group further comprises a single chain variable fragment (scFv) linked to the C- terminus of the light chain constant domain by an amino acid linker. In some embodiments, no more than 5% non-immune cells are transfected by the LNP. In some embodiments, half-life of the nucleic acid delivered by the LNP or a polypeptide encoded by the nucleic acid delivered by the LNP is at least 10% longer than half-life of nucleic acid delivered by a reference LNP or a polypeptide encoded by the nucleic acid delivered by the reference LNP. In some embodiments, at least 10% immune cells are transfected by theLNP. In some embodiments, expression level of the nucleic acid delivered by the LNP is atleast 10% higher than expression level of nucleic acid delivered by a reference LNP. In some embodiments, the nucleic acid is DNA or RNA. In some embodiments, theRNA is an mRNA, tRNA, siRNA, gRNA (guide RNA), circRNA(circular RNA), ribozymes,decoy RNA, or microRNA. In some embodiments, the mRNA encodes a receptor, a growthfactor, a hormone, a cytokine, an antibody, an antigen, an enzyme, or a vaccine. In someembodiments, the mRNA encodes a polypeptide capable of regulating immune response in theimmune cell. In some embodiments, the mRNA encodes a polypeptide capable ofreprogramming the immune cell. In some embodiments, no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or10% of non-immune cells are transfected by the LNP. In some embodiments, no more than1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of undesired immune cells that are not meant to be the destination of the delivery are transfected by the LNP. The undesired immune cells may be immune cells not bound by the immune cell targeting group. The undesired immune cells may be immune cells other than macrophages, for instance wherein the undesired immune cells are immune cells other than M2a macrophages, M2b macrophages, and / or M2c macrophages. The undesired immune cells may be immune cells other than B cells. The undesired immune cells may be immune cells other than NK cells. The undesired immune cellsmay be immune cells other than T cells, for example CD4+ T cells and / or CD8+ T cells. Theundesired immune cells may be immune cells other than NK cells and T cells, for example NKcells and CD4+ T cells and / or CD8+ T cells. In some embodimens, the immune cells aremonocytes. In some embodiments, the immune cells are dentritic cells. In some embodiments, the half-life of the nucleic acid delivered by the LNP to the immune cell or a polypeptide encoded by the nucleic acid delivered by the LNP is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times,or longer than the half-life of nucleic acid delivered by a reference LNP to the immune cell ora polypeptide encoded by the nucleic acid delivered by the reference LNP. In some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more immune cells that are meant to be the destination of the delivery are transfectedby the LNP. Immune cells that are meant to be the destination of the delivery may be immunecells bound by the immune cell targeting group. Immune cells that are meant to be the destination of the delivery may be macrophages, for example M2a macrophages, M2bmacrophages, and / or M2c macrophages. Immune cells that are meant to be the destination ofthe delivery may be B cells. Immune cells that are meant to be the destination of the deliverymay be NK cells. Immune cells that are meant to be the destination of the delivery may be Tcells, for example CD4+ T cells and / or CD8+ T cells. Immune cells that are meant to be thedestination of the delivery may be NK cells and T cells, for example NK cells and CD4+ Tcells and / or CD8+ T cells. In some embodimens, the immune cells are monocytes. In someembodiments, the immune cells are dentritic cells. In some embodiments, expression level of the nucleic acid delivered by the LNP is at least 5%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, 1.5 time, 2 times, 3 times, 4 times, 5 times, 10 times, 15 times, 20 times or more higher than expression level of nucleic acid in the same immune cells delivered by a reference LNP. In some embodiments, the antibody is an immunoglobulin single variable (ISV)domain, and the ISV domain is a VHH. In some embodiments, the free PEG lipid comprises aPEG having a molecular weight of at least 2000 daltons. In some embodiments, the PEG has a molecular weight of about 3000 to 5000 daltons. In some embodiments, the antibody is a Fab. In some embodiments, the Fab binds CD206, and the free PEG lipid in the LNP comprises a PEG having a molecular weight of about 2000 daltons. In some embodiments, the Fab is an anti-CD206 antibody, and the free PEG lipid in the LNP comprises a PEG having a molecular weight of about 3000 to 3500 daltons. Various aspects and embodiments of the invention are described in further detail below. BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1A, FIG. 1B, and FIG. 1C depict the structure (FIG. 1A), proton NMRspectrum (FIG. 1B), and LC-CAD chromatogram (FIG. 1C) of purified lipid 40.FIG. 2A, FIG. 2B, and FIG. 2C depict the structure (FIG. 2A), proton NMRspectrum (FIG. 2B), and LC-CAD chromatogram (FIG. 2C) of purified lipid 41.FIG. 3A, FIG. 3B, and FIG. 3C depict the structure (FIG. 3A), proton NMRspectrum (FIG. 3B), and LC-CAD chromatogram (FIG. 3C) of purified lipid 42.FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D depict the structure (FIG. 4A), protonNMR spectrum (FIG. 4B), HPLC-ELSD chromatogram (FIG. 4C), and LC-CADchromatogram (FIG. 4D) of purified lipid 43. FIG. 5A, FIG. 5B, and FIG. 5C depict the structure (FIG. 5A), proton NMRspectrum (FIG. 5B), and LC-CAD chromatogram (FIG. 5C) of purified lipid 46.FIG. 6A, FIG. 6B, FIG. 6C, and FIG. 6D depict the structure (FIG. 6A), protonNMR spectrum (FIG. 6B), HPLC-ELSD chromatogram (FIG. 6C), and LC-CADchromatogram (FIG. 6D) of purified lipid 52. FIG. 7A, FIG. 7B, FIG. 7C, and FIG. 7D depict physiochemical characterizationresults of parent LNPs comprising lipids 15, 26, 25A, 27, 28, 40, or ALC-0315. FIG.7A depictshydrodynamic diameter (DLS) pre (“Parent LNPs”) and post (“FT LNPs”) 1x freeze-thawcycle. FIG. 7B depicts polydispersity index (DLS) pre (“Parent LNPs”) and post (“FT LNPs”)1x freeze-thaw (FT) cycle. FIG. 7C depicts charge (zeta potential) of LNPs at pH 5.5 or pH7.4. FIG. 7D depicts total and dye accessible RNA (Ribogreen Assay) of LNPs. FIG. 8A and FIG. 8B depict physiochemical characterization of parent (“Parent LNPs”) and aCD206 targeted LNPs (“Targeted LNPs”)), where LNPs comprise lipids 15, 26, 25A, 27, 28, 40, or ALC-0315. FIG. 8A depicts hydrodynamic diameter (DLS). FIG. 8B depicts polydispersity index (DLS). FIG.9A, FIG.9B, FIG.9C, and FIG.9D depict physiochemical characterization ofparent LNPs (DLS), comprising lipids 15A, 17A, 18A, 19A, 21A, 20A, 46, or 40. FIG. 9Adepicts hydrodynamic diameter (DLS) of pre (“Zav”) and post (“FT_Zav”) 1x freeze-thawcycle. FIG. 9B. depicts polydispersity index (DLS) pre (“PDI_4C”) and post (“PDI_FT”) 1xfreeze-thaw cycle. FIG. 9C depicts charge (zeta potential) of LNPs, at pH 5.5 or pH 7.4. FIG.9D depicts total and dye accessible RNA (Ribogreen Assay) of LNPs.FIG. 10A, FIG. 10B, and FIG. 10C depict results of LNPs binding and GFP proteinexpression using LNPs comprising comparator lipid ALC-0315; αCD206 targeted LNPscomprising lipid 15, 15A, 26, 40, 27, or 28; parent (non-targeted) LNPs comprising lipid 15;and buffer (PBS) control. FIG. 10A depicts %GFP+ Macrophages. FIG. 10B depicts % DiI+Macrophages. FIG. 10C depicts mean fluorescence intensity (MFI) of GFP+ Macrophages. FIG. 11A, FIG.11B, FIG.11C, and FIG. 11D depict results of Parent and αCD206 targeted LNPs binding and GFP protein expression using LNPs comprising lipid 15, 40, 17A, 18A, 19A, 21A, 20A, or 46, and PBS buffer control (“No LNP”) in macrophages derived from Human PBMC Donor 108. FIG.11A depicts %GFP+ Macrophages. FIG.11B depicts % DiI+ Macrophages. FIG. 11C depicts mean fluorescence intensity (MFI) of GFP+ Macrophages. FIG. 11D depicts mean fluorescence intensity (MFI) of DiI+ Macrophages. FIG. 12A, FIG.12B, FIG.12C, and FIG. 12D depict results of Parent and αCD206 targeted LNPs binding and GFP protein expression using LNPs comprising lipid 15, 40, 17A, 18A, 19A, 21A, 20A, or 46, and PBS buffer control (“No LNP”) in macrophages derived from Human PBMC Donor 282. FIG.12A depicts %GFP+ Macrophages. FIG.12B depicts % DiI+ Macrophages. FIG. 12C depicts mean fluorescence intensity (MFI) of GFP+ Macrophages. FIG. 12D depicts mean fluorescence intensity (MFI) of DiI+ Macrophages. FIG. 13A, FIG. 13B, FIG. 13C, and FIG. 13D depict the physicochemicalcharacterization of mCherry-mRNA Lipid 40 LNPs and 1.5 mole% and 3.5 mole% DSG-PEGlipid. FIG. 13A depicts the hydrodynamic diameter (DLS) of parent LNPs pre- and post- 1Xfreeze-thaw cycle. FIG. 13B depicts the polydispersity Index (DLS) of parent LNPs pre- andpost- 1X freeze-thaw cycle. FIG. 13C depicts the charge (Zeta Potential) of parent LNPs at pH5.5 and pH 7.4. FIG.13D depicts the total and dye accessible RNA (Ribogreen Assay) of parent LNPs. FIG. 14A, FIG. 14B, FIG. 14C, and FIG. 14D depict the physicochemicalcharacterization of mCherry-mRNA Lipid 40 LNPs and 3.5 mole% DPG-PEG and DSG-PEGlipids. FIG. 14A depicts the LNP diameter pre- and post- 1X freeze-thaw cycle. FIG. 14Bdepicts the polydispersity Index (DLS) of LNPs pre- and post- 1X freeze-thaw cycle. FIG. 14Cdepicts the charge (Zeta Potential) of LNPs at pH 5.5 and pH 7.4. FIG. 14D depicts the totaland dye accessible RNA (Ribogreen Assay) of LNPs. FIG. 15A, FIG. 15B, FIG. 15C, and FIG. 15D depict mCherry expression and LNPuptake (DiI label) in M2 Macrophages using mCherry-mRNA LNPs based on Lipid 40 and 1.5mole % and 3.5 mole % DSG-PEG lipid. LNP and buffer (PBS) control. FIG. 15A depicts%mCherry+ Macrophages. FIG. 15B depicts Mean Fluorescence Intensity (MFI) of mCherry+Macrophages. FIG. 15C depicts %DiI+ Macrophages. FIG. 15D depicts Mean FluorescenceIntensity (MFI) of DiI+ Macrophages.FIG. 16A, FIG. 16B, FIG. 16C, and FIG. 16D depict mCherry expression and LNPuptake (DiI label) in M2 Macrophages using mCherry / DiI-mRNA LNPs based on Lipid 40 and3.5 mole % DSG-PEG or 3.5 mole % DPG-PEG lipid. LNP and buffer (PBS) control. FIG.16A depicts %mCherry+ Macrophages. FIG. 16B depicts Mean Fluorescence Intensity (MFI)of mCherry+ Macrophages. FIG. 16C depicts %DiI+ Macrophages. FIG. 16D depicts MeanFluorescence Intensity (MFI) of DiI+ Macrophages.FIG. 17 depicts hemagglutinin (HA) expression 20 hours post HA-mRNA LNPs based on Lipid 40, 46, ALC-0315, CL-1191 and SM-102 Ionizable Lipids dosed in vitro (1ug / 1E6 cells) to human dendritic cells. HA expression in human dendritic cells, quantified as MeanFluorescence Intensity (MFI) of Alexa-647 conjugated secondary Ab, 20 hours post-HA-mRNA LNP dose of 1 ug / 1E6 cells: Relative Expression of LNPs based on Lipid 40, Lipid46, and ALC-0315, SM-102, and benchmark control (CL-1191) ionizable lipids. FIG. 18 depicts hemagglutinin (HA) expression 20 hours post HA-mRNA LNPsbased on Lipid 40, 46, and CL-1191 Ionizable Lipids dosed in vitro (1ug / 1E6 cells) to human Skeletal Muscle Cells. HA expression in human Skeletal Muscle cells, quantified as Mean Fluorescence Intensity (MFI) of Alexa-647 conjugated secondary Ab, 20 hours post-HA-mRNA LNP dose of 1 ug / 1E6 cells: Relative Expression of LNPs based on Lipid 40, Lipid46, and benchmark control (CL-1191) ionizable lipids. FIG. 19A, FIG. 19B, and FIG. 19C depict results of C57BL / 6 mice engrafted with MC-38 tumor (n = 4) dosed (1.5 mg / kg) with Lipid 40 LNPs formulated with 1.5 or 3.5 mole% DSG-PEG. FIG. 19A depicts lipid concentration (ng / g) in blood 10 minutes, 6 hour and 24hours post dose. FIG. 19B depicts percent of injected lipid dose in blood 10 minutes, 6 hourand 24 hours post dose. FIG. 19C depicts lipid concentration in blood, liver, spleen, lung andtumor tissue 24 hours post dose. FIG. 20A, FIG. 20B, and FIG. 20C depict results of C57BL / 6 mice engrafted with MC-38 tumor (n = 4) dosed (1.0 mg / kg) with Lipid 40 LNPs formulated with 3.5 mole % DPG-PEG or DSG-PEG. FIG. 20A depicts lipid concentration (ng / g) in blood 10 minutes, 6 hourand 24 hour post dose. FIG. 20B depicts percent of injected lipid dose in blood 10 minutes, 6hour and 24 hour post dose. FIG. 20C depicts lipid concentration in blood, liver, spleen, lungand tumor tissue 24 hours post dose. FIG. 21A and FIG. 21B depict results of C57BL / 6 mice engrafted with MC-38 tumor (n = 4) dosed (1.5 mg / kg) with Lipid 40 mCherry-LNPs with 1.5 or 3.5 mole % DSG- PEG. FIG.21A depicts mCherry expression monitored (FACS) in tumor, liver, spleen and lungtissues 24 hour post dose in macrophages. FIG. 21B depicts mCherry expression monitored(FACS) in tumor, liver, spleen and lung tissues 24 hour post dose in monocytes. FIG. 22A and FIG. 22B depict results of C57BL / 6 mice engrafted with MC-38 tumor (n = 4) dosed (1.5 mg / kg) with Lipid 40 mCherry-LNPs with 1.5 mole % DSG-PEG. FIG. 22A depicts mCherry expression monitored (FACS) in relevant cell types 24 hours post dose in liver. FIG. 22B depicts mCherry expression monitored (FACS) in relevant cell types24 hours post dose in spleen.FIG. 23A, FIG. 23B, FIG. 23C, FIG. 23D, FIG. 23E, and FIG. 23F depict results ofC57BL / 6 mice engrafted with MC-38 tumor (n = 4) dosed (1.0 mg / kg) with Lipid 40 mCherry-LNPs with 3.5 mole % DSG-PEG and 3.5 mole % DPG-PEG. FIG. 23A depicts mCherryexpression monitored (FACS) 24 hours post dose in liver macrophages. FIG. 23B depictsmCherry expression monitored (FACS) 24 hours post dose in liver monocytes. FIG. 23Cdepicts mCherry expression monitored (FACS) 24 hours post dose in spleen macrophages.FIG. 23D depicts mCherry expression monitored (FACS) 24 hours post dose in spleenmonocytes. FIG. 23E depicts mCherry expression monitored (FACS) 24 hours post dose inlung macrophages. FIG. 23F depicts mCherry expression monitored (FACS) 24 hours postdose in lung monocytes. DETAILED DESCRIPTION The invention provides ionizable cationic lipids, lipid-immune cell targeting group conjugates, and lipid nanoparticle compositions comprising such ionizable cationic lipids and / or lipid-immune cell (e.g., macrophage, monocytes, or dendritic cells) targeting groupconjugates, medical kits containing such lipids and / or conjugates, and methods of making andusing, such lipids and conjugates.The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, cell biology, and biochemistry. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E.Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.I. DEFINITIONSTo facilitate an understanding of the present invention, a number of terms and phrases are defined below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which thisinvention belongs. The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae set forth herein should beconstrued according to the standard rules of chemical valency known in the chemical arts. Inaddition, when a chemical group is a diradical, for example, it is understood a that the chemical groups can be bonded to their adjacent atoms in the remainder of the structure in one or bothorientations, for example, -OC(O)- is interchangeable with -C(O)O- or -OC(S)- isinterchangeable with -C(S)O-. The terms “a” and “an” as used herein mean “one or more” and include the pluralunless the context is inappropriate. In some embodiments, “one or more” is 1 or 2. In someembodiments, “one or more” is 1, 2, or 3. In some embodiments, “one or more” is 1, 2, 3, or 4. In some embodiments, “one or more” is 1, 2, 3, 4, or 5. In some embodiments, “one or more” is 1, 2, 3, 4, 5, or more. The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referredto herein as C1-C12alkyl, C1-C10alkyl, or C1-C6alkyl, respectively. In some embodiments, alkylis optionaly substituted. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. The term “alkylene” refers to a diradical of an alkyl group. In some embodiments,alkylene is optionaly substituted. An exemplary alkylene group is –CH2CH2-. The term “haloalkyl” refers to an alkyl group that is substituted with at least onehalogen. For example, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.“Alkenyl” refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en- 1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). “Alkynyl” refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least onecarbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl(e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3- yn-1-yl). The term “oxo” is art-recognized and refers to a “=O” substituent. For example, acyclopentane substituted with an oxo group is cyclopentanone. The term “morpholinyl” refers to a substituent having the structure of: , which is optionally substituted. The term “piperidinyl” refers to a substituent having a structure of: , which is optionally substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted” group may have a suitablesubstituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at each position. Combinations ofsubstituents envisioned under this invention are preferably those that result in the formation ofstable or chemically feasible compounds. In some embodiments, “optionally substituted” isequivalent to “unsubstituted or substituted.” In some embodiments, “optionally substituted” indicates that the designated atom or group is optionally substituted with one or moresubstituents independently selected from optional substituents provided herein. In someembodiments, optional substituent may be selected from the group consisting of: C1-6alkyl,cyano, halogen, -O-C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3- to 7-membered heterocyclyl, 5-to 6-membered heteroaryl, and phenyl. In some embodiments, optional substituent is alkyl,cyano, halogen, halo, azide, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(O)alkyl, -CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, or heteroaryl. In some embodiments, optional substituent is -ORs1, -NRs2Rs3, -C(O)Rs4, - C(O)ORs5, C(O)NRs6Rs7, -OC(O)Rs8, -OC(O)ORs9, -OC(O)NRs10R11, -NRs12C(O)Rs13, or - NRs14C(O)ORs15, wherein Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11, Rs12, Rs13, Rs14,and Rs15 are each independently H, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, 5- to 10-memberedheteroaryl, or 3- to 10-membered heterocyclyl, each of which is optionally substituted.The term “haloalkyl” refers to an alkyl group that is substituted with at least onehalogen. For example, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, bridged cyclic (e.g., adamantyl), or spirocyclic hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6carbons, referred to herein, e.g., as "C4-8cycloalkyl," derived from a cycloalkane. In someembodiments, cycloalkyl is optionally substituted. Exemplary cycloalkyl groups include, butare not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unlessspecified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate,phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certainembodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted. The terms “heterocyclyl” and “heterocyclic group” are art-recognized and refer tosaturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3-to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen,oxygen, and sulfur. In some embodiments, heterocyclyl is optionally substituted. The numberof ring atoms in the heterocyclyl group can be specified using Cx-Cx nomenclature where x isan integer specifying the number of ring atoms. For example, a C3-C7heterocyclyl group refersto a saturated or partially unsaturated 3- to 7-membered ring structure containing one to fourheteroatoms, such as nitrogen, oxygen, and sulfur. The designation “C3-C7” indicates that theheterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms thatoccupy a ring atom position. One example of a C3heterocyclyl is aziridinyl. Heterocycles maybe, for example, mono-, bi-, or other multi-cyclic ring systems (e.g., fused, spiro, bridgedbicyclic). A heterocycle may be fused to one or more aryl, partially unsaturated, or saturatedrings. Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl, thiopyranyl, xanthenyl, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, andthe like. Unless specified otherwise, the heterocyclic ring is optionally substituted at one ormore positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, oxo, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, the heterocyclyl group is not substituted, i.e., it is unsubstituted. The term “aryl” is art-recognized and refers to a carbocyclic aromatic group. Insome embodiments, aryl is optionally substituted. Representative aryl groups include phenyl,naphthyl, anthracenyl, and the like. The term “aryl” includes polycyclic ring systems havingtwo or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic and, e.g., theother ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and / or aryls. Unless specifiedotherwise, the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(O)alkyl, CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroarylmoieties, -CF3, -CN, or the like. In certain embodiments, the aromatic ring is substituted at oneor more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments,the aromatic ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the arylgroup is a 6- to 10-membered ring structure. In some embodiments, the aryl group is a C6-C14aryl. The term “heteroaryl” is art-recognized and refers to aromatic groups that includeat least one ring heteroatom. In some embodiments, heteroaryl is optionally substituted. Incertain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.Unless specified otherwise, the heteroaryl ring may be substituted at one or more ring positionswith, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, C(O)alkyl, -CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, -CF3, -CN, or the like. The term “heteroaryl” alsoincludes polycyclic ring systems having two or more rings in which two or more carbons arecommon to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls,and / or aryls. In certain embodiments, the heteroaryl ring is substituted at one or more ringpositions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, theheteroaryl ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the heteroarylgroup is a 5- to 10-membered ring structure, alternatively a 5- to 6-membered ring structure,whose ring structure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen, and sulfur. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety represented by the general formula –N(R10)(R11), wherein R10and R11each independently represent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl, or (CH2)m-R12; or R10and R11, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R12represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero oran integer in the range of 1 to 8. In certain embodiments, R10 and R11 each independentlyrepresent hydrogen, alkyl, alkenyl, or -(CH2)m-R12. The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, asdefined above, having an oxygen radical attached thereto. In some embodiments, alkoxyl isoptionally substituted. Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen.Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles analkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, O-alkynyl, -O-(CH2)m-R12, where m and R12 are described above. The term “haloalkoxyl” refers to an alkoxyl groupthat is substituted with at least one halogen. For example, -O-CH2F, -O-CHF2, -O-CF3, and thelike. In certain embodiments, the haloalkoxyl is an alkoxyl group that is substituted with atleast one fluoro group. In certain embodiments, the haloalkoxyl is an alkoxyl group that issubstituted with from 1-6, 1-5, 1-4, 2-4, or 3 fluoro groups. The symbol “ ” indicates a point of attachment.The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers ordiastereomers. The term “stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by the symbols “R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom. Thepresent invention encompasses various stereoisomers of these compounds and mixturesthereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers ordiastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognizethat a structure may denote a chiral center implicitly. It is understood that graphical depictionsof chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise. Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric orstereogenic centers, or by preparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolution are exemplified by (1)attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well- known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizingthe compound in a chiral solvent. Further, enantiomers can be separated using supercriticalfluid chromatographic (SFC) techniques described in the literature. Still further, stereoisomerscan be obtained from stereomerically-pure intermediates, reagents, and catalysts by well- known asymmetric synthetic methods. Geometric isomers can also exist in the compounds of the present invention. Thesymbol “ ” denotes a bond that may be a single, double or triple bond as described herein.The present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond orarrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbondouble bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and“E” are used in accordance with IUPAC standards. Unless otherwise specified, structuresdepicting double bonds encompass both the “E” and “Z” isomers.Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and“trans” represents substituents on opposite sides of the double bond. The arrangement ofsubstituents around a carbocyclic ring are designated as “cis” or “trans.” The term “cis”represents substituents on the same side of the plane of the ring and the term “trans” representssubstituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.” The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usuallyfound in nature. Examples of isotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e., 3H) andcarbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may affordcertain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in, e.g., the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. As used herein, the terms “subject” and “patient” refer to organisms to be treatedby the methods of the present invention. Such organisms are preferably mammals (e.g.,murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans. As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable fordiagnostic or therapeutic use in vivo or ex vivo.As used herein, the term “pharmaceutically acceptable excipient” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wettingagents. The compositions also can include stabilizers and preservatives. For examples ofcarriers, stabilizers and adjuvants, see Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro; Lippincott, Williams & Wilkins, Baltimore, MD, 2006. As is known to those of skill in the art, “salts” of the compounds of the presentinvention may be derived from inorganic or organic acids and bases. Examples of acids include,but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselvespharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4 alkyl, and the like. Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and thelike. Other examples of salts include anions of the compounds of the present inventioncompounded with a suitable cation such as Na+, NH4+, and NW4+(wherein W is a C1-4 alkyl group), and the like. Abbreviations as used herein include diisopropylethylamine (DIPEA); 4- dimethylaminopyridine (DMAP); tetrabutylammonium iodide (TBAI); 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC); benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP), 9-Fluorenylmethoxycarbonyl (Fmoc), tetrabutyldimethylsilylchloride (TBDMSCl), hydrogen fluoride (HF), phenyl (Ph), bis(trimethylsilyl)amine (HMDS),dimethylformamide (DMF); methylene chloride (DCM); tetrahydrofuran (THF); high-performance liquid chromatography (HPLC); mass spectrometry (MS), evaporative lightscattering detector (ELSD), electrospray (ES)); nuclear magnetic resonance spectroscopy (NMR). As used herein, the term “effective amount” refers to the amount of a compound(e.g., a nucleic acid, e.g., an mRNA) sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations, applications or dosagesand is not intended to be limited to a particular formulation or administration route. The termeffective amount can be considered to include therapeutically and / or prophylactically effective amounts of a compound. The phrase "therapeutically effective amount" as used herein means that amount ofa compound (e.g., a nucleic acid, e.g., an mRNA), material, or composition comprising acompound (e.g., a nucleic acid, e.g., an mRNA) which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in a mammal, for example, a human, or a subject (e.g., a human subject) at a reasonable benefit / risk ratio applicable to any medical treatment. The phrase "prophylactically effective amount" as used herein means that amountof a compound (e.g., a nucleic acid, e.g., an mRNA), material, or composition comprising acompound (e.g., a nucleic acid, e.g., an mRNA) which is effective for producing some desiredprophylactic effect in at least a sub-population of cells in a mammal, for example, a human, ora subject (e.g., a human subject) by reducing, minimizing or eliminating the risk of developinga condition or the reducing or minimizing severity of a condition at a reasonable benefit / risk ratio applicable to any medical treatment. As used herein, the terms “treat,” “treating,” and “treatment” include any effect,e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in theimprovement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components. Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spiritand scope of the present invention, whether explicit or implicit herein. For example, wherereference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the presentinvention, unless otherwise understood from the context. In other words, within thisapplication, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the presentteachings and invention(s). For example, it will be appreciated that all features described anddepicted herein can be applicable to all aspects of the invention(s) described and depicted herein. It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more ofthe recited objects unless otherwise understood from the context and use. The expression“and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context. The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically statedotherwise. As used herein, the term “about” refers to a ±10% variation from the nominal valueunless otherwise indicated or inferred. As used herein, unless otherwise indicated, the term “antibody” means any antigen- binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen. It is understood the term encompasses an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as an Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or an antigen-binding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including an intact antibody, antigen-binding fragment, or Fc fragmentthat has been modified or engineered. Examples of antigen-binding fragments include Fab,Fab’, (Fab’)2, Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. Examples ofantibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). The term alsoencompasses an immunoglobulin single variable domain(e.g., a VHH). The numbering of aminoacid residues in antibodies disclosed herein is according to Kabat, unless otherwise explicitly stated. As used here, an “antibody that binds to X” (i.e., X being a particular antigen), or“an anti-X antibody”, is an antibody that specifically recognizes the antigen X.As used herein, a “buried interchain disulfide bond” or an “interchain burieddisulfide bond” refers to a disulfide bond on a polypeptide which is not readily accessible to water soluble reducing agents, or is effectively “buried” in the hydrophobic regions of the polypeptide, such that it is unavailable to both reducing agents and for conjugation to otherhydrophilic PEGs. Buried interchain disulfide bonds are further described inWO2017096361A1, which is incorporated by reference in its entirety. As used herein, specificity of the targeted delivery by an LNP is defined by the ratiobetween % of a desired immune cell type that receives the delivered nucleic acid (e.g., on-target delivery), and % of an undesired immune cell type that is not meant to be the destinationof the delivery, but receives the delivered nucleic acid (e.g., off-target delivery). For example, the specificity is higher when more desired immune cells receive the delivered nucleic acid,while less undesired immune cells receive the delivered nucleic acid. Specificity of the targeteddelivery by an LNP can also be defined the ratio of amount of nucleic acid being delivered tothe desired immune cells (e.g., on-target delivery) and amount of nucleic acid being delivered to the undesired immune cells (e.g., off-target delivery). Specificity of the delivery can be determined using any suitable method. As a non-limiting example, expression level of the nucleic acid in the desired immune cell type can be measured and compared to that of a different immune cell type that is not meant to be the destination of the delivery. As used herein, in some embodiments, a reference LNP is an LNP that does not have the immune cell targeting group but is otherwise the same as the tested LNP. In someother embodiments, a reference LNP is an LNP that has a different ionizable cationic lipid butis otherwise the same as the tested LNP. In some embodiments, a reference LNP comprises D- Lin-MC3-DMA as the ionizable cationic lipid which is different from the ionizable cationic lipid in a tested LNP, but is otherwise the same as the tested LNP. As used herein, a humanized antibody is an antibody which is wholly or partially of non-human origin and whose protein sequence has been modified to replace certain amino acids, for instance that occur at the corresponding position(s) in the framework regions of the VH and VL domains in a sequence of antibody from a human being, to increase its similarity to antibodies produced naturally in humans, in order to avoid or minimize an immune response in humans. For example, using techniques of genetic engineering, the variable domains of a non-human antibodies of interest may be combined with the constant domains of human antibodies. The constant domains of a humanized antibody are most of the time human CH and CL domains. As used herein, the term “structural lipid” refers to sterols and also to lipids containing sterol moieties. The “percent identity” between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two amino acid sequences may be determined using the algorithmof E. Meyers and W. Miller (Comput. Appl. Biosci. 4: 11-17 (1988)) which has beenincorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch (Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www gcg com), using either a Blossum 62 matrix or a PAM250matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.It should be understood that the order of steps or order for performing certainactions is immaterial so long as the present invention remain operable. Moreover, two or moresteps or actions may be conducted simultaneously. At various places in the present specification, substituents are disclosed in groupsor in ranges. It is specifically intended that the description include each and every individualsubcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl”is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl. Byway of other examples, an integer in the range of 0 to 40 is specifically intended to individuallydisclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does notpose a limitation on the scope of the invention unless claimed. No language in the specificationshould be construed as indicating any non-claimed element as essential to the practice of the present invention. Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. As a general matter, compositions specifying a percentage are by weight unlessotherwise specified. Further, if a variable is not accompanied by a definition, then the previousdefinition of the variable controls. Immunoglobulin single variable domain In some embodiments, the immune cell targeting group of the LNPs as described herein comprise an immunoglobulin single variable domain, such as a VHH. The term “immunoglobulin single variable domain” (ISV), interchangeably used with “single variable domain,” defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. This sets immunoglobulin single variable domains apart from “conventional” immunoglobulins (e.g., monoclonal antibodies) or their fragments (such as Fab, Fab’, F(ab’)2, scFv, di-scFv), wherein twoimmunoglobulin domains, in particular two variable domains, interact to form an antigenbinding site. Typically, in conventional immunoglobulins, a heavy chain variable domain (VH) and a light chain variable domain (VL) interact to form an antigen binding site. In this case, the complementarity determining regions (CDRs) of both VH and VL will contribute to the antigen binding site, i.e. a total of 6 CDRs will be involved in antigen binding site formation. In view of the above definition, the antigen-binding domain of a conventional 4-chain antibody (such as an IgG, IgM, IgA, IgD or IgE molecule; known in the art) or of a Fab, a F(ab')2 fragment, an Fv fragment such as a disulfide linked Fv or a scFv fragment, or a diabody (all known in the art) derived from such conventional 4-chain antibody, would normally not be regarded as an immunoglobulin single variable domain, as, in these cases, binding to the respective epitope of an antigen would normally not occur by one (single) immunoglobulin domain but by a pair of (associating) immunoglobulin domains such as light and heavy chain variable domains, i.e., by a VH-VL pair of immunoglobulin domains, which jointly bind to an epitope of the respective antigen. In contrast, immunoglobulin single variable domains are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain. The binding site of an immunoglobulin single variable domain is formed by a single VH, a single VHHor single VLdomain. Hence, the antigen binding site of an immunoglobulin single variable domain is formed by no more than three CDRs. As such, the single variable domain may be a light chain variable domain sequence (e.g., a VL-sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g., a VH-sequence or VHH sequence) or a suitable fragment thereof; as long as it is capable of forming a single antigen binding unit (i.e., a functional antigen binding unit that essentially consists of the single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit). An immunoglobulin single variable domain (ISV) can for example be a heavy chain ISV, such as a VH, VHH, including a camelized VH or humanized VHH. In one embodiment, it is a VHH, including a camelized VH or humanized VHH. Heavy chain ISVs can be derived from a conventional four-chain antibody or from a heavy chain antibody. For example, the immunoglobulin single variable domain may be a (single) domain antibody (or an amino acid sequence that is suitable for use as a single domain antibody), a"dAb" or dAb (or an amino acid sequence that is suitable for use as a dAb) or a VHH; othersingle variable domains, or any suitable fragment of any one thereof. In particular, the immunoglobulin single variable domain may be a VHH (e.g., ahumanized VHH or camelized VH) or a suitable fragment thereof.“VHH domains”, also known as VHHs, VHH antibody fragments, and VHH antibodies, have originally been described as the antigen binding immunoglobulin variable domain of “heavy chain antibodies” (i.e., of “antibodies devoid of light chains”; Hamers-Casterman et al. 1993 (Nature 363: 446-448). The term “VHH domain” has been chosen in order to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VL domains”). For a further description of VHH’s, reference is made to the review article by Muyldermans 2001 (Reviews in Molecular Biotechnology 74: 277-302). For the term “dAb’s” and “domain antibody”, reference is for example made to Ward et al. 1989 (Nature 341: 544), to Holt et al. 2003 (Trends Biotechnol. 21: 484); as well as to for example WO 2004 / 068820, WO 2006 / 030220, WO 2006 / 003388 and other published patent applications of Domantis Ltd. It should also be noted that, although less preferred in the context of the present invention because they are not of mammalian origin, single variable domains can be derived from certain species of shark (for example, the so-called “IgNAR domains”, see for example WO 2005 / 18629). Typically, the generation of immunoglobulins involves the immunization of experimental animals, fusion of immunoglobulin producing cells to create hybridomas and screening for the desired specificities. Alternatively, immunoglobulins can be generated byscreening of naïve, immune or synthetic libraries, e.g., by phage display.The generation of immunoglobulin sequences, such as VHHs, has been described extensively in various publications, among which WO 1994 / 04678, Hamers-Casterman et al. 1993 (Nature 363: 446-448) and Muyldermans et al. 2001 (Reviews in Molecular Biotechnology 74: 277-302, 2001). In these methods, camelids are immunized with the target antigen in order to induce an immune response against said target antigen. The repertoire of VHHs obtained from said immunization is further screened for VHHs that bind the target antigen. In these instances, the generation of antibodies requires purified antigen for immunization and / or screening. Antigens can be purified from natural sources, or in the course of recombinant production. Immunization and / or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens. Immunoglobulin sequences of different origin, comprising mouse, rat, rabbit, donkey, human and camelid immunoglobulin sequences can be used herein. Also, fully human, humanized or chimeric sequences can be used in the method described herein. For example, camelid immunoglobulin sequences and humanized camelid immunoglobulin sequences, or camelized domain antibodies, e.g., camelized dAb as described by Ward et al. 1989 (Nature 341: 544), WO 1994 / 04678, and Davis and Riechmann (1994, Febs Lett., 339:285-290; and 1996, Prot. Eng., 9:531-537) can be used herein. Moreover, the ISVs are fused forming a multivalent and / or multispecific construct (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al.2001 (J. Biol. Chem., Vol.276, 10.7346-7350) as well as to for example WO 1996 / 34103 and WO 1999 / 23221). A “humanized VHH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but that has been “humanized”, i.e. by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence (and in particular in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being (e.g., indicated above). This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the prior art (e.g., WO 2008 / 020079). Again, it should be noted that such humanized VHHs can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material. A “camelized VH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VH domain, but that has been “camelized”, i.e. by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VHdomain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a (camelid) heavy chain antibody. This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the description in the prior art (e.g., Davies and Riechman 1994, FEBS 339: 285; 1995, Biotechnol.13: 475; 1996, Prot. Eng.9: 531; and Riechman 1999, J. Immunol. Methods 231: 25). Such “camelizing” substitutions are inserted at amino acid positions that form and / or are present at the VH-VL interface, and / or at the so-called Camelidae hallmark residues, as defined herein (see for example WO 1994 / 04678 and Davies and Riechmann (1994 and 1996, supra). In one embodiment, the VH sequence that is used as a starting material or starting point for generating or designing the camelized VH is a VH sequence from a mammal, such as the VH sequence of a human being, such as a VH3 sequence. However, it should be noted that such camelized VH can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material. The structure of an immunoglobulin single variable domain sequence can be considered to be comprised of four framework regions (“FRs”), which are referred to in the art and herein as “Framework region 1” (“FR1”); as “Framework region 2” (“FR2”); as “Framework region 3” (“FR3”); and as “Framework region 4” (“FR4”), respectively; which framework regions are interrupted by three complementary determining regions (“CDRs”), which are referred to in the art and herein as “Complementarity Determining Region 1” (“CDR1”); as “Complementarity Determining Region 2” (“CDR2”); and as “Complementarity Determining Region 3” (“CDR3”), respectively. In such an immunoglobulin sequence, the framework sequences may be any suitable framework sequences, and examples of suitable framework sequences will be clear to the skilled person, for example on the basis the standard handbooks and the further disclosure and prior art mentioned herein. The framework sequences are (a suitable combination of) immunoglobulin framework sequences or framework sequences that have been derived from immunoglobulin framework sequences (for example, by humanization or camelization). For example, the framework sequences may be framework sequences derived from a light chain variable domain (e.g., a VL-sequence) and / or from a heavy chain variable domain (e.g., a VH-sequence or VHH sequence). In one particular aspect, the framework sequences are either framework sequences that have been derived from a VHH-sequence (in which said framework sequences may optionally have been partially or fully humanized) or are conventional VH sequences that have been camelized (as defined herein). In particular, the framework sequences present in the ISV sequence described herein may contain one or more of hallmark residues (as defined herein), such that the ISV sequence is a VHH, (e.g., a humanized VHH or camelized VH). Non-limiting examples of (suitable combinations of) such framework sequences will become clear from the further disclosure herein. The total number of amino acid residues in a VH domain and a VHH domain will usually be in the range of from 110 to 120, often between 112 and 115. It should however be noted that smaller and longer sequences may also be suitable for the purposes described herein. However, it should be noted that the ISVs described herein is not limited as to the origin of the ISV sequence (or of the nucleotide sequence used to express it), nor as to the way that the ISV sequence or nucleotide sequence is (or has been) generated or obtained. Thus, theISV sequences may be naturally occurring sequences (from any suitable species) or syntheticor semi-synthetic sequences. In a specific but non-limiting aspect, the ISV sequence is a naturally occurring sequence (from any suitable species) or a synthetic or semi-synthetic sequence, including but not limited to “humanized” (as defined herein) immunoglobulin sequences (such as partially or fully humanized mouse or rabbit immunoglobulin sequences, and in particular partially or fully humanized VHHsequences), “camelized” (as defined herein) immunoglobulin sequences (and in particular camelized VH sequences), as well as ISVs that have been obtained by techniques such as affinity maturation (for example, starting from synthetic, random or naturally occurring immunoglobulin sequences), CDR grafting, veneering, combining fragments derived from different immunoglobulin sequences, PCR assembly using overlapping primers, and similar techniques for engineering immunoglobulin sequences well known to the skilled person; or any suitable combination of any of the foregoing. Similarly, nucleotide sequences may be naturally occurring nucleotide sequences or synthetic or semi-synthetic sequences, and may for example be sequences that are isolated by PCR from a suitable naturally occurring template (e.g., DNA or RNA isolated from a cell), nucleotide sequences that have been isolated from a library (and in particular, an expression library), nucleotide sequences that have been prepared by introducing mutations into a naturally occurring nucleotide sequence (using any suitable technique known per se, such as mismatch PCR), nucleotide sequence that have been prepared by PCR using overlapping primers, or nucleotide sequences that have been prepared using techniques for DNA synthesis known per se. Generally, VHH sequences (including (partially) humanized VHH sequences and camelized VH sequences) can be characterized by the presence of one or more “Hallmark residues” (as described herein) in one or more of the framework sequences (again as further described herein). Thus, generally, a VHH, can be defined as an immunoglobulin sequence with the (general) structureFR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which one or more of the Hallmark residues are as further defined herein. In particular, a VHHcan be an immunoglobulin sequence with the (general) structureFR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which the framework sequences are as further defined herein. More in particular, a VHHcan be an immunoglobulin sequence with the (general)structureFR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 toCDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which: oneor more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table A below. Table A: Hallmark Residues in VHHs In one embodiment, the immunoglobulin single variable domain has certain amino acid substitutions in the framework regions effective in preventing or reducing binding of so- called “pre-existing antibodies” to the polypeptides. ISVs in which (i) the amino acid residue at position 112 is one of K or Q; and / or (ii) the amino acid residue at position 89 is T; and / or (iii) the amino acid residue at position 89 is L and the amino acid residue at position 110 is one of K or Q; and (iv) in each of cases (i) to (iii), the amino acid at position 11 is preferably V have been described in WO2015 / 173325. Polypeptides The immunoglobulin single variable domains may form part of a protein or polypeptide, which may comprise or essentially consist of one or more (at least one) immunoglobulin single variable domains and which may optionally further comprise one or more further amino acid sequences (all optionally linked via one or more suitable linkers). The term “immunoglobulin single variable domain” may also encompass such polypeptides. The one or more immunoglobulin single variable domains may be used as a binding unit in such aprotein or polypeptide, which may optionally contain one or more further amino acids that can serve as a binding unit, so as to provide a monovalent, multivalent or multispecific polypeptide of the invention, respectively (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al. 2001 (J. Biol. Chem. 276: 7346), as well as to for example WO 1996 / 34103, WO 1999 / 23221 and WO 2010 / 115998). The polypeptides may comprise or essentially consist of one immunoglobulin single variable domain, as outlined above. Such polypeptides are also referred to herein as monovalent polypeptides. The term “multivalent” indicates the presence of multiple ISVs in a polypeptide. In one embodiment, the polypeptide is “bivalent”, i.e., comprises or consists of two ISVs. In one embodiment, the polypeptide is “trivalent”, i.e., comprises or consists of three ISVs. In another embodiment, the polypeptide is “tetravalent”, i.e. comprises or consists of four ISVDs. The polypeptide can thus be “bivalent”, “trivalent”, “tetravalent”, “pentavalent”, “hexavalent”, “heptavalent”, “octavalent”, “nonavalent”, etc., i.e., the polypeptide comprises or consists of two, three, four, five, six, seven, eight, nine, etc., ISVs, respectively. In one embodiment the multivalent ISV polypeptide is trivalent. In another embodiment the multivalent ISV polypeptide is tetravalent. In still another embodiment, the multivalent ISV polypeptide is pentavalent. In one embodiment, the multivalent ISV polypeptide can also be multispecific. The term “multispecific” refers to binding to multiple different target molecules (also referred to as antigens). The multivalent ISV polypeptide can thus be “bispecific”, “trispecific”, “tetraspecific”, etc., i.e., can bind to two, three, four, etc., different target molecules, respectively. For example, the polypeptide may be bispecific-trivalent, such as a polypeptide comprising or consisting of three ISVs, wherein two ISVs bind to a first target and one ISV binds to a second target different from the first target. In another example, the polypeptide may be trispecific-tetravalent, such as a polypeptide comprising or consisting of four ISVs, wherein one ISV binds to a first target, two ISVs bind to a second target different from the first target and one ISV binds to a third target different from the first and the second target. In still another example, the polypeptide may be trispecific-pentavalent, such as a polypeptide comprising or consisting of five ISVs, wherein two ISVs bind to a first target, two ISVs bind to a second target different from the first target and one ISV binds to a third target different from the first and the second target. In one embodiment, the multivalent ISV polypeptide can also be multiparatopic. The term “multiparatopic” refers to binding to multiple different epitopes on the same target molecules (also referred to as antigens). The multivalent ISV polypeptide can thus be “biparatopic”, “triparatopic”, etc., i.e., can bind to two, three, etc., different epitopes on the same target molecules, respectively. In another aspect, the polypeptide of the invention that comprises or essentially consists of one or more immunoglobulin single variable domains (or suitable fragments thereof), may further comprise one or more other groups, residues, moieties or binding units. Such further groups, residues, moieties, binding units or amino acid sequences may or may not provide further functionality to the immunoglobulin single variable domain (and / or to the polypeptide in which it is present) and may or may not modify the properties of the immunoglobulin single variable domain. For example, such further groups, residues, moieties or binding units may be one or more additional amino acids, such that the compound, construct or polypeptide is a (fusion) protein or (fusion) polypeptide. In a preferred but non-limiting aspect, said one or more other groups, residues, moieties or binding units are immunoglobulins. Even more preferably, said one or more other groups, residues, moieties or binding units are chosen from the group consisting of domain antibodies, amino acids that are suitable for use as a domain antibody, single domain antibodies, amino acids that are suitable for use as a single domain antibody, “dAb”s, amino acids that are suitable for use as a dAb, or VHHs. Alternatively, such groups, residues, moieties or binding units may for example be chemical groups, residues, moieties, which may or may not by themselves be biologicallyand / or pharmacologically active. For example, and without limitation, such groups may belinked to the one or more immunoglobulin single variable domain so as to provide a “derivative” of the immunoglobulin single variable domain. In another embodiment, said further residues may be effective in preventing or reducing binding of so-called “pre-existing antibodies” to the polypeptides. For this purpose,the polypeptides and constructs may contain a C-terminal extension (X)n (SEQ ID NO: 150)(in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I), for which reference is made to WO 2012 / 175741.Accordingly, the polypeptide may further comprise a C-terminal extension (X)n (SEQ ID NO:151), in which n is 1 to 5, such as 1, 2, 3, 4 or 5, and in which X is a naturally occurring amino acid, preferably no cysteine. In the polypeptides described above, the one or more immunoglobulin single variable domains and the one or more groups, residues, moieties or binding units may be linked directly to each other and / or via one or more suitable linkers or spacers. For example, when the one or more groups, residues, moieties or binding units are amino acids, the linkers may also be an amino acid, so that the resulting polypeptide is a fusion protein or fusion polypeptide. As used herein, the term “linker” denotes a peptide that fuses together two or more ISVs into a single molecule. The use of linkers to connect two or more (poly)peptides is well known in the art. Further exemplary peptidic linkers are shown in Table B. One often usedclass of peptidic linker are known as the “Gly-Ser” or “GS” linkers. These are linkers that essentially consist of glycine (G) and serine (S) residues, and usually comprise one or more repeats of a peptide motif such as the GGGGS (SEQ ID NO:154) motif (for example, having the formula (Gly-Gly-Gly-Gly-Ser)n (SEQ ID NO: 152) in which n may be 1, 2, 3, 4, 5, 6, 7 or more). Some often-used examples of such GS linkers are 9GS linkers (GGGGSGGGS, SEQ ID NO: 157), 15GS linkers (n=3) and 35GS linkers (n=7). Reference is for example made to Chen et al. 2013 (Adv. Drug Deliv. Rev. 65(10): 1357–1369) and Klein et al. 2014 (Protein Eng. Des. Sel. 27 (10): 325-330). Table B: Linker sequences (“ID” refers to the SEQ ID NO as used herein) In one aspect, the disclosure also relates to such amino acid sequences and / or VHHsthat can bind to and / or are directed against CD8 and that comprise CDR sequences thatare generally as further defined herein, to suitable fragments thereof, as well as to polypeptides that comprise or essentially consist of one or more of such VHHsand / or suitable fragments. In some aspect, the disclosure relates to VHHs with SEQ ID NO: 77. In particular, the disclosure in some specific aspects provides: I) amino acid sequences that are directed against CD8 and that have at least 80%, preferably at least 85%, such as 90% or 95% or more sequence identity with SEQ ID NO: 77;II) amino acid sequences that cross-block the binding of the amino acid sequence of SEQ ID NO: 77 to CD8 and / or that compete with at least the amino acid sequence of SEQ ID NO: 77for binding to CD8; Such amino acid sequences may be as further described herein (and may for example be VHHs); as well as polypeptides of the disclosure that comprise one or more of such amino acid sequences (which may be as further described herein), and particularly bispecific (or multispecific) polypeptides as described herein, and nucleic acid sequences that encodesuch amino acid sequences and polypeptides. Such amino acid sequences and polypeptides do not include any naturally occurring ligands. In some embodiments, the CD8 is derived from a mammalian animal, such as a human being. In one specific, but non-limiting aspect, the disclosure relates to an amino acid sequence directed against CD8, that comprises: a) the amino acid sequence of SEQ ID NO: 77; b) amino acid sequences that have at least 80% amino acid identity with a SEQ ID NO: 77, orc) amino acid sequences that have 3, 2, or 1 amino acid difference with SEQ ID NO: 77;or any suitable combination thereof. In some embodiments, disclosed is a VHH against CD8, which consist of 4 framework regions (FR1 to FR4 respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively). In some embodiments, in such a VHH: (I) CDR1 comprises or essentially consists of an amino acid sequence of GSTFSDYG (SEQ ID NO: 100), or amino acid sequences that have at least 80%, at least 90%, at least 95%, at least 99% or more sequence identity with GSTFSDYG (SEQ ID NO: 100), in which (1) any amino acidsubstitution is a conservative amino acid substitution; and / or (2) said amino acid sequence onlycontains amino acids substitutions, and no amino acid deletions or insertions, compared to GSTFSDYG (SEQ ID NO: 100); and / or from the group consisting of amino acids sequences that have 2 or only 1 amino acid difference(s) with GSTFSDYG (SEQ ID NO: 100), in which any amino acid substitution is a conservative amino acid substitution; and / or said amino acid sequence only contains amino acid substitutions, and no amino acid deletions or insertions, compared to GSTFSDYG (SEQ ID NO: 100). (II) CDR2 comprises or essentially consists of an amino acid sequence of IDWNGEHT (SEQ ID NO: 101), or amino acid sequences that have at least 80%, at least 90%, at least 95%, at least 99% or more sequence identity with IDWNGEHT (SEQ ID NO: 101), in which (1) any amino acidsubstitution is a conservative amino acid substitution; and / or (2) said amino acid sequence onlycontains amino acids substitutions, and no amino acid deletions or insertions, compared to IDWNGEHT (SEQ ID NO: 101); and / or from the group consisting of amino acids sequences that have 2 or only 1 amino acid difference(s) with IDWNGEHT (SEQ ID NO: 101), in which any amino acid substitution is a conservative amino acid substitution; and / or said amino acid sequence only contains amino acid substitutions, and no amino acid deletions or insertions, compared to IDWNGEHT (SEQ ID NO: 101). (III) CDR3 comprises or essentially consists of an amino acid sequence of AADALPYTVRKYNY (SEQ ID NO: 102), or amino acid sequences that have at least 80%, at least 90%, at least 95%, at least 99% or more sequence identity with AADALPYTVRKYNY (SEQ ID NO: 102), in which (1) any aminoacid substitution is a conservative amino acid substitution; and / or (2) said amino acid sequenceonly contains amino acids substitutions, and no amino acid deletions or insertions, compared to AADALPYTVRKYNY (SEQ ID NO: 102); and / or from the group consisting of amino acids sequences that have 2 or only 1 amino acid difference(s) with AADALPYTVRKYNY (SEQ ID NO: 102), in which any amino acid substitution is a conservative amino acid substitution; and / or said amino acid sequence only contains amino acid substitutions, and no amino acid deletions or insertions, compared to AADALPYTVRKYNY (SEQ ID NO: 102). CD8 VHHsas disclosed herein may comprise one, two or all three of the CDRs explicitly listed above. In some embodiments, the CD8 VHHcomprises: CDR1: GSTFSDYG (SEQ ID NO: 100), based on IMGT designation; CDR2: IDWNGEHT (SEQ ID NO: 101), based on IMGT designation; and CDR3: AADALPYTVRKYNY (SEQ ID NO: 102), based on IMGT designation. In the VHHs of the disclosure that comprise the combinations of CDRs mentionedabove, each CDR can be replaced by a CDR chosen from the group consisting of amino acid sequences that have at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% sequence identity with the mentioned CDRs; in which: (1) any amino acid substitution is preferably a conservative amino acid substitution; and / or (2) said amino acid sequence preferably only contains amino acid substitutions, and no amino acid deletions or insertions, compared to the above amino acid sequence(s); and / or chosen from the group consisting of amino acid sequences that have 3, 2 or only 1 (as indicated in the preceding paragraph) “amino acid difference(s)” with the mentioned CDR(s) one of the above amino acid sequences, in which: (1) any amino acid substitution is preferably a conservative amino acid substitution; and / or (2) said amino acid sequence preferably only contains amino acid substitutions, and no amino acid deletions or insertions, compared to the above amino acid sequence(s). In one embodiment, the CD8 VHH is BDSn: Anti-CD8 BDSn Nb sequence (CDR1, CDR2, CDR3 underlined based on IMGT designation): EVQLVESGGGLVQAGGSLRLSCAASGSTFSDYGVGWFRQAPGKGREFVADIDWNG EHTSYADSVKGRFATSRDNAKNTAYLQMNSLKPEDTAVYYCAADALPYTVRKYNY WGQGTQVTVSSGGCGGHHHHHH (SEQ ID NO: 77) In some embodiments, a CD8 VHH of the present disclosure binds to CD8 with a dissociation constant (KD) of 10−5to 10−12moles / liter (M) or less, and preferably 10−7to 10−12 moles / liter (M) or less and more preferably 10−8to 10−12moles / liter (M), and / or with an association constant (KA) of at least 107M−1, preferably at least 108M−1, more preferably at least 109M−1, such as at least 1012M−1; and in particular with a KD less than 500 nM, preferably less than 200 nM, more preferably less than 10 nM, such as less than 5 nM. The KD and KA values of the VHH of the disclosure against vWF can be determined in a manner known per se,for example using the assay described herein. More generally, the VHHs described hereinpreferably have a dissociation constant with respect to vWF that is as described in this paragraph. Generally, it should be noted that the term VHH as used herein in its broadest sense is not limited to a specific biological source or to a specific method of preparation. For example,as will be discussed in more detail below, the VHHs can be obtained (1) by isolating the VHHdomain of a naturally occurring heavy chain antibody; (2) by expression of a nucleotide sequence encoding a naturally occurring VHH domain; (3) by “humanization” (as described below) of a naturally occurring VHH domain or by expression of a nucleic acid encoding a such humanized VHH domain; (4) by “camelization” (as described below) of a naturally occurring VH domain from any animal species, in particular a species of mammal, such as from a human being, or by expression of a nucleic acid encoding such a camelized VH domain; (5) by “camelisation” of a “domain antibody” or “Dab” as described by Ward et al (supra), or by expression of a nucleic acid encoding such a camelized VH domain; (6) using synthetic or semi-synthetic techniques for preparing proteins, polypeptides or other amino acid sequences;(7) by preparing a nucleic acid encoding a VHH using techniques for nucleic acid synthesis,followed by expression of the nucleic acid thus obtained; and / or (8) by any combination of the foregoing. Suitable methods and techniques for performing the foregoing will be clear to theskilled person based on the disclosure herein and for example include the methods andtechniques described in more detail hereinbelow. In some embodiments, the CD8 VHHs of the present disclosure do not have an aminoacid sequence that is exactly the same as (i.e. as a degree of sequence identity of 100% with) the amino acid sequence of a naturally occurring VH domain, such as the amino acid sequence of a naturally occurring VH domain from a mammal, and in particular from a human being. One class of CD8 VHHs of the disclosure comprises VHHs with an amino acidsequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but that has been “humanized”, i.e. by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4- chain antibody from a human being (e.g., indicated above). It should be noted that suchhumanized CD8 VHHs of the present disclosure can be obtained in any suitable manner knownper se (i.e. as indicated under points (1)-(8) above) and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material. Another class of CD8 VHHs of the present disclosure comprises VHHs with an aminoacid sequence that corresponds to the amino acid sequence of a naturally occurring VH domain that has been “camelized”, i.e. by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a heavy chain antibody. This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the further description below. Reference is also made to WO 94 / 04678. Such camelization may preferentially occur at amino acid positions which are present at the VH-VL interface and at the so-called Camelidae hallmark residues (see for example also WO 94 / 04678), as also mentioned below. In some embodiments, the VH domain or sequence that is used as a starting material or starting point for generating or designing the camelized VHH is a VH sequence from a mammal, e.g.,VH sequence of ahuman being. It should be noted that such camelized VHHs of the present disclosure can beobtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material. For example, both “humanization” and “camelization” can be performed by providing a nucleotide sequence that encodes such a naturally occurring VHH domain or VH domain, respectively, and then changing, in a manner known per se, one or more codons in said nucleotide sequence such that the new nucleotide sequence encodes a humanized or camelized VHH of the present disclosure, respectively, and then expressing the nucleotide sequence thus obtained in a manner known per se so as to provide the desired VHH. Alternatively, based on the amino acid sequence of a naturally occurring VHH domain or VH domain, respectively, the amino acid sequence of the desired humanized or camelized VHH of the present disclosure, respectively, can be designed and then synthesized de novo using techniques for peptide synthesis known per se. Also, based on the amino acid sequence or nucleotide sequence of a naturally occurring VHH domain or VH domain, respectively, anucleotide sequence encoding the desired humanized or camelized VHH can be designed andthen synthesized de novo using techniques for nucleic acid synthesis known per se, after which the nucleotide sequence thus obtained can be expressed in a manner known per se so as to provide the desired VHH. Other suitable ways and techniques for obtaining VHHs and / or nucleotide sequences and / or nucleic acids encoding the same, starting from (the amino acid sequence of) naturally occurring VH domains or preferably VHH domains and / or from nucleotide sequencesand / or nucleic acid sequences encoding the same will be clear from the skilled person, and mayfor example comprising combining one or more amino acid sequences and / or nucleotidesequences from naturally occurring VH domains (such as one or more FR's and / or CDR's) with one or more one or more amino acid sequences and / or nucleotide sequences from naturally occurring VHH domains (such an one or more FR's or CDR's), in a suitable manner so as to provide (a nucleotide sequence or nucleic acid encoding) a VHH. Also provided are compounds and constructs, and in particular proteins and polypeptides that comprise or essentially consists of at least one such amino acid sequence and / or VHH of the disclosure (or suitable fragments thereof), and optionally further comprises one or more other groups, residues, moieties or binding units. In some embodiments, such further groups, residues, moieties, binding units or amino acid sequences may or may not provide further functionalityto the amino acid sequence and / or VHH (and / or to the compound or construct in which it ispresent) and may or may not modify the properties of the amino acid sequence and / or VHH. The disclosure also encompasses any polypeptide of the present disclosure that has been glycosylated at one or more amino acid positions, usually depending on the host used toexpress the polypeptide. A polypeptide can comprise an amino acid sequence of a CD8 VHHof the present disclosure, which is fused at its amino terminal end, at its carboxy terminal end, or both at its amino terminal end and at its carboxy terminal end with at least one further aminoacid sequence. Such further amino acid sequence may comprise at least one further VHH, soas to provide a polypeptide that comprises at least two, such as three, four or five, VHHs, inwhich said VHHs may optionally be linked via one or more linker sequences (as definedherein). Polypeptides of comprising CD8 VHH of the present disclosure and one or moreanother multivalent polypeptides. In a multivalent polypeptide, the two or more VHHs maybe the same or different. For example, the two or more VHHs in a multivalent polypeptide:· may be directed against the same antigen, i.e. against the same parts or epitopes of saidantigen or against two or more different parts or epitopes of said antigen; and / or:· may be directed against the different antigens;· or a combination thereof.Thus, a bivalent polypeptide, for example:· may comprise two identical VHH;· may comprise a first VHH directed against a first part or epitope of an antigen and a secondVHH directed against the same part or epitope of said antigen or against another part or epitopeof said antigen;or may comprise a first VHH directed against a first antigen and a second VHH directed againsta second antigen different from said first antigen; whereas a trivalent Polypeptide of the Invention for example:· may comprise three identical or different VHHs directed against the same or different partsor epitopes of the same antigen;· may comprise two identical or different VHHs directed against the same or different parts orepitopes on a first antigen and a third VHH directed against a second antigen different fromsaid first antigen; or· may comprise a first VHH directed against a first antigen, a second VHH directed against asecond antigen different from said first antigen, and a third VHH directed against a third antigendifferent from said first and second antigen. The CD8 VHHs and polypeptides as disclosed herein can also be introduced andexpressed in one or more cells, tissues or organs of a multicellular organism, for example for prophylactic and / or therapeutic purposes (e.g., as a gene therapy). For this purpose, thenucleotide sequences encoding the CD8 VHHs or polypeptides as disclosed herein can beintroduced into the cells or tissues in any suitable way, for example as such (e.g., using liposomes) or after they have been inserted into a suitable gene therapy vector (for example derived from retroviruses such as adenovirus, or parvoviruses such as adeno-associated virus).As will also be clear to the skilled person, such gene therapy may be performed in vivo and / orin situ in the body of a patent by administering a nucleic acid of the invention or a suitable gene therapy vector encoding the same to the patient or to specific cells or a specific tissue or organ of the patient; or suitable cells (often taken from the body of the patient to be treated, such as explanted lymphocytes, bone marrow aspirates or tissue biopsies) may be treated in vitro with a nucleotide sequence of the invention and then be suitably (re-)introduced into the body of the patient. All this can be performed using gene therapy vectors, techniques and delivery systems which are well known to the skilled person, for Culver, K. W., “Gene Therapy”, 1994, p. xii, Mary Ann Liebert, Inc., Publishers, New York, N.Y.). Giordano, Nature F Medicine 2 (1996), 534-539; Schaper, Circ. Res. 79 (1996), 911-919; Anderson, Science 256 (1992), 808-813; Verma, Nature 389 (1994), 239; Isner, Lancet 348 (1996), 370-374; Muhlhauser, Circ. Res.77 (1995), 1077-1086; Onodera, Blood 91; (1998), 30-36; Verma, Gene Ther.5 (1998), 692-699; Nabel, Ann. N.Y. Acad. Sci.: 811 (1997), 289-292; Verzeletti, Hum. Gene Ther. 9 (1998), 2243-51; Wang, Nature Medicine 2 (1996), 714-716; WO 94 / 29469; WO 97 / 00957, U.S. Pat. No. 5,580,859; 1 U.S. Pat. No. 5,589,5466; or Schaper, Current Opinion in Biotechnology 7 (1996), 635-640. For example, in situ expression of ScFv fragments (Afanasieva et al., Gene Ther., 10, 1850-1859 (2003)) and of diabodies (Blanco et al., J. Immunol, 171, 1070-1077 (2003)) has been described in the art. Accordingly, nucleic acid sequences encoding the CD8 VHHs as described herein,and expression construct and host cells comprising the nucleic acid sequence are also provided. Also disclosed are methods of using CD8 VHHs and polypeptides of the presentdisclosure. In some embodiments, a polypeptide comprising a CD8 VHH can be used in thelipid nanoparticles of the present disclosure for delivering a nucleic acid into an immune cell, as described herein. In some embodiments, CD8 VHHsand polypeptides of the present disclosure can be used to treat a condition or a disease in a subject in need thereof. In some embodiments, such conditions or diseases include, but are not limited to, cancer, infections, immune disorders, autoimmune diseases. In some embodiments, a polypeptide comprising a CD8 VHH can be used in animaging agent. In some embodiments, the imaging agent allows for the detection of human CD8 which is a specific biomarker found on the surface of a subset of T-cell for diagnostic imaging of the immune system. Imaging of CD8 allows for the in vivo detection of T-cell localization. Changes in T-cell localization can reflect the progression of an immune response and can occur over time as a result of various therapeutic treatments or even disease states. In some embodiments, it is used for imaging T-cell localization for immunotherapy. In addition, CD8 plays a role in activating downstream signaling pathways that are important for the activation of cytolytic T cells that function to clear viral pathogens and provide immunity to tumors. CD8 positive T cells can recognize short peptides presented within the MHCI protein of antigen presenting cells. In some embodiments, a polypeptidecomprising a CD8 VHH can potentiate signaling through the T cell receptor and enhance theability of a subject to clear viral pathogens and respond to tumor antigens. Thus, in some embodiments, the antigen binding constructs provided herein can be agonists and can activate the CD8 target.II. IONIZABLE CATIONIC LIPIDSProvided herein are ionizable cationic lipids that can be used to produce lipidnanoparticle compositions to facilitate the delivery of a payload (e.g., a nucleic acid, such as aDNA or RNA, such as an mRNA) disposed therein to cells, e.g., mammalian cells, e.g., humancells, e.g., immune cells. The ionizable cationic lipids have been designed to enableintracellular delivery of a nucleic acid, e.g., mRNA, to the cytosolic compartment of a targetcell type and rapidly degrade into non-toxic components. The complex functionalities of theionizable cationic lipids are facilitated by the interplay between the chemistry and geometry ofthe ionizable lipid head group, the hydrophobic “acyl-tail” groups and the linkers connectingthe head group and the acyl tail groups. Typically, the pKa of the ionizable amine head groupis designed to be in the range of 6-8, such as between 6.2-7.4, or between 6.7-7.2, such that itremains strongly cationic under acidic formulation conditions (e.g., pH 4 – pH 5.5), neutral orslightly anionic in physiological pH (7.4) and cationic in the early and late endosomalcompartments (e.g., pH 5.5 – pH 7). The acyl-tail groups play a key role in fusion of the lipidnanoparticle with endosomal membranes and membrane destabilization through structuralperturbation. The three-dimensional structure of the acyl-tail (determined by its length, anddegree and site of unsaturation) along with the relative sizes of the head group and tail groupare thought to play a role in promoting membrane fusion, and hence lipid nanoparticleendosomal escape (a key requirement for cytosolic delivery of a nucleic acid payload). Thelinker connecting the head group and acyl tail groups is designed to degrade by physiologicallyprevalent enzymes (e.g., esterases, or proteases) or by acid catalyzed hydrolysis.In one aspect, the present invention provides a compound represented by Formula (I): (I), or a salt thereof, wherein: R1and R2are each C1-3 alkylene; R3is C1-3 alkylene or a bond; R1Aand R2Aare each a bond or C1-10 alkylene; R3Ais a bond or C1-3 alkylene; R1A1, R2A1, R3A1, and R3A2are each H; R1A2and R2A2are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2; R1A3and R2A3are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2; R3A3is -C(O)ORa1; Ra1and Ra2are each independently C1-20 alkyl; R3Bis ; R3B1is C4-6 alkylene; and R3B2and R3B3are each C1-3 alkyl. Any of the variables or substitutents provided herein is unsubstituted or substitutedwith one or more substituents. In some embodiments, any of the variables or substituents provided herein is optionaly substituted. In some embodiments, any of the variables orsubstituents provided herein is optionaly substituted with one or more substituentsindependently selected from the group consisting of -ORs1, -NRs2Rs3, -C(O)Rs4, -C(O)ORs5, C(O)NRs6Rs7, -OC(O)Rs8, -OC(O)ORs9, -OC(O)NRs10R11, -NRs12C(O)Rs13, and - NRs14C(O)ORs15, wherein Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11, Rs12, Rs13, Rs14,and Rs15 are each indpenednetly H, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, 5- to 10-memberedheteroaryl, or 3- to 10-membered heterocyclyl, each of which is optionally substituted.In some embodiments, R1and R2are each C1-3 alkylene. In some embodiments, R1and R2are each methylene. In some embodiments, R3is C1-3 alkylene or a bond. In some embodiments, R3is a bond. In some embodiments, R1and R2are each methylene, and R3is a bond. In some embodiments, R1Aand R2Aare each a bond or C1-10 alkylene. In some embodiments, R3Ais a bond or C1-3 alkylene. In some embodiments, R1Aand R2Aare each abond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, or-(CH2)10-. In some embodiments, R1Aand R2Aare each a bond, -(CH2)2-, -(CH2)5-, -(CH2)7-, or -(CH2)9-. In some embodiments, R3Ais a bond, -CH2-, or -(CH2)2-. In some embodiments, R3Ais -CH2-. In some embodiments, R1A1, R2A1, R3A1, and R3A2are each H. In some embodiments, R1A2and R2A2are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2. In some embodiments, R1A3and R2A3are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2. In some embodiments, R3A3is -C(O)ORa1. In some embodiments, R1A2and R2A2are each -OC(O)(C1-15 alkyl), -C(O)O(C1-15 alkyl), -OC(O)CH(C1-10 alkyl)(C1-10 alkyl), -C(O)OCH(C1-10 alkyl)(C1-10 alkyl), - (CH2)C(O)O(C1-10 alkyl), or -(CH2)OC(O)(C1-10 alkyl). In some embodiments, R1A2and R2A2are each -OC(O)(C1-10 alkyl), -C(O)O(C1-10 alkyl), -OC(O)CH(C6 alkyl)(C8 alkyl), - C(O)OCH(C2-3 alkyl)(C5-6 alkyl), or -(CH2)C(O)O(C10 alkyl). In some embodiments, R1A2and R2A2are each , , , , , , , , or , each of which is optionally substituted. In some embodiments, R1A3and R2A3are each H, -OC(O)(C1-15 alkyl), or - C(O)O(C1-15 alkyl). In some embodiments, R1A3and R2A3are each H, -OC(O)(C5-10 alkyl), - C(O)O(C6-10 alkyl), or -(CH2)C(O)O(C10 alkyl). In some embodiments, R1A3and R2A3are each H, , , , , , , , , , , or , each of which is optionally substituted. In some embodiments, R3A3 is -C(O)OCH(C1-5 alkyl)(C1-10 alkyl). In someembodiments, R3A3 is -C(O)OCH(C3 alkyl)(C6 alkyl). In some embodiments, R3A3 is, which is optionally substituted. In some embodiments, R3B1 is C4-6 alkylene. In some embodiments, R3B2 and R3B3are each C1-3 alkyl. In some embodiments, R3B1 is -(CH2)4-. In some embodiments, R3B1 is -(CH2)5-. In some embodiments, R3B1 is -(CH2)6-. In some embodiments, R3B2 and R3B3 are eachmethyl. In some embodiments, R3B2 and R3B3 are each ethyl. In some embodiments,is , , or , each of which is optionally substituted. In some embodiments, R3B1is unsubstituted or substituted. In some embodiments, R3B1is optionally substituted. In some embodiemnts, R3B1is unsubstituted. In some embodiemnts, R3B1is not substituted with oxo. In some embodiments, R3B is . In some embodiments, R3B is H. Insome embodiments, R3B is unsubstituted or substituted. In some embodiments, R3B isunsubstituted. In some embodiments, R3B2and R3B3are each independently and optionally substituted. In some embodiments, R3B2and R3B3are each independently H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of -OH and -O-(C1-6alkyl). In some embodiments, R3B2and R3B3are each independently H or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of -ORs1, -NRs2Rs3, -C(O)Rs4, -C(O)ORs5, C(O)NRs6Rs7, -OC(O)Rs8, -OC(O)ORs9, -OC(O)NRs10R11, -NRs12C(O)Rs13, and -NRs14C(O)ORs15, wherein Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11, Rs12, Rs13, Rs14,and Rs15 are each independently H, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, 5- to 10-memberedheteroaryl, or 3- to 10-membered heterocyclyl, each of which is optionally substituted. In someembodiments, R3B2and R3B3are each independently H, methyl, ethyl, propyl, butyl, or pentyl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of -OH and -O-(C1-6 alkyl). In some embodiments, R3B2and R3B3are each independently methyl or ethyl, each optionally substituted with one or more - OH. In some embodiments, R3B2and R3B3are each methyl or each ethyl, each optionally substituted with one or more -OH. In some embodiments, R3B2and R3B3are each unsubstituted methyl. In one aspect, the present invention provides a compound represented by Formula (Ia): (Ia), or a salt thereof, wherein R1A, R2A, R3A, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, and R3A3are as defined for Formula (I) or any variation or embodiment thereof.In some embodiments, provided is a compound of Formula (II):

[0002] (II), or a salt thereof. In some embodiments, R1, R2, and R3are each independently a bond or C1-3 alkylene. In some embodiments, R1A, R2A, and R3Aare each independently a bond or C1-10 alkylene. In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, and R3A3are each independently H, C1-20 alkyl, C1-20 alkenyl, -(CH2)0-10C(O)ORa1, or -(CH2)0-10OC(O)Ra2. In some embodiments, Ra1and Ra2are each independently C1-20 alkyl or C1-20 alkenyl. In some embodiments, R3Bis . In some embodiments, R3B1is C4-6 alkylene. In some embodiments, R3B2and R3B3are each independently H or C1-6 alkyl. In some embodiments, R1, R2, and R3are each independently a bond or C1-3 alkylene. In some embodiments, R1, R2, and R3are each independently a bond or methylene. In some embodiments, R1and R2are each methylene and R3is a bond. In some embodiments, R1, R2, and R3are each methylene. In some embodiments, R1, R2, and R3are each independently unsubstituted or substituted. In some embodiments, R1, R2, and R3are unsubstituted. In some embodiments, R1A, R2A, and R3Aare each independently a bond or C1-10 alkylene. In some embodiments, R1A, R2A, and R3Aare each independently a bond or -(CH2)1- 10-. In some embodiments, R1Aand R2Aare each independently a bond, -CH2-, -(CH2)2-, - (CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, or -(CH2)8-. In some embodiments, R1Aand R2Aare each a bond, each -CH2-, each -(CH2)2-, each -(CH2)3-, each -(CH2)4-, each -(CH2)5-, each -(CH2)6-, each -(CH2)7-, or each -(CH2)8-. In some embodiments, R1Aand R2Aare each

[0003] independently a bond, -(CH2)2-, -(CH2)4-, -(CH2)6-, -(CH2)7-, or -(CH2)8-. In some embodiments, R1Aand R2Aare each a bond, each -(CH2)2-, each -(CH2)4-, each -(CH2)6-, each -(CH2)7-, or each -(CH2)8-. In some embodiments, R3Ais a bond, -CH2-, -(CH2)2-, or -(CH2)7-. In some embodiments, R1A, R2A, and R3Aare each independently unsubstituted or substituted. In some embodiments, R1A, R2A, and R3Aare unsubstituted. In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, and R3A3are each independently H, C1-20 alkyl, C1-20 alkenyl, -(CH2)0-10C(O)ORa1, or -(CH2)0-10OC(O)Ra2. In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, and R3A3are each independently H, C1-15 alkyl, -CH=CH-(C1-15 alkyl), -CH=CH-CH2-CH=CH-(C1-10 alkyl), - (CH2)0-4C(O)OCH(C1-10 alkyl)(C1-15 alkyl), -(CH2)0-4OC(O)CH(C1-10 alkyl)(C1-15 alkyl), - (CH2)0-4C(O)OCH2(C1-15 alkyl), or -(CH2)0-4OC(O)CH2(C1-15 alkyl). In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, R3A3, R1, R2, R3, R1A, R2A, and R3Aare each independently unsubstituted or substituted. In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, R3A3, R1, R2, R3, R1A, R2A, and R3Aare each unsubstituted. In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, and R3A3are each independently unsubstituted or substituted. In some embodiments, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, and R3A3are each unsubstituted. In some embodiments, R1, R2, R3, R1A, R2A, and R3Aare each independently unsubstituted or substituted. In some embodiments, R1, R2, R3, R1A, R2A, and R3Aare each unsubstituted. In some embodiments, R1, R2, and R3are each unsubstituted. In some embodiemnts, R3B1is unsubstituted. In some embodiemnts, R3B1is not substituted with oxo. In some embodiments, R1A1and R2A1are each independently -CH=CH-(C1-15 alkyl), -CH=CH-CH2-CH=CH-(C1-10alkyl), -(CH2)0-4C(O)OCH(C1-10alkyl)(C1-15alkyl), or -(CH2)0-4OC(O)CH(C1-10 alkyl)(C1-15 alkyl); and R1A2, R1A3, R2A2, and R2A3are each H. In some embodiments, R1A1and R2A1are each -CH=CH-(C1-15 alkyl), -CH=CH-CH2-CH=CH-(C1-10 alkyl), -(CH2)0-4C(O)OCH(C1-10 alkyl)(C1-15 alkyl), or -(CH2)0-4OC(O)CH(C1-10 alkyl)(C1-15 alkyl); and R1A2, R1A3, R2A2, and R2A3are each H. In some embodiments, R1A1and R2A1are each , , , 57 , , , or . In some embodiments, R1A1and R2A1are each . In some embodiments, R1A2, R1A3, R2A2, and R2A3are each H. In some embodiments, R1A1and R2A1are each C1-15 alkyl; R1A2and R2A2are each C1-15 alkyl; and R1A3and R2A3are each H. In some embodiments, R1A1and R2A1are each ; and R1A2and R2A2are each . In some embodiments, R1A3and R2A3are each H. In some embodiments, R1Aand R2Aare each a bond. In some embodiments, R1A1and R2A1are each -(CH2)0-4OC(O)CH2(C1-15 alkyl); R2A1and R2A2are each -(CH2)0-4C(O)OCH2(C1-15 alkyl); and R1A3and R2A3are each H. In some embodiments, R1A1and R2A1are each ; and R2A1and R2A2are each . In some embodiments, R1A3and R2A3are each H. In some embodiments, R1Aand R2Aare each a bond. In some embodiments, R1A1and R2A1are each -C(O)OCH2(C1-15 alkyl); R1A2and R2A2are each -(CH2)0-4C(O)OCH2(C1-15 alkyl); and R1A3and R2A3are each H. In some embodiments, R1A1and R2A1are each ; and R1A2and R2A2are each . In some embodiments, R1A1and R2A1are each ; and R2A1and R2A2are each . In some embodiments, R1A3and R2A3are each H. In some embodiments, R1Aand R2Aare each a bond. In some embodiments, R3A1, R3A2, and R3A3are each independently H, C1-15 alkyl, -(CH2)0-4C(O)OCH(C1-5 alkyl)(C1-10 alkyl), -(CH2)0-4OC(O)CH(C1-5 alkyl)(C1-10 alkyl), - (CH2)0-4C(O)OCH2(C1-10 alkyl), or -(CH2)0-4OC(O)CH2(C1-10 alkyl). In some embodiments, R3A1and R3A2are each independently C1-15 alkyl; and R3A3is H. In some embodiments, R3A1and R3A2are each independently ethyl, propyl, butyl, pentyl, hexyl, or heptyl. In some embodiments, R3A1and R3A2are each independently ethyl, , , , or . In some embodiments, R3A3is H. In some embodiments, R3Ais a bond. In some embodiments, R3A1is C1-15 alkyl; and R3A2and R3A3are each H. In some embodiments, R3A1is . In some embodiments, R3A2and R3A3are each H. In some embodiments, R3Ais a bond. In some embodiments, R3A1is -C(O)OCH(C1-5 alkyl)(C1-10 alkyl); and R3A2and R3A3are each H. In some embodiments, R3A1is or . In some embodiments, R3A1is . In some embodiments, R3Ais ethylene or -(CH2)2-. In some embodiments, R3A2and R3A3are each H. In some embodiments, R3A1is -(CH2)0-4OC(O)CH2(C1-10 alkyl); R3A2is -(CH2)0- 4(O)OCH2(C1-10 alkyl); and R3A3is H. In some embodiments, R3A1is or ; and R3A2is . In some embodiments, R3A3is H. In some embodiments, R3Ais a bond. In some embodiments, R3A1is -(CH2)0-4C(O)OCH2(C1-10 alkyl); R3A2is -(CH2)0- 4C(O)OCH2(C1-10 alkyl); and R3A3is H. In some embodiments, R3A1is ; and R3A2is or . In some embodiments, R3A3is H. In some embodiments, R3Ais a bond. In some embodiments, R3A1, R3A2, and R3A3are each H. Ra1and Ra2are each independently C1-20 alkyl or C1-20 alkenyl. In some embodiments, Ra1and Ra2are each independently -(CH2)0-15CH3 or -CH(C1-10 alkyl)(C1-15 alkyl). In some embodiments, Ra1and Ra2are each independently , , , , , , , , or , each of which is optionally substituted. In some embodiments, Ra1and Ra2are each independently unsubstituted or substituted. In some embodiments, Ra1and Ra2are unsubstituted. In some embodiments, R3Bis . In some embodiments, R3Bis H. In some embodiments, R3Bis unsubstituted or substituted. In some embodiments, R3Bis unsubstituted. In some embodiments, R3B1is C4-6 alkylene. In some embodiments, R3B1is unsubstituted or substituted. In some embodiments, R3B1is optionally substituted. In some embodiments, R3B2and R3B3are each independently and optionally substituted. In some embodiments, R3B2and R3B3are each independently H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of -OH and -O-(C1-6 alkyl). In some embodiments, R3B2and R3B3are each independently H or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of -ORs1, -NRs2Rs3, -C(O)Rs4, -C(O)ORs5, C(O)NRs6Rs7, -OC(O)Rs8, -OC(O)ORs9, -OC(O)NRs10R11, -NRs12C(O)Rs13, and -NRs14C(O)ORs15, wherein Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11, Rs12, Rs13, Rs14,and Rs15 are each indpenednetly H, C1-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, 5- to 10-memberedheteroaryl, or 3- to 10-membered heterocyclyl, each of which is optionally substituted. In someembodiments, R3B2and R3B3are each independently H, methyl, ethyl, propyl, butyl, or pentyl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of -OH and -O-(C1-6 alkyl). In some embodiments, R3B2and R3B3are each independently methyl or ethyl, each optionally substituted with one or more - OH. In some embodiments, R3B2and R3B3are each methyl or each ethyl, each optionally substituted with one or more -OH. In some embodiments, R3B2and R3B3are each unsubstituted methyl. In some embodiments, is , , , , or , each of which is optionally substituted.III. LIPID-IMMUNE CELL TARGETING GROUP CONJUGATESAs discussed herein, the LNPs may be targeted to a particular cell type, e.g., animmune cell, e.g., a macrophages, monocytes, or dendritic cells. This can be accomplished byusing one or more of the lipids described herein. Furthermore, targeting can be enhanced byincluding a targeting group at a solvent accessible surface of an LNP particle. For example,targeting groups may include a member of a specific binding pair, e.g., an antibody-antigenpair, a ligand-receptor pair, etc. In certain embodiments, the targeting group is an antibody.Targeting can be implemented, for example, by using lipid-immune cell targeting group conjugates described herein. Optionally, the targeting moiety is an antibody fragment without an Fc component. Previous attempts to target circulating immune cells with LNPs have employed full antibodies(WO 2016 / 189532 Al). Liposomes or lipid based particles with conjugated full antibodies clearmore quickly from the circulation due to engagement of the Fc, reducing their potential for reaching the target cell of interest (Harding et al. (1997) Biochim Biophys. Acta 1327, 181- 192; Sapra et al. (2004) Clin Cancer Res 10, 1100-1111; Aragnol et al., (1986) Proc Natl AcadSci USA 83, 2699-2703). Liposomes targeted with antibody fragments retain their long

[0004] circulating properties, like those targeted to EGFR (Mamot et al., (2005) Cancer Res 65, 11631- 11638), ErbB2 (Park et al. (2002) Clin Cancer Res 8, 1172-1181), or EphA2 (Kamoun et al.,2019 Nat. Biomed. Eng 3, 264-280). In addition, lipid based carriers can be prepared using amicellar insertion process that allows for the nearly quantitative incorporation of the antibody conjugation following its separate manufacturing (Nellis et al. (2005) Biotechnol Prog 21, 221- 232), compared to a highly inefficient insertion when conjugating full IgGs (Ishida et al. (1999) FEBS Lett. 460, 129-133) or the need to complete conjugation directly on an intact LNP (WO2016 / 189532 Al). scFv, Fab, or VHH fragments can also be directly conjugated to activatedPEG-lipids to make insertable conjugates. In some embodiments, PEG-(lipid) is equivalent to (lipid)-PEG. In certain embodiments, a targeting group may be a surface-bound antibody orsurface bound antigen binding fragment thereof, which can permit tuning of cell targetingspecificity. This is especially useful since highly specific antibodies can be raised against anepitope of interest for the desired targeting site. In one embodiment, multiple differentantibodies can be incorporated into, and presented at the surface of an LNP, where eachantibody binds to different epitopes on the same antigen or different epitopes on differentantigens. Such approaches can increase the avidity and specificity of targeting interactions toa particular target cell. Atargeting group or combination of targeting groups can be selected based on thedesired localization, function, or structural features of a given target cell. For example, in orderto target a T-cell, T-cell population or T-cell subpopulation, one or more antibodies or antigenbinding fragments or antigen binding derivatives thereof may be selected that target a T-cell,such as via a T-cell surface antigen. Exemplary T-cell surface antigens include, but are notlimited to, for example, CD2, CD3, CD4, CD5, CD7, CD8, CD28, CD39, CD69, CD103,CD137, CD45, T-cell receptor (TCR) β, TCR-a, TCR-a / b,TCR-g / d, PD1, CTLA4, TIM3,LAG3, CD18, IL-2 receptor, CD11a, GL7, TLR2, TLR4, TLR5 and IL-15 receptor. In orderto target an NK cell, or NK cell population, one or more antibodies, antigen binding fragments or antigen binding derivatives thereof may be selected that target an NK cell such as via a NKcell surface antigen. Exemplary NK cell surface antigens include, but are not limited to, CD48,CD56, CD85a, CD85c, CD85d, CD85e, CD85f, CD85i, CD85j, CD158b2, CD161, CD244, CD16a, CD16b, IL-2 receptor, CD27, CD28, CD48, CD69, CD70, CD86, CD112, CD122,CD155, CD161, CD244, CD266, CD314 / NKG2D, CD336 / NKP44, CD337 / NKP30. In63 order to target a B cell or B cell population, one or more antibodies, antigen binding fragments or antigen binding derivatives thereof may be selected that target a B cell such as via a B cellantigen. Exemplary B cell antigens include, but are not limited to, CD19 for all B cells exceptplasma cells, CD19, CD25, and CD30 for activated B cells, CD27, CD38, CD78, CD138, and CD319 for plasma cells, CD20, CD27, CD40, CD80 and PDL-2 for memory cells, Notch2,CD1, CD21, and CD27 for marginal zone B cells, CD21, CD22, and CD23 for follicular Bcells, and CD1, CD5, CD21, CD24, and TLR4 for regulatory B cells. In order to target a macrophage, macrophage polulation or macrophage subpopulation, one or more antibodies or antigen binding fragments or antigen binding derivatives thereof may be selected that target a macrophage, such as via a macrophage surface antigen. In some embodiments, the antigen is a M1 macrophage specific antigen. In some embodiments, the antigen is a M2 macrophage specific antigen. Exemplary macrophagesurface antigens include, but are not limited to, for example, CDIIB, CD80, CD86, HLA,CD68, CD163, CD206. In some embodiments, tumor macrophages are targeted, and theantigen is CD206. In order to target a monocyte, monocyte population or monocyte subpopulation, one or more antibodies or antigen binding fragments or antigen binding derivatives thereof may be selected that target a monocyte, such as via a monocyte surface antigen. Exemplary monocyte surface antigens include, but are not limited to, for example, CD14, CCR2, CCR5,CD62L, HLA, CD68, CXCR1, CXCR3, and CD11c.In order to target a dendritic cell, dendritic cell population or dendritic subpopulation, one or more antibodies or antigen binding fragments or antigen binding derivatives thereof may be selected that target a dendritic cell, such as via a dendritic surfaceantigen. Exemplary dendritic surface antigens include, but are not limited to, for example,DEC205 (see Katakowski, 2016:24(1):146-155, Molecular Therapy).In certain embodiments, targeting can be implemented, for example, by using lipid-immune cell targeting group conjugates described herein. Exemplary lipid-immune celltargeting group conjugates can include compounds of Formula (II),[Lipid] – [optional linker] – [immune cell targeting group, e.g., macrophage targeting molecule,e.g., anti-CDIIB antibody, anti-CD80 antibody, anti-CD86 antibody, anti-CD68 antibody, anti-CD163 antibody, and / or anti-CD206 antibody.] (Formula II). In some embodiments, the immune cell targeting group is a polypeptide, and the lipid is conjugated to the N-terminus, C-terminus, or anywhere in the middle part of the polypeptide. In certain embodiments, the targeting group or targeting molecule is a T-cell targeting agent, for example, an antibody, that binds to a T-cell antigen selected from the group consisting of CD2, CD3, CD4, CD5, CD7, CD8, CD28, CD137, CD45, T-cell receptor (TCR)β,TCR-a, TCR-a / b,TCR-g / d, PD1, CTLA4, TIM3, LAG3, CD18, IL-2 receptor, CD11a,TLR2, TLR4, TLR5, IL-7 receptor, or IL-15 receptor. In certain embodiments, the T cellantigen may be CD2, and the targeting group can be, for example, an anti-CD2 antibody. Incertain embodiments, the T cell antigen may be CD3, and the targeting group can be, forexample, an anti-CD3 antibody. In certain embodiments, the T cell antigen may be CD4, andthe targeting group can be, for example, an anti-CD4 antibody. In certain embodiments, the Tcell antigen may be CD5, and the targeting group can be, for example, an anti-CD5 antibody. In certain embodiments, the T cell antigen may be CD7, and the targeting group can be, forexample, an anti-CD7 antibody. In certain embodiments, the T cell antigen may be CD8, andthe targeting group can be, for example, an anti-CD8 antibody. In certain embodiments, the Tcell antigen may be TCR β, and the targeting group can be, for example, an anti-TCR βantibody. In some embodiments, the antibody is a human or humanized antibody.An exemplary CD2 binding agent can be an antibody selected from the group consisting of 9.6 (https: / / academic.oup.com / intimm / article / 10 / 12 / 1863 / 744536), 9-1 (https: / / academic.oup.com / intimm / article / 10 / 12 / 1863 / 744536), TS2 / 18.1.1 (ATCC HB-195), Lo-CD2b (ATCC PTA-802), Lo-CD2a / BTI-322 (US Patent 6849258B1), Sipilzumab / MEDI-507 (US Patent 6849258B1 / en), 35.1 (ATCC HB-222), OKT11 (ATCC CRL-8027), RPA-2.1(PCT Publication WO2020023559A1), AF1856 (R&D Systems), MAB18562 (R&D Systems), MAB18561 (R&D Systems), MAB1856 (R&D Systems), PAB30359 (Abnova Corporation),10299-1 (Abnova Corporation), and antigen binding fragments thereof. In certainembodiments, the binding agent comprises a heavy chain variable domain (VH) and a light chain variable domain (VL) of an antibody selected from the group consisting of AF1856 (R&D Systems), MAB18562 (R&D Systems), MAB18561 (R&D Systems), MAB1856 (R&DSystems), PAB30359 (Abnova Corporation), and 10299-1 (Abnova Corporation). In certainembodiments, the binding agent comprises the heavy chain CDR1, CDR2, and CDR3and thelight chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991)Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, Bethesda),Chothia (see, e.g., Chothia C & Lesk A M, (1987), J. MOL. BIOL. 196: 901-917), MacCallum(see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDRdetermination method known in the art, of the VH and VL sequences of an antibody selected from the group consisting of AF1856 (R&D Systems), MAB18562 (R&D Systems), MAB18561 (R&D Systems), MAB1856 (R&D Systems), PAB30359 (Abnova Corporation), and 10299-1 (Abnova Corporation). An exemplary CD2 binding agent can also be selected from antibodies or antibodyfragments employing CDRs of clones 9.6, 9-1, TS2 / 18.1.1, Lo-CD2b, Lo-CD2a, BTI-322, sipilzumab, 35.1, OKT11, RPA-2.1, SQB-3.21, LT2, TS1 / 8, UT329, 4F22, OX-34, UQ2 / 42,MU3, U7.4, NFN-76, or MOM-181-4-F(E).An exemplary CD3 binding agent (CD3γ / δ / ε, CD3γ, CD3δ, CD3γ / ε, CD3δ / ε, orCD3ε) can be an antibody selected from the group consisting of MEM-57 (CD3γ / δ / ε, EnzoLife Sciences), MAB100 (CD3ε, R&D Systems), CD3-H5 (CD3ε, Abnova Corporation), CD3-12 (CD3ε, Cell Signaling Technology), LE-CD3 (CD3ε, Santa Cruz Biotechnology, Inc.), NBP1- 31250 (CD3γ, Novus Biologicals), 16669-1-AP (CD3δ, Invitrogen) and antigen bindingfragments thereof. In certain embodiments, the binding agent comprises a VH domain and a VLdomain of an antibody selected from the group consisting of MEM-57 (CD3γ / δ / ε, EnzoLifeSciences), MAB100 (CD3ε, R&D Systems), CD3-H5 (CD3ε, Abnova Corporation), CD3-12 (CD3ε, Cell Signaling Technology), LE-CD3 (CD3ε, Santa Cruz Biotechnology, Inc.), NBP1-31250 (CD3γ, Novus Biologicals), and 16669-1-AP (CD3δ, Invitrogen). In certainembodiments, the binding agent comprises the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991) Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, Bethesda),Chothia (see, e.g., Chothia C & Lesk A M, (1987), J. MOL. BIOL. 196: 901-917), MacCallum(see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDR determination method known in the art, of the VH and VL sequences of an antibody selected from the group consisting of MEM-57 (CD3γ / δ / ε, EnzoLife Sciences), MAB100 (CD3ε, R&D Systems), CD3-H5 (CD3ε, Abnova Corporation), CD3-12 (CD3ε, Cell Signaling Technology), LE-CD3 (CD3ε, Santa Cruz Biotechnology, Inc.), NBP1-31250 (CD3γ, Novus Biologicals), and 16669-1-AP (CD3δ, Invitrogen). An exemplary CD3 binding agent can also be selected from antibodies or antibody fragments employing CDRs of clones hsp34, OKT-3, UCHT1, 38.1, HIT3a, RFT8, SK7, BC3, SP34-2, HU291, TRX4, Catumaxomab, teplizumab, 3-106, 3-114, 3-148, 3-190, 3-271, 3-550, 4-10, 4-48, H2C, F12Q, I2C, SP7, 3F3A1, CD3-12, 301, RIV9, JB38-29, JE17-74, GT0013,4E2, 7A4, 4D10A6, SPV-T3b, M2AB, ICO-90, 30A1 or Hu38E4.v1 (US Patent Application20200299409A1), REGN5458 (US Patent Application 20200024356A1), Blinatumomab(https: / / go.drugbank.com / drugs / DB09052 / polypeptide_sequences.fasta). In someembodiments, the conjugate comprises a Fab, wherein the Fab comprises (a) a heavy chain fragment comprising the amino acid sequence of SEQ ID NO: 1 and a light chain fragment comprising the amino acid sequence of SEQ ID NO: 2 or 3. An exemplary CD4 binding agent can be an antibody selected from the group consisting of Ibalizumab (https: / / www.genome.jp / dbget-bin / www_bget?D09575), AF1856 (R&D Systems), MAB554 (R&D Systems), BF0174 (Affinity Biosciences), PAB31115(Abnova Corporation), CAL4 (Abcam), and antigen binding fragments thereof. In certainembodiments, the binding agent comprises a VH domain and a VL domain of an antibodyselected from the group consisting of AF1856 (R&D Systems), MAB554 (R&D Systems),BF0174 (Affinity Biosciences), PAB31115 (Abnova Corporation), and CAL4 (Abcam). Incertain embodiments, the binding agent comprises the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991) Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, Bethesda),Chothia (see, e.g., Chothia C & Lesk A M, (1987), J. MOL. BIOL. 196: 901-917), MacCallum(see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDR determination method known in the art, of the VH and VL sequences of an antibody selectedfrom the group consisting of AF1856 (R&D Systems), MAB554 (R&D Systems), BF0174(Affinity Biosciences), PAB31115 (Abnova Corporation), and CAL4 (Abcam). An exemplary CD4 binding agent can also be selected from antibodies or antibody fragments employing CDRs of clones Ibalizumab, OKT4, RPA-T4, S3.5, SK3, N1UG0, RIV6, OTI18E3, MEM-241, B486A1, RFT-4g, 7E14, MDX.2, MEM-115, MEM-16, ICO-86, Edu- 2, or ilbalizumab. An exemplary CD5 binding agent can be an antibody selected from the group consisting of He3, MAB1636 (R&D Systems), AF1636 (R&D Systems), MAB115 (R&D Systems), C5 / 473 + CD5 / 54 / F6 (Abcam), CD5 / 54 / F6 (Abcam), 65152 (Proteintech), andantigen binding fragments thereof. In some embodiments, the binding agent comprises a VHdomain and a VL of an antibody selected from the group consisting of MAB1636 (R&D Systems), AF1636 (R&D Systems), MAB115 (R&D Systems), C5 / 473 + CD5 / 54 / F6 (Abcam),CD5 / 54 / F6 (Abcam), and 65152 (Proteintech). In certain embodiments, the binding agentcomprises the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991) Sequences of Proteins ofImmunological Interest, NIH Publication No. 91-3242, Bethesda), Chothia (see, e.g., ChothiaC & Lesk A M, (1987), J. MOL. BIOL. 196: 901-917), MacCallum (see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDR determination method known in the art, of the VH and VL sequences of an antibody selected from the group consisting of MAB1636 (R&D Systems), AF1636 (R&D Systems), MAB115 (R&D Systems), C5 / 473 + CD5 / 54 / F6 (Abcam), CD5 / 54 / F6 (Abcam), and 65152 (Proteintech). An exemplary CD5 binding agent can also be selected from antibodies or antibodyfragments employing CDRs of clones of zolimomab, 5D7, L17F12, and UCHT2, 1D8, 3I21,4H10, 8J23, 5O4, 4H2, 5G2, 8G8, 6M4, 2E3, 4E24, 4F10, 7J9, 7P9, 8E24, 6L18, 7H7, 1E7, 8J21, 7I11, 8M9, 1P21, 2H11, 3M22, 5M6, 5H8, 7I19, 1A2, 8E15, 8C10, 3P16, 4F3, 5M24, 5O24, 7B16, 1E8, 2H16, BLa1, 1804, DK23, Cris1, MEM-32, H65, 4C7, OX-19, Leu-1, 53- 7.3, 4H8E6, T101, EP2952, D-9, H-3, HK231, N-20, Y2 / 178, H-300, CD5 / 54 / F6, Q-20, CC17,MOM-18539-S(P), or MOM-18885-S(P).An exemplary CD7 binding agent can be an antibody selected from the group consisting of MAB7579 (R&D Systems), AF7579 (R&D Systems), EPR22065 (Abcam), 1G10D8 (Proteintech), NBP2-32097 (Novus Biologicals), NBP2-38440 (Novus Biologicals),and antigen binding fragments thereof. In certain embodiments, the binding agent comprises aVH domain and a VL of an antibody selected from the group consisting of MAB7579 (R&DSystems), AF7579 (R&D Systems), EPR22065 (Abcam), 1G10D8 (Proteintech), NBP2-32097(Novus Biologicals), and NBP2-38440 (Novus Biologicals). In certain embodiments, thebinding agent comprises the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991) Sequences of Proteins ofImmunological Interest, NIH Publication No. 91-3242, Bethesda), Chothia (see, e.g., ChothiaC & Lesk A M, (1987), J. MOL. BIOL. 196: 901-917), MacCallum (see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDR determination method known inthe art, of the VH and VL sequences of an antibody selected from the group consisting ofMAB7579 (R&D Systems), AF7579 (R&D Systems), EPR22065 (Abcam), 1G10D8 (Proteintech), NBP2-32097 (Novus Biologicals), and NBP2-38440 (Novus Biologicals). An exemplary CD7 binding agent can also be selected from antibodies or antibody fragments employing CDRs of clones TH-69, 3Afl1, T3-3A1, 124-1D1, 3A1f, CD7-6B7, or VHH6. An exemplary CD8 (CD8α, CD8α / α, CD8α / β or CD8β) binding agent can be anantibody selected from the group consisting of 2.43 (Invitrogen), Du CD8-1 (CD8α, Invitrogen), 9358-CD (CD8α / β, R&D Systems), MAB116 (CD8α, R&D Systems), ab4055 (CD8α, Abcam), C8 / 144B (CD8α, Novus Biologicals), YTS105.18 (CD8α, NovusBiologicals), TRX2 (https: / / patents.justia.com / patent / 20170198045), and antigen bindingfragments thereof. In certain embodiments, the binding agent comprises a VH domain and a VLdomain of an antibody selected from the group consisting of 2.43 (Invitrogen), 51.1 (ATCCHB-230), Du CD8-1 (CD8α, Invitrogen), 9358-CD (CD8α / β, R&D Systems), MAB116 (CD8α, R&D Systems), ab4055 (CD8α, Abcam), C8 / 144B (CD8α, Novus Biologicals), andYTS105.18 (CD8α, Novus Biologicals). In certain embodiments, the binding agent comprisesthe heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991) Sequences of Proteins of ImmunologicalInterest, NIH Publication No. 91-3242, Bethesda), Chothia (see, e.g., Chothia C & Lesk A M,(1987), J. MOL. BIOL.196: 901-917), MacCallum (see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDR determination method known in the art, of the VH andVL sequences of an antibody selected from the group consisting of 2.43 (Invitrogen), Du CD8-1 (CD8α, Invitrogen), 9358-CD (CD8α / β, R&D Systems), MAB116 (CD8α, R&D Systems), ab4055 (CD8α, Abcam), C8 / 144B (CD8α, Novus Biologicals), and YTS105.18 (CD8α, Novus Biologicals). An exemplary CD8 binding agent can also be selected from antibodies or antibody fragments employing CDRs of clones OKT-8, 51.1, S6F1, TRX2, and UCHT4, SP16, 3B5, C8-144B, HIT8a, RAVB3, LT8, 17D8, MEM-31, MEM-87, RIV11, DK-25, YTC141.1HL, orYTC182.20. In some embodiments, the conjugate comprises a Fab, wherein the Fab comprisesa heavy chain fragment comprising the amino acid sequence of SEQ ID NO: 6 and a light chain fragment comprising the amino acid sequence of SEQ ID NO: 7. An exemplary CD137 binding agent can be selected from antibodies or antibodyfragments employing CDRs of clones 4B4-1, P566, or Urelumab. An exemplary CD28 bindingagent can be selected from antibodies or antibody fragments employing CDRs of clone TAB08. An exemplary CD45 binding agent can be selected from antibodies or antibody fragmentsemploying CDRs of clones BC8, 9.4, 4B2, Tu116, or GAP8.3. An exemplary CD18 bindingagent can be selected from antibodies or antibody fragments employing CDRs of clones 1B4,TS1 / 18, MEM-48, YFC118-3, TA-4, MEM-148, or R3-3, 24. An exemplary CD11a bindingagent can be selected from antibodies or antibody fragments employing CDRs of cloneMHM24 or Efalizumab. An exemplary IL-2 receptor binding agent can be selected from ofantibodies or antibody fragments employing CDRs of clones YTH 906.9HL, IL2R.1, BC96, B-B10, 216, MEM-181, ITYV, MEM-140, ICO-105, Daclizumab, or from the group consistingof IL2 or fragments of IL2. An exemplary IL-15R binding agent can be selected fromantibodies or antibody fragments employing CDRs of clones JM7A4, or OTI3D5, or from thegroup consisting of IL15 or fragments of IL15. An exemplary TLR2 binding agent can beselected from antibodies or antibody fragments employing CDRs of clones JM22-41, TL2.1,11G7, or TLR2.45. An exemplary TLR4 binding agent can be selected from antibodies orantibody fragments employing CDRs of clones HTA125, or 76B357-1. An exemplary TLR5binding agent can be selected from antibodies or antibody fragments employing CDRs ofclones 85B152-5, or 9D759-2. An exemplary GL7 binding agent can be selected fromantibodies or antibody fragments employing CDRs of clone GL7. An exemplary PD1 binding agent can be selected from antibodies or antibody fragments employing CDRs of clones MIH4, J116, J150, OTIB11, OTI17B10, OTI3A1, orOTI16D4. In addition, exemplary anti-PD-1 antibodies are described, for example, in U.S.Patent Nos. 8,952,136, 8,779,105, 8,008,449, 8,741,295, 9,205,148, 9,181,342, 9,102,728,9,102,727, 8,952,136, 8,927,697, 8,900,587, 8,735,553, and 7,488,802. Exemplary anti-PD-1antibodies include, for example, nivolumab (Opdivo®, Bristol-Myers Squibb Co.), pembrolizumab (Keytruda®, Merck Sharp & Dohme Corp.), PDR001 (NovartisPharmaceuticals), and pidilizumab (CT-011, Cure Tech). Exemplary anti-PD-L1 antibodies aredescribed, for example, in U.S. Patent Nos. 9,273,135, 7,943,743, 9,175,082, 8,741,295,8,552,154, and 8,217,149. Exemplary anti-PD-L1 antibodies include, for example,atezolizumab (Tecentriq®, Genentech), durvalumab (AstraZeneca), MEDI4736, avelumab, and BMS 936559 (Bristol Myers Squibb Co.). An exemplary CTLA-4 binding agent can be selected from antibodies or antibody fragments employing CDRs of clones ER4.7G.11 [7G11], OTI9G4, OTI9F3, OTI3A5, A3.4H2.H12, 14D3, OTI3A12, OTI1A11, OTI1E8, OTI3B11, OTI3D2, OTI10C8, OTI2E9,OTI6F1, OTI7D3, OTI85B, OTI12C6. Exemplary anti-CTLA-4 antibodies are described inU.S. Patent Nos.6,984,720, 6,682,736, 7,311,910; 7,307,064, 7,109,003, 7,132,281, 6,207,156, 7,807,797, 7,824,679, 8,143,379, 8,263,073, 8,318,916, 8,017,114, 8,784,815, and 8,883,984, International (PCT) Publication Nos. WO98 / 42752, WO00 / 37504, and WO01 / 14424, andEuropean Patent No. EP 1212422 B1. Exemplary CTLA-4 antibodies include ipilimumab ortremelimumab. An exemplary TCR β binding agent can be an antibody selected from the group consisting of H57-597 (Invitrogen), 8A3 (Novus Biologicals), R73 (TCRα / β, Abcam), E6Z3S(TRBC1 / TCRβ, Cell Signaling Technology), and antigen binding fragments thereof. In certainembodiments, the binding agent comprises a VH domain and a VL of an antibody selected from the group consisting of H57-597 (Invitrogen), 8A3 (Novus Biologicals), R73 (TCRα / β,Abcam), and E6Z3S (TRBC1 / TCRβ, Cell Signaling Technology). In certain embodiments, thebinding agent comprises the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3, determined under Kabat (see, Kabat et al., (1991) Sequences of Proteins ofImmunological Interest, NIH Publication No. 91-3242, Bethesda), Chothia (see, e.g., ChothiaC & Lesk A M, (1987), J. MOL. BIOL. 196: 901-917), MacCallum (see, MacCallum R M et al., (1996) J. MOL. BIOL. 262: 732-745), or any other CDR determination method known inthe art, of the VH and VL sequences of an antibody selected from the group consisting of H57-597 (Invitrogen), 8A3 (Novus Biologicals), R73 (TCRα / β, Abcam), and E6Z3S (TRBC1 / TCRβ, Cell Signaling Technology). An exemplary CD137 binding agent can be selected from antibodies or antibody fragments employing CDRs of clones 4B4-1, P566, or Urelumab. In some embodiments, the immune cell targeting group comprises an antibodyselected from the group consisting of a Fab, F(ab’)2, Fab’-SH, Fv, and scFv fragment. In someembodiments, the antibody is a human or humanized antibody. In some embodiments, theimmune cell targeting group comprises a Fab or an immunoglobulin single variable domain,such as a VHH. In some embodiments, the immune cell targeting group comprises a Fab thatdoes not comprise a natural interchain disulfide bond. For example, in some embodiments, theFab comprises a heavy chain fragment that comprises a C233S substitution, and / or a light chainfragment that comprises a C214S substitution, numbering according to Kabat. In someembodiments, the immune cell targeting group comprises a Fab that comprises one or morenon-native interchain disulfide bonds. In some embodiments, the interchain disulfide bonds arebetween two non-native cysteine residues on the light chain fragment and heavy chainfragment, respectively. For example, in some embodiments, the Fab comprises a heavy chainfragment that comprises F174C substitution, and / or a light chain fragment that comprisesS176C substitution, numbering according to Kabat. In some embodiments, the Fab comprisesa heavy chain fragment that comprises F174C and C233S substitutions, and / or a light chainfragment that comprises S176C and C214S substitutions, numbering according to Kabat. Insome embodiments, the immune cell targeting group comprises a C-terminal cysteine residue.In some embodiments, the immune cell targeting group comprises a Fab that comprises acysteine at the C-terminus of the heavy or light chain fragment. In some embodiments, the Fabfurther comprises one or more amino acids between the heavy chain of the Fab and the C-terminal cysteine. For example, in some embodiments, the Fab comprises two or more aminoacids derived from an antibody hinge region (e.g., a partial hinge sequence) between the C-terminus of the Fab and the C-terminal cysteine. In some embodiments, the Fab comprises aheavy chain variable domain linked to an antibody CH1 domain and a light chain variable domain linked to an antibody light chain constant domain, wherein the CH1 domain and the light chain constant domain are linked by one or more interchain disulfide bonds, and wherein the immune cell targeting group further comprises a single chain variable fragment (scFv) linked to the C-terminus of the light chain constant domain by an amino acid linker. In some embodiments, the Fab antibody is a DS Fab, a NoDS Fab, a bDS Fab, a bDS Fab-ScFv, as demonstrated in FIG 47. In some embodiments, the immune cell targeting group comprises animmunoglobulin single variable domain, such as a VHH. In some embodiments, the VHHcomprises a cysteine at the C-terminus. In some embodiments, the VHH further comprises aspacer comprising one or more amino acids between the VHH domain and the C-terminal cysteine. In some embodiments, the spacer comprises one or more glycine residues, e.g., two glycine residues. In some embodiments, the immune cell targeting group comprises two ormore VHH domains. In some embodiments, the two or more VHH domains are linked by anamino acid linker. In some embodiments, the amino acid linker comprises one or more glycineand / or serine residues (e.g., one or more repeats of the sequence GGGGS). In someembodiments, the immune cell targeting group comprises a first VHHdomain linked to an antibody CH1 domain and a second VHH domain linked to an antibody light chain constant domain, and wherein the antibody CH1 domain and the antibody light chain constant domain are linked by one or more disulfide bonds (e.g., interchain disulfide bonds). In someembodiments, the immune cell targeting group comprises a VHH domain linked to an antibody CH1 domain, and wherein the antibody CH1 domain is linked to an antibody light chain constant domain by one or more disulfide bonds. In some embodiments, the CH1 domaincomprises F174C and C233S substitutions, and the light chain constant domain comprises S176C and C214S substitutions, numbering according to Kabat. In some embodiments, theantibody is a ScFv, a VHH, a 2xVHH, a VHH-CH1 / empty Vk, or a VHH1-CH1 / VHH-2-Nb bDS, as demonstrated in FIG. 31. An exemplary targeting moiety may have an amino sequence as set forth below: KTHTC ( Q ) ( Q ) Anti-CD8 BDSn Nb sequence (SEQ ID NO: 77) 12D2 bDS LC (SEQ ID NO: 85): QFVLTQPNSVSTNLGSTVKLSCKRSTGNIGSNYVNWYQQHEGRSPTTMIYRDDKRPD GVPDRFSGSIDRSSNSALLTINNVQTEDEADYFCQSYSSGIVFGGGTKLTVLSQPKAA PSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGVETTKPSKQSN NKYAACSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAESS Anti-CD288G8A Fab sequence 8G8A bDS HC (SEQ ID NO: 86): EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIQWVKQKPGQGLEWIGSINPYND YTKYNEKFKGKATLTSDKSSITAYMEFSLTSEDSALYCARWGDGNYWGRGTLTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTCPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSSDKTHTCGGHHH HHH 8G8A bDS LC (SEQ ID NO: 87): DIEMTQSPAIMSASLGERVTMTCTASSSVSSSYFHWYQKPGSSPKLCIYSTSNLASGV PPRFSGSGSTSYSLTISMEAEDAATYFCHQYHRSPTFGGGTKLETKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLC STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGES Anti-CD282E12 Fab sequence 2E12 bDS HC (SEQ ID NO: 88): QVQLKESGPGLVAPSQSLSITCTVSGFSLTGYGVNWVRQPPGKGLEWLGMIWGDGS TDYNSALKSRLSITKDNSKSQVFLKMNSLQTDDTARYYCARDGYSNFHYYVMDYW GQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTCPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSSDK THTCGGHHHHHH 2E12 bDS LC (SEQ ID NO: 89): DIVLTQSPASLAVSLGQRATISCRASESVEYYVTSLMQWYQQKPGQPPKLLISAASNV ESGVPARFSGSGSGTDFSLNIHPVEEDDIAMYFCQQSRKVPWTFGGGTKLEIKRRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLCSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGES Anti-CD28 CD28.9.3 Fab sequence CD28.9.3 bDS HC (SEQ ID NO: 90): QVKLQQSGPGLVTPSQSLSITCTVSGFSLSDYGVHWVRQSPGQGLEWLGVIWAGGG TNYNSALMSRKSISKDNSKSQVFLKMNSLQADDTAVYYCARDKGYSYYYSMDYW GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTCPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSSD KTHTCGGHHHHHH CD28.9.3 bDS LC (SEQ ID NO: 91): DIVLTQSPAS LAVSLGQRAT ISCRASESVEYYVTSLMQWY QQKPGQPPKL LIFAASNVES GVPARFSGSG SGTNFSLNIHPVDEDDVAMY FCQQSRKVPY TFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLCSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGES Anti-CD28 HzTN228 Fab sequence HzTN228 bDS HC (SEQ ID NO: 92): In some embodiments, the targeting moiety comprises a polypeptide sequence as disclosed herein. In some embodiments, the targeting moiety comprises all six CDRs of a polypeptide sequence as disclosed herein. In some embodiments, the targeting moiety comprises CDR1, CDR2, and CDR3 of an immunoglobulin single variable domain (ISVD) as disclosed herein. In further embodiments, the targeting moiety binds to the same epitope on the targeting molecule that a polypeptide sequence as disclosed herein binds to. In further embodiments, the targeting moiety competes with a polypeptide sequence as disclosed herein to bind to the same epitope on the targeting molecule. In certain embodiments, the targeting group or immune cell targeting group (e.g.,macrophage targeting agent) may be covalently coupled to a lipid via a polyethylene glycol(PEG) containing linker. In other embodiments, the lipid used to create a conjugate may be selected from distearoyl-phosphatidylethanolamine (DSPE): , dipalmitoyl-phosphatidylethanolamine (DPPE): , dimyrstoyl-phosphatidylethanolamine (DMPE): , distearoyl-glycero-phosphoglycerol (DSPG): , dimyristoyl-glycerol (DMG): , distearoylglycerol (DSG): , andN-palmitoyl-sphingosine (C16-ceramide). The immune cell targeting group can be covalently coupled to a lipid either directlyor via a linker, for example, a polyethylene glycol (PEG) containing linker. In certainembodiments, the PEG is PEG 1000, PEG 2000, PEG 3400, PEG 3000, PEG 3450, PEG 4000,or PEG 5000. In certain, embodiments, the PEG is PEG 2000.In some embodiments, the lipid-immune cell targeting group conjugate is presentin the lipid blend in a range of 0.001-0.5 mole percent, 0.001-0.3 mole percent, 0.002-0.2 mole percent, 0.01-0.1 mole percent, 0.1-0.3 mole percent, or 0.1-0.2 mole percent. In certain embodiments, the lipid immune-cell targeting agent conjugate comprisesDSPE, a PEG component and a targeting antibody. In certain embodiments, the antibody is aT-cell targeting agent, for example, an anti-CD2 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD7 antibody, an anti CD8 antibody, or an anti-TCR β antibody. An exemplary lipid-immune cell targeting group conjugate comprises DSPE andPEG 2000, for example, as described in Nellis et al. (2005) BIOTECHNOL. PROG. 21, 205-220.An exemplary conjugate comprises the structure of Formula (III), where the scFv representsan engineered antibody binding site that binds to a target of interest. In certain embodiments,the engineered antibody binding site binds to any of the targets described hereinabove. Incertain embodiments, the engineered antibody binding site can be, for example, an engineeredanti-CD3 antibody or an engineered anti-CD8 antibody. In certain embodiments, theengineered antibody binding site can be, for example, an engineered anti-CD2 antibody or an engineered anti-CD7 antibody. An example of a compound of Formula (III) is as shown below: (III).It is contemplated that the scFv in Formula (III) may be replaced with an intact antibody or anantigen fragment thereof (e.g., a Fab).Another example of a compound of Formula (IV) is as shown below: (IV),the production of which is described in Nellis et al. (2005) supra, or U.S. Patent No. 7,022,336.It is contemplated that the Fab in Formula (IV) may be replaced with an intact antibody or anantigen fragment thereof (e.g., an (Fab’)2 fragment) or an engineering antibody binding site(e.g., an scFv). Other lipid immune cell target group conjugates are described, for example, in U.S.Patent No. 7,022,336, where the targeting group may be replaced with a targeting group ofinterest, for example, a targeting group that binds a T-cell or NK cell surface antigen as described hereinabove. In certain embodiments, the lipid component of an exemplary conjugate of Formula(II) can be any of the lipids described herein. In some embodiments, the lipid component of aconjugate of Formula (II) is based on an ionizable, cationic lipid described herein, for example,an ionizable, cationic lipid of Formula (I), Formula (Ia), Formula (Ib), or a slat thereof. Forexample, an exemplary ionizable, cationic lipid can be selected from Table 1, or a salt thereof. In certain embodiments, the conjugate based on a lipid of the present disclosure may include: ,where scFv represents an engineered antibodybinding site that binds a target described hereinabove, e.g., CD2, CD3, CD7, or CD8. In certain embodiments, the lipid blend may further comprise free PEG-lipid so as to reducethe amount of non-specific binding via the targeting group. The free PEG-lipid can be the sameor different from the PEG-lipid included in the conjugate. In certain embodiments, the freePEG-lipid is selected from the group consisting of PEG-distearoyl-phosphatidylethanolamine (PEG-DSPE) or PEG-dimyrstoyl-phosphatidylethanolamine (PEG-DMPE), N- (Methylpolyoxyethylene oxycarbonyl)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-PEG) 1,2-Dimyristoyl-rac-glycero-3-methylpolyoxyethylene (PEG-DMG), 1,2- Dipalmitoyl-rac-glycero-3-methylpolyoxyethylene (PEG-DPG), 1,2-Dioleoyl-rac-glycerol, methoxypolyethylene Glycol (DOG-PEG) 1,2-Distearoyl-rac-glycero-3- methylpolyoxyethylene (PEG-DSG), N-palmitoyl-sphingosine-1- {succinyl[methoxy(polyethylene glycol)] (PEG-ceramide), DSPE-PEG-cysteine, or aderivative thereof, all with average PEG lengths between 2000-5000, with 2000, 3400, or 5000.A final composition may comprise a mixture of two or more of these pegylated lipids. In certainembodiments, the LNP composition comprises a mixture of PEG-lipids with myristoyl andstearic acyl chains. In certain embodiments, the LNP composition comprises a mixture of PEG-lipids with palmitoyl and stearoyl acyl chains. In certain embodiments, the derivative of the PEG-lipid has a methyoxy, hydroxyl or a carboxylic acid end group at the PEG terminus. The lipid-immune cell targeting group conjugate can be incorporated into LNPs as described below, for example, in LNPs comprising, for example, an ionizable cationic lipid, asterol, a neutral phospholipid and a PEG-lipid. It is contemplated that, in certain embodiments,the LNPs comprising the lipid-immune cell targeting group can comprise an ionizable cationiclipid described herein or a cationic lipid described, for example, in U.S. Patent No. 10,221,127,10,653,780 or U.S. Published application No. US2018 / 0085474, US2016 / 0317676,International Publication No. WO2009 / 086558, or Miao et al. (2019) NATURE BIOTECH37:1174-1185, or Jayaraman et al. (2012) ANGEW CHEM INT. 51: 8529-8533.In some embodiments, the cationic lipid can be selected from an ionizable cationiclipid set forth in Table 1, or a salt thereof.Table 1. Lipids Structures(Lipid 40) (Lipid 41) (Lipid 42) (Lipid 43) (Lipid 44) (Lipid 45) (Lipid 46) (Lipid 47) (Lipid 48) (Lipid 49) (Lipid 50) (Lipid 51) (Lipid 52) (Lipid 53) (Lipid 54) (Lipid 55) (Lipid 56) (Lipid 57)

[0005] (Lipid 58) (Lipid 59)

[0006] (Lipid 60) (Lipid 61) (Lipid 62)

[0007] (Lipid 63) (Lipid 64) (Lipid 65) (Lipid 66)

[0008] In some embodiments, the cationic lipid is lipid 40, lipid 41, lipid 42, lipid 43, lipid 46, or lipid 52, or a salt thereof. In some embodiments, the cationic lipid is lipid 40. Any variation or embodiment of R1, R2, R3, R1A, R2A, R3A, R1A1, R1A2, R1A3, R2A1,R2A2, R2A3, R3A1, R3A2, R3A3, Ra1, Ra2, R3B, R3B1, R3B2, R3B3, Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11, Rs12, Rs13, Rs14, or Rs15provided herein can be combined with every other variation or embodiment of R1, R2, R3, R1A, R2A, R3A, R1A1, R1A2, R1A3, R2A1, R2A2, R2A3, R3A1, R3A2, R3A3, Ra1, Ra2, R3B, R3B1, R3B2, R3B3, Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11, Rs12, Rs13, Rs14, or Rs15, as if each combination had been individually and specifically described. The LNPs can be formulated using the methods and other components described below in the following sections.IV. LIPID NANOPARTICLE COMPOSITIONSThe invention provides a lipid nanoparticle (LNP) composition comprising a lipid blend that comprises an ionizable cationic lipid described herein and / or a lipid-immune celltargeting agent conjugate described herein. In certain embodiments, the lipid blend maycomprise an ionizable, cationic lipid described herein and one or more of a sterol, a neutral phospholipid, a PEG-lipid, and a lipid-immune cell targeting group conjugate. In certain embodiments, the ionizable, cationic lipid described herein may be present in the lipid blend in a range of 30-70 mole percent, 30-60 mole percent 30-50 molepercent, 40-70 mole percent, 40-60 mole percent, 40-50 mole percent, 50-70 mole percent, 50-60 mole percent, or of about 30 mole percent, about 35 mole percent, about 40 mole percent, about 45 mole percent, about 50 mole percent, about 55 mole percent, about 60 mole percent, about 65 mole percent, or about 70 mole percent. STEROL In certain embodiments, the lipid blend of the lipid nanoparticle may comprise asterol component, for example, one or more sterols selected from the group consisting ofcholesterol, fecosterol, β-sitosterol, ergosterol, campesterol, stigmasterol, stigmastanol,brassicasterol. In certain embodiments, the sterol is cholesterol.The sterol (e.g., cholesterol) may be present in the lipid blend in a range of 20-70 mole percent, 20-60 mole percent, 20-50 mole percent, 30-70 mole percent, 30-60 mole percent, 30-50 mole percent, 40-70 mole percent, 40-60 mole percent, 40-50 mole percent, 50- 70 mole percent, 50-60 mole percent, or about 20 mole percent, about 25 mole percent, about 30 mole percent, about 35 mole percent, about 40 mole percent, about 45 mole percent, about50 mole percent, about 55 mole percent, about 60 mole percent or about 65 mole percent.NEUTRAL PHOSPHOLIPID In certain embodiments, the lipid blend of the lipid nanoparticle may comprise oneor more neutral phospholipids. The neutral phospholipid can be selected from the groupconsisting of phosphatidylcholine, phosphatidylethanolamine, distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), hydrogenated soy phosphatidylcholine (HSPC), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), sphingomyelin (SM). Other neutral phospholipids can be selected from the group consisting of distearoyl- phosphatidylethanolamine (DSPE), dimyrstoyl-phosphatidylethanolamine (DMPE), distearoyl-glycero-phosphocholine (DSPC), hydrogenated soy phosphatidylcholine (HSPC), dioleoyl-glycero-phosphoethanolamine (DOPE), dilinoleoyl-glycero-phosphocholine (DLPC), dimyristoyl-glycero-phosphocholine (DMPC), dioleoyl-glycero-phosphocholine (DOPC), dipalmitoyl-glycero-phosphocholine (DPPC), diundecanoyl-glycero-phosphocholine (DUPC), palmitoyl-oleoyl-glycero-phosphocholine (POPC), dioctadecenyl-glycero- phosphocholine, oleoyl-cholesterylhemisuccinoyl-glycero-phosphocholine, hexadecyl- glycero-phosphocholine, dilinolenoyl-glycero-phosphocholine, diarachidonoyl-glycero-3- phosphocholine, didocosahexaenoyl-glycero-phosphocholine, or sphingomyelin. The neutral phospholipid may be present in the lipid blend in a range of 1-10 mole percent, 1-15 mole percent, 1-12 mole percent, 1-10 mole percent, 3-15 mole percent, 3-12mole percent, 3-10 mole percent, 4-15 mole percent, 4-12 mole percent, 4-10 mole percent, 4-8 mole percent, 5-15 mole percent, 5-12 mole percent, 5-10 mole percent, 6-15 mole percent, 6-12 mole percent, 6-10 more percent, or about 1 mole percent, about 2 mole percent, about 3 mole percent, about 4 mole percent, about 5 mole percent, about 6 mole percent, about 7 mole percent, about 8 mole percent, about 9 mole percent, about 10 mole percent, about 11 mole percent, about 12 mole percent, about 13 mole percent, about 14 mole percent, or about 15 mole percent. PEG-LIPIDThe lipid blend of the lipid nanoparticle may include one or more PEG or PEG-modified lipids. Such species may be alternately referred to as PEGylated lipids. A PEG lipidis a lipid modified with polyethylene glycol. As noted above, free PEG-lipids can be includedin the lipid blend to reduce or eliminate non-specific binding via a targeting group when a lipid- immune cell targeting group is included in the lipid blend. A PEG lipid may be selected from the non-limiting group consisting of PEG- modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, and PEG-modifieddialkylglycerols. For example, a PEG lipid may be PEG- dioleoylgylcerol (PEG-DOG), PEG-dimyristoyl-glycerol (PEG-DMG), PEG-dipalmitoyl-glycerol (PEG-DPG), PEG-dilinoleoyl- glycero-phosphatidyl ethanolamine (PEG-DLPE), PEG-dimyrstoyl-phosphatidylethanolamine(PEG-DMPE), PEG-dipalmitoyl- phosphatidylethanolamine (PEG-DPPE), PEG-distearoylglycerol (PEG-DSG), PEG-diacylglycerol (PEG-DAG, e.g., PEG-DMG, PEG-DPG,and PEG-DSG), PEG-ceramide, PEG-distearoyl-glycero-phosphoglycerol (PEG-DSPG), PEG-dioleoyl-glycero-phosphoethanolamine (PEG-DOPE), 2-[(polyethylene glycol)-2000]- N,N-ditetradecylacetamide, or a PEG-distearoyl-phosphatidylethanolamine (PEG-DSPE) lipid. In certain embodiments, the blend may comprise a free PEG-lipid that can be selected from the group consisting of PEG-distearoylglycerol (PEG-DSG), PEG- diacylglycerol (PEG-DAG, e.g., PEG-DMG, PEG-DPG, and PEG-DSG), PEG-dimyristoyl- glycerol (PEG-DMG), PEG-distearoyl-phosphatidylethanolamine (PEG-DSPE) and PEG-dimyrstoyl-phosphatidylethanolamine (PEG-DMPE). In some embodiments, the free PEG-lipid comprises a diacylphosphatidylcholines comprising Dipalmitoyl (C16) chain or Distearoyl (C18) chain. The PEG-lipid may be present in the lipid blend in a range of 1-10 mole percent, 1-8 mole percent, 1-7 mole percent, 1-6 mole percent, 1-5 mole percent, 1-4 mole percent, 1-3mole percent, 2-8 mole percent, 2-7 mole percent, 2-6 mole percent, 2-5 mole percent, 2-4 molepercent, 2-3 mole percent, or about 1 mole percent, about 2 mole percent, about 3 mole percent,about 4 mole percent, or about 5 mole percent. In some embodiments, the PEG-lipid is a freePEG-lipid. In some embodiments, the PEG-lipid may be present in the lipid blend in the range of 0.01-10 mole percent, 0.01-5 mole percent, 0.01-4 mole percent, 0.01-3 mole percent, 0.01- 2 mole percent, 0.01-1 mole percent, 0.1-10 mole percent, 0.1-5 mole percent, 0.1-4 mole percent, 0.1-3 mole percent, 0.1-2 mole percent, 0.1-1 mole percent, 0.5-10 mole percent, 0.5- 5 mole percent, 0.5-4 mole percent, 0.5-3 mole percent, 0.5-2 mole percent, 0.5-1 mole percent, 1-2 mole percent, 3-4 mole percent, 4-5 mole percent, 5-6 mole percent, or 1.25-1.75 molepercent. In some embodiments, the PET-lipid may be about 0.5 mole percent, about 1 molepercent, about 1.5 mole percent, about 2 mole percent, about 2.5 mole percent, about 3 mole percent, about 3.5 mole percent, about 4 mole percent, about 4.5 mole percent, about 5 molepercent, or about 5.5 mole percent of the lipid blend. In some embodiments, the PEG-lipid is afree PEG-lipid. In some embodiments, the lipid anchor length of PEG-lipid is C14 (as in PEG-DMG). In some embodiments, the lipid anchor length of PEG-lipid is C16 (as in DPG). Insome embodiments, the lipid anchor length of PEG-lipid is C18 (as in PEG-DSG). In someembodiments, the back bone or head group of PEG-lipid is diacyl glycerol orphosphoethanolamine. In some embodiments, the PEG-lipid is a free PEG-lipid.A LNP of the present disclosure may comprise one or more free PEG-lipid that is not conjugated to an immune cell targeting group, and a PEG-lipid that is conjugated to immune cell targeting group. In some embodiments, the free PEG-lipid comprises the same or a different lipid as the lipid in the lipid-immune cell targeting group conjugate. IMMUNE CELL TARGETING GROUP CONJUGATE In certain embodiments, the lipid blend can also include a lipid-immune celltargeting group conjugate.The lipid-immune cell targeting group conjugate may be present in the lipid blendin a range of 0.001-0.5 mol percent, 0.001-0.1 mole percent, 0.01-0.5 mole percent, 0.05-0.5mole percent, 0.1-0.5 mole percent, 0.1-0.3 mole percent, 0.1-0.2 mole percent, 0.2-0.3 mole percent, of about 0.01 mole percent, about 0.05 mole percent, about 0.1 mole percent, about 0.15 mole percent, about 0.2 mole percent, about 0.25 mole percent, about 0.3 mole percent, about 0.35 mole percent, about 0.4 mole percent, about 0.45 mole percent, or about 0.5 mole percent. In addition to the lipids present in the lipid blend, the LNP compositions may furthercomprise a payload, for example, a payload described hereinbelow. In certain embodiments,the payload is a nucleic acid, for example, DNA or RNA, for example, an mRNA, transferRNA (tRNA), a microRNA, or small interfering RNA (siRNA). In certain embodiments, the number of the nucleotides in the nucleic acid is from about 400 to about 6000. PRODUCTION OFLIPIDNANOPARTICLESIn some embodiments, the LNPs are produced by using either rapid mixing by anorbital vortexer or by microfluidic mixing. Orbital vortexer mixing is accomplished by rapidaddition of lipids solution in ethanol to the aqueous solution of a nucleic acid of interestfollowed immediately by vortexing at 2,500 rpm. In some embodiments, the LNPs areproduced using a microfluidic mixing step. In some embodiments, microfluidic mixing isachieved mixing the aqueous and organic streams at a controlled flow rates in a microfluidicchannel using, e.g., a NanoAssemblr device and microfluidic chips featuring optimized mixingchamber geometry (Precision Nanosystems, Vancouver, BC). In some embodiments, the LNPsare produced using a microfluidic mixing step to rapidly mix the ethanolic lipid solution and aqueous nucleic acid solution, resulting in encapsulation of the nucleic acid in the solid lipidnanoparticles. The nanoparticle suspension is then buffer exchanged into an all aqueous bufferusing membrane filtration device of choice for ethanol removal and nanoparticle maturation.In certain embodiments, the resulting LNP compositions comprise a lipid blend comprising, for example, from about 40 mole percent to about 60 mole percent of one or more ionizable cationic lipids described herein, from about 35 mole percent to about 50 mole percent of one or more sterols, from about 5 mole percent to about 15 mole percent of one or more neutral lipids, and from about 0.5 mole percent to about 5 mole percent of one or more PEG- lipids. PHYSICAL PROPERTIES OF LIPID NANOPARTICLES The characteristics of an LNP composition may depend on the components, theirabsolute or relative amounts, contained in a lipid nanoparticle (LNP) composition.Characteristics may also vary depending on the method and conditions of preparation of the LNP composition. LNP compositions may be characterized by a variety of methods. For example,microscopy (e.g., transmission electron microscopy or scanning electron microscopy) may beused to examine the morphology and size distribution of an LNP composition. Dynamic lightscattering or potentiometry (e.g., potentiometric titrations) may be used to measure zetapotentials. Dynamic light scattering may also be utilized to determine particle sizes.Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern,Worcestershire, UK) may also be used to measure multiple characteristics of an LNPcomposition, such as particle size, polydispersity index, and zeta potential. RNA encapsulatedefficiency is determined by a combination of methods relying on RNA binding dyes (ribogreen,cybergreen to determine dye accessible RNA fraction) and LNP de-formulation followed by HPLC analysis for total RNA content. In some embodiments, the LNP may have a mean diameter in the range of 1-250nm, 1-200 nm, 1-150 nm, 1-100 nm, 50-250 nm, 50-200 nm, 50-150 nm, 50-100 nm, 75-250nm, 75-200 nm, 75-150 nm, 75-100 nm, 100-250 nm, 100-200 nm, 100-150 nm. In certainembodiments, the LNP compositions may have a mean diameter of about 1nm, about 10 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm,about 150 nm, about 160 nm, about 170 nm, about 180 nm, about 190 nm, or about 200 nm. Insome embodiments, the LNP has a mean diameter of about 100 nm. In some embodiments, LNPs comprising an ionizable cationic lipid describedherein, prepared and characterized using methods described herein, show average diameter change after a freeze-thaw of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, show average diameter change after a freeze-thaw of less than 30%. In some embodiments, the freeze-thaw and diameter measurements are conducted with 10% sucrose in MES pH 6.5 buffer. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, show average diameterchange upon targeting antibody insertion of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,35, or 40%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, show average diameter change upon targeting antibody insertion of less than 15%. In some embodiments, the diameter change upon targeting antibody insertion is measured in pH 6.5 MES using a 37°C incubation for 4 hours. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have average LNP diameter of less than 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nm. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have average LNP diameter of less than 100 nm. Alternatively or in addition, the LNP compositions may have a polydispersity indexin a range from 0.05-1, 0.05-0.75, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.08-1, 0.08-0.75,0.08-0.5, 0.08-0.4, 0.08-0.3, 0.08-0.2, 0.1-1, 0.1-0.75, 0.1-0.5, 0.1-0.4, 0.1-0.3, 0.1-0.2. Incertain embodiments, the polydispersity index is in the range of 0.1-0.25, 0.1-0.2, 0.1-0.19, 0.1-0.18, 0.1-0.17, 0.1-0.16, or 0.1-0.15. In some embodiments, the LNP compositions or LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have polydispersity of less than 0.4, 0.3, 0.25, 0.2, 0.15, 0.1, or 0.05. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have polydispersity of less than 0.25. Alternatively or in addition, the LNP compositions may have a zeta potential ofabout -30 mV to about +30 mV. In certain embodiments, the LNP composition has a zetapotential of about -10 mV to about +20 mV. The zeta potential may vary as a function of pH.As a result, in certain embodiments, the LNP compositions may have a zeta potential of about0 mV to about + 30 mV or about +10 mV to + 30 mV or about + 20 mV to about + 30 mV atpH 5.5 or pH 5, and / or a zeta potential of about -30 mV to about + 5 mV or about – 20 mV toabout + 15 mV at pH 7.4. In some embodiments, the LNP compositions or LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have Zeta Potential at pH 7.4 greater than -10, -9, -8, -7, -6, -5.5, -5, -4.5, -4, -3.5, -3, -2.5, -2, -1.5, -1, or -0.5 mV. In some embodiments, the LNP compositions LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have Zeta Potential at pH 7.4 greater than -10 mV. In some embodiments, the LNP compositions LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have Zeta Potential at pH 7.4 greater than -1 mV. In some embodiments, the LNP compositions LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have Zeta Potential at pH 5.5 greater than -1, 0, 1, 2, 3, 4, 4.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, or 25mV. In some embodiments, the LNP compositions LNPs comprising an ionizable cationic lipiddescribed herein, prepared and characterized using methods described herein, have Zeta Potential at pH 5.5 greater than 5 mV. In some embodiments, the LNP compositions LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, have Zeta Potential at pH 5.5 greater than 15 mV. SELECTIVE ORGAN DELIVERY In some embodiments, the LNP described herein has high liver avoidance. In some embodiments, the LNP comprises about 1.5 mol% of free PEG-lipid. In some embodiments,the LNP comprises about 1 to about 2 mol% of free PEG-lipid. In some embodiments, the freePEG-lipid is DSG-PEG. In some embodiments, the LNP comprising about 3.5 mol% of DSG-PEG has high liver targeting.In some embodiments, liver avoidance is measured with imaging (e.g., ex vivo luciferase imaging). In some embodiments, liver avoidance is measured as a non-liver / liver ratio. In some embodiments, the non-liver / liver ratio is the level of LNP accumulation, cargo delivery, or cargo expression in a non-liver organ (e.g., spleen) relative to that in the liver. In some embodiments, liver avoidance is measured certain period of time (e.g., 24 hours) after dosing the subject with the LNP. In some embodiments, the non-liver / liver ratio is about 1 to about 1.5. In some embodiments, the non-liver / liver ratio is about 1.25. In some embodiments, the LNP described herein has high liver targeting. In someembodiments, the LNP comprises about 3.5 mol% of free PEG-lipid. In some embodiments, the LNP comprises about 3 to about 4 mol% of free PEG-lipid. In some embodiments, the freePEG-lipid is DSG-PEG. In some embodiments, the free PEG-lipid is DPG-PEG. In someembodiments, the LNP comprising about 3.5 mol% of DSG-PEG or about 3.5 mol% of DPG- PEG has high liver targeting. In some embodiments, liver targeting is measured with imaging (e.g., ex vivo luciferase imaging). In some embodiments, liver targeting is measured as a liver / non-liver ratio. In some embodiments, the liver / non-liver ratio is the level of LNP accumulation, cargo delivery, or cargo expression in the liver relative to that in a non-liver organ (e.g., spleen). In some embodiments, liver targeting is measured certain period of time (e.g., 24 hours) afterdosing the subject with the LNP. In some embodiments, the liver / non-liver ratio is about 1 toabout 2, or about 1.5 to about 2. In some embodiments, the liver / non-liver ratio is about 1.6 or about 1.8.V. PAYLOADSThe LNP compositions may comprise an agent, for example, a nucleic acid molecule for delivery to a cell (e.g., an immune cell) or tissue, for example, a cell (e.g., an immune cell) or tissue in a subject. The LNP compositions of the present invention may include a nucleic acid, forexample, a DNA or RNA, such as an mRNA, tRNA, microRNA, siRNA, gRNA (guide RNA),circRNA(circular RNA), ribozymes, decoy RNA or dicer substrate siRNA. It is contemplatedthat nucleic acids can contain naturally occurring components, such as, naturally occurringbases, sugars or linkage groups (e.g., phosphodiester linkage groups) or may contain non-naturally occurring components or modifications, (e.g., thioester linkage groups). For example,the nucleic acid can be synthesized to contain base, sugar, and / or linker modifications knownto those skilled in the art. Furthermore, the nucleic acids can be linear or circular, or have anydesired configuration. The LNP compositions can include multiple nucleic acid molecules, forexample, multiple RNA molecules, which can be the same or different. In certain embodiments, the payload is an mRNA. In certain embodiments, aparticular LNP composition may comprise a number of mRNA molecules that can be the sameor different. In certain embodiments, one or more LNP compositions including one or moredifferent mRNAs may be combined, and / or simultaneously contacted, with a cell. It iscontemplated that an mRNA may include one or more of a stem loop, a chain terminatingnucleoside, a polyA sequence, a polyadenylation signal, and / or a 5' cap structure. The mRNAmay encode a receptor, such as a chimeric antigen receptor (CAR), for use in for example, animmune disorder, inflammatory disorder or cancer. In addition, the mRNA may encode anantigen for use in a therapeutic or prophylactic vaccine, for example, for treating or preventing an infection by a pathogen, for example, a microbial or viral pathogen, or for reducing or ameliorating the side effects caused directly or indirectly by such an infection. In certain embodiments, the LNP composition may include one or more other components including, but not limited to, one or more pharmaceutically acceptable excipients, small hydrophobic molecules, therapeutic agents, carbohydrates, polymers, permeability enhancing molecules, and surface altering agents. In some embodiments, the wt / wt ratio of the lipid component to the payload (e.g.,mRNA) in the resulting LNP composition is from about 1:1 to about 50:1. In certainembodiments, the wt / wt ratio of the lipid component to the payload (e.g., mRNA) in theresulting composition is from about 5:1 to about 50:1. In certain embodiments, the wt / wt ratiois from about 5:1 to about 40:1. In certain embodiments, the wt / wt ratio is from about 10:1 toabout 40:1. In certain embodiments, the wt / wt ratio is from about 15:1 to about 25:1.In certain embodiments, the encapsulation efficiency of the payload (e.g., mRNA)in the lipid nanoparticles is at least 50%. In certain embodiments, the encapsulation efficiencyis at least 80%, at least 90%, or greater than 90%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, exhibit encapsulation efficiency of greater than 50, 55, 60, 65, 70, 75, 80, 82.5, 85, 87.5, 90, 92.5, 95, 97.5, or 99%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, exhibit encapsulation efficiency of greater than 87.5%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, exhibit dye accessible RNA of less than 50, 45, 40, 35, 30, 25, 20, 17.5, 15, 12.5, 10, 7.5, 5, 2.5, or 1%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, exhibit dye accessible RNA of less than 12.5%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, exhibit total mRNA recovery of greater than 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%. In some embodiments, LNPs comprising an ionizable cationic lipid described herein, prepared and characterized using methods described herein, exhibit total mRNA recovery of greater than 80%. RNA PAYLOAD In certain embodiments, the RNA payload is an mRNA, tRNA, microRNA, orsiRNA payload. In certain embodiments, the lipid nanoparticle compositions are optimized for thedelivery of RNA, e.g., mRNA, to a target cell for translation within the cell. An mRNA maybe a naturally or non-naturally occurring mRNA. An mRNA may include one or more modifiednucleobases, nucleosides, or nucleotides. The nucleobases may be selected from the non-limiting group consisting of adenine,guanine, uracil, cytosine, 7-methylguanine, 5-methylcytosine, 5-hydroxymethylcytosine,thymine, pseudouracil, dihydrouracil, N1-methylpseudouracil, hypoxanthine, and xanthine. Insome embodiments, nucleobase is N1-methylpseudouracil. A nucleoside of an mRNA is a compound including a sugar molecule (e.g., a 5- carbon or 6-carbon sugar, such as pentose, ribose, arabinose, xylose, glucose, galactose, or adeoxy derivative thereof) in combination with a nucleobase. A nucleoside may be a canonicalnucleoside (e.g., adenosine, guanosine, cytidine, uridine, 5-methyluridine, deoxyadenosine, deoxyguanosine, deoxycytidine, deoxyuridine, and thymidine) or an analog thereof and may include one or more substitutions or modifications. A nucleotide of an mRNA is a compound containing a nucleoside and a phosphate group or alternative group (e.g., boranophosphate, thiophosphate, selenophosphate,phosphonate, alkyl group, amidate, and glycerol). A nucleotide may be a canonical nucleotide(e.g., adenosine, guanosine, cytidine, uridine, 5-methyluridine, deoxyadenosine, deoxyguanosine, deoxycytidine, deoxyuridine, and thymidine monophosphates) or an analog thereof and may include one or more substitutions or modifications including but not limited to alkyl, aryl, halo, oxo, hydroxyl, alkyloxy, and / or thio substitutions; one or more fused or open rings; oxidation; and / or reduction of the nucleobase, sugar, and / or phosphate oralternative component. A nucleotide may include one or more phosphate or alternative groups.For example, a nucleotide may include a nucleoside and a triphosphate group. A "nucleosidetriphosphate" (e.g., guanosine triphosphate, adenosine triphosphate, cytidine triphosphate, and uridine triphosphate) may refer to the canonical nucleoside triphosphate or an analog or derivative thereof and may include one or more substitutions or modifications as described herein. An mRNA may include a 5' untranslated region, a 3' untranslated region, and / or acoding or translating sequence. An mRNA may include any number of base pairs, includingtens, hundreds, or thousands of base pairs. Any number (e.g., all, some, or none) ofnucleobases, nucleosides, or nucleotides may be an analog of a canonical species, substituted,modified, or otherwise non-naturally occurring. In certain embodiments, all of a particularnucleobase type may be modified. For example, all cytosine in an mRNA may be 5-methylcytosine. In certain embodiments, one or more or all uridine bases may be N1-methylpseudouridines. In certain embodiments, an mRNA may include a 5' cap structure, a chain terminating nucleotide, a stem loop, a polyA sequence, and / or a polyadenylation signal. A cap structure or cap species is a compound including two nucleoside moieties joined by a linker and may be selected from a naturally occurring cap, a non-naturally occurringcap or a cap analog. A cap species may include one or more modified nucleosides and / or linkermoieties. For example, a natural mRNA cap may include a guanine nucleotide and a guanine(G) nucleotide methylated at the 7 position joined by a triphosphate linkage at their 5' positions,e.g., m7G(5')ppp(5')G, commonly written as m7GpppG. A cap species may also be an anti-reverse cap analog. A non-limiting list of possible cap species includes m7GpppG,m7Gpppm7G, m73'dGpppG, m7Gpppm7G, m73'dGpppG, and m2702'GppppG. Alternatively or in addition, an mRNA may include a chain terminating nucleoside. For example, a chain terminating nucleoside may include those nucleosides deoxygenated atthe 2' and / or 3' positions of their sugar group. Such species may include 3'-deoxyadenosine(cordycepin), 3'-deoxyuridine, 3'-deoxycytosine, 3'-deoxyguanosine, 3'-deoxythymine, and 2',3'-dideoxynucleosides, such as 2',3'-dideoxyadenosine, 2',3'-dideoxyuridine, 2',3'- dideoxycytosine, 2',3'-dideoxyguanosine, and 2',3'-dideoxythymine. Alternatively or in addition, an mRNA may include a stem loop, such as a histonestem loop. A stem loop may include 1, 2, 3, 4, 5, 6, 7, 8, or more nucleotide base pairs. Forexample, a stem loop may include 4, 5, 6, 7, or 8 nucleotide base pairs. A stem loop may belocated in any region of an mRNA. For example, a stem loop may be located in, before, or afteran untranslated region (a 5' untranslated region or a 3' untranslated region), a coding region, or a polyA sequence or tail. Alternatively or in addition, an mRNA may include a polyA sequence and / orpolyadenylation signal. A polyA sequence may be comprised entirely or mostly of adeninenucleotides or analogs or derivatives thereof. A polyA sequence may be a tail located adjacentto a 3' untranslated region of an mRNA. An mRNA may encode any polypeptide of interest, including any naturally or non-naturally occurring or otherwise modified polypeptide. A polypeptide encoded by an mRNAmay be of any size and may have any secondary structure or activity. In some embodiments, apolypeptide encoded by an mRNA may have a therapeutic effect when expressed in a cell. Insome embodiments, the mRNA may encode an antibody, enzyme, growth factor, hormone,cytokine, viral protein (e.g., a viral capsid protein), antigen, vaccine, or receptor. In someembodiments, the mRNA may encode an engineered receptor such as a CAR or an antigen foruse in a therapeutic vaccine (e.g., a cancer vaccine) or a prophylactic vaccine (e.g., a vaccinefor minimizing the risk or severity of an infection by a microbial or viral pathogen). In someembodiments, the mRNA encodes a polypeptide capable of regulating immune response in theimmune cell. In some embodiments, the mRNA encodes a polypeptide capable ofreprogramming the immune cell. In some embodiments, the mRNA encodes a synthetic T cellreceptor (synTCR) or a Chimeric Antigen Receptor (CAR). Alipid composition may be designed for one or more specific applications ortargets. For example, an LNP composition may be designed to deliver mRNA to a particular cell, tissue, organ, or system or group thereof in a mammal's body, such as the renal system.Physiochemical properties of LNP compositions may be altered in order to increase selectivityfor particular target site within a subject. For instance, particle sizes may be adjusted based onthe fenestration sizes of different organs. The mRNA included in an LNP composition mayalso depend on the desired delivery target or targets. For example, an mRNA may be selectedfor a particular indication, condition, disease, or disorder and / or for delivery to a particular cell, tissue, organ, or system or group thereof (e.g., localized or specific delivery). The amount of mRNA in a lipid composition may depend on the size, sequence,and other characteristics of the mRNA. The amount of mRNA in an LNP may also depend onthe size, composition, desired target, and other characteristics of the LNP composition. Therelative amounts of mRNA and other elements (e.g., lipids) may also vary. The amount ofmRNA in an LNP composition may, for example, be measured using absorption spectroscopy(e.g., ultraviolet-visible spectroscopy). In some embodiments, the one or more mRNAs, lipids, and polymers and amountsthereof may be selected to provide a specific N:P ratio (the ratio of positively-chargeable lipid or polymer amine (N = nitrogen) groups to negatively-charged nucleic acid phosphate (P)groups). The N:P ratio of the composition refers to the molar ratio of nitrogen atoms in one ormore lipids to the number of phosphate groups in an mRNA. In general, a lower N:P ratio ispreferred. A N:P ratio may be dependent on a specific lipid and its pKa. In certainembodiments, the mRNA and LNP composition, and / or their relative amounts may be selectedto provide an N:P ratio from about 1:1 to about 30:1, or from about 1:1 to about 20:1. In certainembodiments, the N:P ratio can be, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. Incertain embodiments, the N:P ratio may be from about 2:1 to about 5:1. In certainembodiments, the N:P ratio may be about 4:1. In other embodiments, the N:P ratio is fromabout 4:1 to about 8:1. For example, the N:P ratio may be about 4:1, about 4.5:1, about 4.6:1,about 4.7:1, about 4.8:1, about 4.9:1, about 5.0:1, about 5.1:1, about 5.2:1, about 5.3:1, about5.4:1, about 5.5:1, about 5.6:1, about 5.7:1, about 6.0:1, about 6.5:1, or about 7.0:1.The amount of mRNA in a nanoparticle composition may depend on the size,sequence, and other characteristics of the mRNA. The amount of mRNA in a nanoparticlecomposition may also depend on the size, composition, desired target, and other characteristicsof the nanoparticle composition. The relative amounts of mRNA and other elements (e.g.,lipids) may also vary. In some embodiments, the wt / wt ratio of the lipid component to an mRNA in a nanoparticle composition may be from about 5:1 to about 50:1, such as 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1,40:1, 45:1, and 50:1. For example, the wt / wt ratio of the lipid component to an mRNA may befrom about 10:1 to about 40:1. The amount of mRNA in a nanoparticle composition may, forexample, be measured using absorption spectroscopy (e.g., ultraviolet-visible spectroscopy). The efficiency of encapsulation of an mRNA describes the amount of mRNA thatis encapsulated or otherwise associated with a lipid composition after preparation, relative tothe initial amount provided. The encapsulation efficiency is desirably high (e.g., close to100%). The encapsulation efficiency may be measured, for example, by comparing the amountof mRNA in a solution containing the lipid composition before and after breaking up the LNPcomposition with one or more organic solvents or detergents. Fluorescence may be used tomeasure the amount of free mRNA in a solution. For the LNP compositions of the invention,the encapsulation efficiency of an mRNA may be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or100%. In certain embodiments, the encapsulation efficiency may be at least 80%.VI. FORMULATION AND MODE OF DELIVERYLNP compositions of the invention may be formulated in whole or in part as apharmaceutical composition. The pharmaceutical compositions may further include one ormore pharmaceutically acceptable excipients or accessory ingredients such as those describedherein. General guidelines for the formulation and manufacture of pharmaceuticalcompositions and agents are available, for example, in Remington's (2006) supra. Conventional excipients and accessory ingredients may be used in any pharmaceutical composition of the invention, except insofar as any conventional excipient or accessoryingredient may be incompatible with one or more components of an LNP composition of theinvention. An excipient or accessory ingredient may be incompatible with a component of anLNP composition if its combination with the component may result in any undesirablebiological effect or otherwise deleterious effect. In some embodiments, one or more excipients or accessory ingredients may makeup greater than 50% of the total mass or volume of a pharmaceutical composition including anLNP composition of the invention. For example, the one or more excipients or accessoryingredients may make up 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more of a pharmaceuticalcomposition. In certain embodiments, the excipient is approved for use in humans and forveterinary use, for example, by United States Food and Drug Administration. In certainembodiments, the excipient is pharmaceutical grade. In certain embodiments, an excipientmeets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia. Relative amounts of the one or more lipids or LNPs, one or more pharmaceutically acceptable excipients, and / or any additional ingredients in a pharmaceutical composition will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. Lipid compositions and / or pharmaceutical compositions including one or moreLNP compositions may be administered to any subject, including a human patient that maybenefit from a therapeutic effect provided by the delivery of a nucleic acid, e.g., an RNA (e.g.,mRNA, tRNA or siRNA) to one or more particular cells, tissues, organs, or systems or groupsthereof, such as the renal system. Although the descriptions provided herein of LNPcompositions and pharmaceutical compositions including LNP compositions are principally directed to compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to anyother mammal. Modification of compositions suitable for administration to humans in order torender the compositions suitable for administration to various animals is understood. A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of singleunit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient (e.g., the payload). Pharmaceutical compositions of the invention may be prepared in a variety of formssuitable for a variety of routes and methods of administration. For example, pharmaceuticalcompositions of the invention may be prepared in liquid dosage forms (e.g., emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, and elixirs), injectable forms, solid dosage forms (e.g., capsules, tablets, pills, powders, and granules), dosage forms for topical and / or transdermal administration (e.g., ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and patches), suspensions, powders, and other forms. Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, nanoemulsions, solutions,suspensions, syrups, and / or elixirs. In addition to active ingredients, liquid dosage forms maycomprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters ofsorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and / or perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents,wetting agents, and / or suspending agents. Sterile injectable preparations may be sterileinjectable solutions, suspensions, and / or emulsions in nontoxic parenterally acceptable diluentsand / or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehiclesand solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodiumchloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables.Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and / or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Other Components In addition, it is contemplated that the pharmaceutical compositions may include one or more components in addition to those described hereinabove. The pharmaceutical compositions may also include one or more permeability enhancer molecules, carbohydrates, polymers, therapeutic agents, surface altering agents, orother components. A permeability enhancer molecule may be a molecule described, forexample, in U.S. patent application publication No. 2005 / 0222064. Carbohydrates may include simple sugars (e.g., glucose) and polysaccharides (e.g., glycogen and derivatives and analogs thereof). The pharmaceutical compositions may also comprise a surface altering agent, including for example, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as dimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrin), polymers (e.g., heparin, polyethylene glycol, and poloxamer), mucolytic agents (e.g., acetylcysteine, mugwort, bromelain, papain, clerodendrum, bromhexine, carbocisteine, eprazinone, mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin β4, dornase alfa, neltenexine, and erdosteine), and DNases (e.g.,rhDNase). A surface altering agent may be disposed within and / or upon the surface of acomposition described herein. In addition to these components, a pharmaceutical composition comprising an LNP composition of the invention may include any substance useful in pharmaceuticalcompositions. For example, the pharmaceutical composition may include one or morepharmaceutically acceptable excipients or accessory ingredients such as, but not limited to, one or more solvents, dispersion media, diluents, dispersion aids, suspension aids, granulating aids, disintegrants, fillers, glidants, liquid vehicles, binders, surface active agents, isotonic agents, thickening or emulsifying agents, buffering agents, lubricating agents, oils, preservatives, andother species. Excipients such as waxes, butters, coloring agents, coating agents, flavorings,and perfuming agents may also be included. Pharmaceutically acceptable excipients are wellknown in the art (see, e.g., Remington's (2006) supra).Dispersing agents may be selected from the non-limiting list consisting of potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, and / or combinations thereof. Surface active agents and / or emulsifiers may include, but are not limited to, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetylalcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glycerylmonostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [TWEEN®20], polyoxyethylene sorbitan [TWEEN® 60], polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], sorbitan monostearate [SPAN®60], sorbitan tristearate [SPAN®65], glyceryl monooleate, sorbitan monooleate [SPAN®80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [MYRJ® 45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylenestearate, and SOLUTOL®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., CREMOPHOR®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether [BRIJ® 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLURONIC®F 68, POLOXAMER® 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or combinations thereof. Examples of preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives,acidic preservatives, and / or other preservatives. Examples of antioxidants include, but are notlimited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and / or sodium sulfite. Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid,phosphoric acid, sodium edetate, tartaric acid, and / or trisodium edetate. Examples ofantimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and / or thimerosal. Examples of antifungal preservatives include, but are notlimited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and / or sorbic acid. Examples of alcohol preservatives include, but are not limitedto, ethanol, polyethylene glycol, benzyl alcohol, phenol, phenolic compounds, bisphenol,chlorobutanol, hydroxybenzoate, and / or phenylethyl alcohol. Examples of acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroascorbic acid, ascorbic acid, sorbic acid, and / or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite. Examples of buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, d-gluconic acid, calcium glycerophosphate, calcium lactate, calcium lactobionate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, amino-sulfonate buffers (e.g., HEPES), magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and / or combinations thereof. In certain embodiments, the lipid nanoparticle compositions and formulations thereof are adapted for administration intravenously, intramuscularly, intradermally,subcutaneously, intra-arterially, intra-tumor, or by inhalation. In certain embodiments, a doseof about 0.001 mg / kg to about 10 mg / kg is administered to a subject. Compositions inaccordance with the present disclosure may be formulated in dosage unit form for ease ofadministration and uniformity of dosage. It will be understood, however, that the total daily usage of a composition of the present disclosure will be decided by an attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or otherwise appropriate dose level (e.g., for imaging) for any particular patient will depend upon a varietyof factors including the severity and identify of a disorder being treated, if any; the one or moremRNAs employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific pharmaceutical composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific pharmaceutical composition employed; and like factors well known in the medical arts.VII. METHODSThe present disclosure provides methods of delivering a payload to a target cell or tissue, for example, a target cell or tissue in a subject, and LNPs or pharmaceutical compositions comprising the LNPs for use in such methods. Any disclosure herein of a methodof, e.g., treating a disease or disorder or, e.g., delivering a nucleic acid to a cell or, e.g.,producing a polypeptide of interest in a cell should be interpreted also as a disclosure of an LNP or pharmaceutical composition comprising said LNP for use in such methods. In certain embodiments, the invention provides a method of producing a polypeptide of interest (e.g., a protein of interest) in a mammalian cell, and LNPs orpharmaceutical compositions comprising the LNPs for use in such methods. Methods ofproducing polypeptides in such a cell involve contacting a cell with an LNP compositioncomprising an RNA of interest (e.g., an mRNA encoding the polypeptide of interest (e.g., aprotein of interest)). Upon contacting the cell with the LNP composition, the mRNA may betaken up and translated in the cell to produce the polypeptide of interest. In general, the step of contacting a mammalian cell with an LNP compositionincluding an mRNA encoding a polypeptide of interest may be performed in vivo, ex vivo, orin vitro. The amount of an LNP composition contacted with a cell, and / or the amount of mRNAtherein, may depend on the type of cell or tissue being contacted, the means of administration,the physiochemical characteristics of the LNP composition and the mRNA (e.g., size, charge,and chemical composition) therein, and other factors. In general, an effective amount of theLNP composition will allow for efficient polypeptide production in the cell. Metrics for efficiency may include polypeptide translation (indicated by polypeptide expression), level of mRNA degradation, and immune response indicators. The step of contacting an LNP composition including an mRNA with a cell mayinvolve or cause transfection where the LNP composition may fuse with the membrane of cellto permit the delivery of the mRNA into the cell. Upon introduction into the cytoplasm of thecell, the mRNA is then translated into a protein or peptide via the protein synthesis machinery within the cytoplasm of the cell. In certain embodiments, the LNP compositions described herein may be used todeliver therapeutic or prophylactic agents to a subject. For example, an mRNA included in anLNP composition may encode a polypeptide and produce the therapeutic or prophylacticpolypeptide upon contacting and / or entry (e.g., transfection) into a cell. In certainembodiments, an mRNA included in an LNP composition of the invention may encode apolypeptide that may improve or increase the immunity of a subject. In certain embodiments, contacting a cell with an LNP composition including anmRNA may reduce the innate immune response of a cell to an exogenous nucleic acid. A cellmay be contacted with a first LNP composition including a first amount of a first exogenousmRNA including a translatable region and the level of the innate immune response of the cellto the first exogenous mRNA may be determined. Subsequently, the cell may be contacted witha second composition including a second amount of the first exogenous mRNA, the second amount being a lesser amount of the first exogenous mRNA compared to the first amount. Alternatively, the second composition may include a first amount of a second exogenousmRNA that is different from the first exogenous mRNA. The steps of contacting the cell withthe first and second compositions may be repeated one or more times. Additionally, efficiency of polypeptide production in the cell may be optionally determined, and the cell may be re-contacted with the first and / or second composition repeatedly until a target protein production efficiency is achieved. The present disclosure provides methods of delivering a nucleic acid (e.g., anmRNA) to a mammalian cell or tissue, for example, a mammalian cell or tissue in a subject.Delivery of an mRNA to such a cell or tissue involves administering an LNP compositionincluding the mRNA to a subject, for example, by injection, e.g., via intramuscular injectionor intravascular delivery into the subject. After administration, the LNP can target and / orcontact a cell, for example, an immune cell, such as a T-cell. Upon contacting the cell with theLNP composition, a translatable mRNA may be translated in the cell to produce a polypeptideof interest. In certain embodiments, an LNP composition of the invention may target aparticular type or class of cells. This targeting may be facilitated using the lipids describedherein to form LNPs, which may also include a targeting group for targeting cells of interest. In certain, embodiments, specific delivery may result in a greater than 2 fold, 5 fold, 10 fold, 15 fold, or 20 fold increase in the amount of mRNA to the targeted destination (e.g., cells that express or express at high levels the receptor of interest which binds to the immune celltargeting group of the LNPs) as compared to another destinations (e.g., cells that either do notexpress or only express at low levels the receptor of interest). LNP compositions of the invention may be useful for treating a disease, disorder,or condition characterized by missing or aberrant protein or polypeptide activity. Upon deliveryof an mRNA encoding the missing or aberrant polypeptide to a cell, translation of the mRNA may produce the polypeptide, thereby reducing or eliminating an issue caused by the absenceof or aberrant activity caused by the polypeptide. Because translation may occur rapidly, themethods and compositions of the invention may be useful in the treatment of acute diseases,disorders, or conditions such as sepsis, stroke, and myocardial infarction. An mRNA includedin an LNP composition of the invention may also be capable of altering the rate of transcriptionof a given species, thereby affecting gene expression. Diseases, disorders, and / or conditions characterized by dysfunctional or aberrant protein or polypeptide activity for which a composition of the invention may be administered include, but are not limited to, cancer and proliferative diseases, genetic diseases (e.g., cysticfibrosis), autoimmune diseases, diabetes, neurodegenerative diseases, cardio- and reno-vascular diseases, and metabolic diseases. Multiple diseases, disorders, and / or conditions maybe characterized by missing (or substantially diminished such that proper protein function doesnot occur) protein activity. Such proteins may not be present, or they may be essentially non-functional. A specific example of a dysfunctional protein is the missense mutation variants ofthe cystic fibrosis transmembrane conductance regulator (CFTR) gene, which produce adysfunctional protein variant of CFTR protein, which causes cystic fibrosis. The presentdisclosure provides a method for treating such diseases, disorders, and / or conditions in asubject by administering an LNP composition including an mRNA and a lipid componentincluding KL10, a phospholipid (optionally unsaturated), a PEG lipid, and a structural lipid, wherein the m RNA encodes a polypeptide that antagonizes or otherwise overcomes an aberrant protein activity present in the cell of the subject. The therapeutic and / or prophylactic compositions described herein may beadministered to a subject using any reasonable amount and any route of administration effective for preventing, treating, diagnosing, or imaging a disease, disorder, and / or condition and / or anyother purpose. The specific amount administered to a given subject may vary depending on thespecies, age, and general condition of the subject, the purpose of the administration, theparticular composition, the mode of administration, and the like. Compositions in accordancewith the present disclosure may be formulated in dosage unit form for ease of administrationand uniformity of dosage. It will be understood, however, that the total daily usage of acomposition of the present disclosure will be decided by an attending physician within the scope of sound medical judgment. ALNP composition including one or more mRNAs may be administered by avariety of routes, for example, orally, intravenously, intramuscularly, intra-arterially,intramedullary, intrathecally, subcutaneously, intraventricularly, trans- or intra-dermally,intradermally, rectally, intravaginally, intraperitoneally, topically, mucosally, nasally,intratumorally. In certain embodiments, an LNP composition may be administeredintravenously, intramuscularly, intradermally, intra-arterially, intratumorally, orsubcutaneously. However, the present disclosure encompasses the delivery of LNPcompositions of the invention by any appropriate route taking into consideration likelyadvances in the sciences of drug delivery. In general, the most appropriate route ofadministration will depend upon a variety of factors including the nature of the LNPcomposition including one or more mRNAs (e.g., its stability in various bodily environmentssuch as the bloodstream and gastrointestinal tract), the condition of the patient (e.g., whetherthe patient is able to tolerate particular routes of administration), etc. LNP compositions including one or more mRNAs may be used in combination withone or more other therapeutic, prophylactic, diagnostic, or imaging agents. By "in combinationwith," it is not intended to imply that the agents must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope ofthe present disclosure. For example, one or more LNP compositions including one or moredifferent mRNAs may be administered in combination. Compositions can be administeredconcurrently with, prior to, or subsequent to, one or more other desired therapeutics or medicalprocedures. In general, each agent will be administered at a dose and / or on a time scheduledetermined for that agent. In some embodiments, the present disclosure encompasses thedelivery of compositions of the invention, or imaging, diagnostic, or prophylactic compositions thereof in combination with agents that improve their bioavailability, reduce and / or modifytheir metabolism, inhibit their excretion, and / or modify their distribution within the body.It will further be appreciated that therapeutically, prophylactically, diagnostically, or imaging active agents utilized in combination may be administered together in a singlecomposition or administered separately in different compositions. In general, it is expected thatagents utilized in combination will be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilized in combination may belower than those utilized individually. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / orprocedures and the desired therapeutic effect to be achieved. It will also be appreciated that thetherapies employed may achieve a desired effect for the same disorder (for example, a composition useful for treating cancer may be administered concurrently with achemotherapeutic agent), or they may achieve different effects (e.g., control of any adverseeffects). In some embodiments, no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10%, no more than 15%, no more than 20%, no more than 25%, no more than 30%, no more than 35%, no more than 40%, no more than 45%, or no more than 50% of cells that are not meant to be the destination of the delivery are transfected by the LNP. In some embodiments, the cells that are not meant to be the destination of the delivery are subject’s non-immune cells. In some embodiments, the cells that are not meant to be thedestination of the delivery are cells not targeted by the method. In some embodiments, the cellsthat are not meant to be the destination of the delivery are subject’s cells not targeted by the method. In some embodiments, the half-life of the nucleic acid delivered by the LNP described herein to the immune cell or a polypeptide encoded by the nucleic acid delivered by the LNP and expressed in the immune cell is at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 2 times, at least 3 times, at least 4 times, or at least 5 times longer than the half-life of the nucleic acid delivered by a reference LNP to the immune cells or a polypeptide encoded by the nucleic acid delivered bythe reference LNP and expressed in the immune cell.In some embodiments, the composition of the LNP differs from the composition of the reference LNP in the type of ionizable cationic lipid, relative amount of ionizable cationic lipid, length of the lipid anchor in PEG lipid, back bone or head group of the PEG lipid, relativeamount of PEG lipid, or type of immune cell targeting group, or any combination thereof. Insome embodiments, the composition of the LNP differs from the composition of the referenceLNP only in the type of ionizable cationic lipid. In some embodiments, the composition of theLNP differs from the composition of the reference LNP only in the amount of PEG lipid. Insome embodiments, the reference LNP comprises cationic Lipid DLin-KC3-DMA, butotherwise as the same as a tested LNP. In some embodiments, the reference LNP comprisescationic Lipid DLin-KC2-DMA, but otherwise as the same as a tested LNP. In someembodiments, the reference LNP comprises cationic Lipid ALC-0315, but otherwise as thesame as a tested LNP. In some embodiments, the reference LNP comprises cationic Lipid SM-102, but otherwise as the same as a tested LNP. In some embodiments, PEG lipid is a free PEGlipid. In some embodiments, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, or at least 95% of the immune cells are transfected by the LNP. In some embodiments,the immune cells are subject’s immune cells. In some embodiments, the immune cells areimmune cells targeted by the method. In some embodiments, the immune cells are subject’simmune cells targeted by the method. In some embodiments, the immune cells aremacrophages, for instance M2a macrophages, M2b macrophages, and / or M2c macrophages. In some embodiments, the immune cells are B cells. In some embodiments, the immune cells are NK cells. In some embodiments, the immune cells are T cells, for example CD4+ T cells and / or CD8+ T cells. In some embodiments, the immune cells are NK cells and T cells, for exampleNK cells and CD4+ T cells and / or CD8+ T cells. In some embodiments, the immune cells aremonocytes. In some embodiments, the immune cells are dendritic cells. In some embodiments, the expression level of the nucleic acid delivered by the LNP is at least at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least80%, at least 90%, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times higher than theexpression level of the nucleic acid delivered by a reference LNP. In some embodiments, theexpression level is measured and compared with a method described herein. In someembodiments, the expression level is measured by the ratio of cells expressing the encodedpolypeptide. In some embodiments, the expression level is measured with FACS. In someembodiments, the expression level is measured by the average amount of the encodedpolypeptide expressed in cells. In some embodiments, the expression level is measured as meanfluorescence intensity. In some embodiments, the expression level is measured by the amountof the encoded polypeptide or other materials secreted by cells.In another aspect, provided herein are methods of targeting the delivery of a nucleicacid to an immune cell of a subject. In some embodiments, the method comprises contactingthe immune cell with a lipid nanoparticle (LNP). In some embodiments, the LNP comprises anionizable cationic lipid. In some embodiments, the LNP comprises a conjugate comprising thecompound of the following formula: [Lipid] – [optional linker] – [immune cell targetinggroup]. In some embodiments, the LNP comprises a sterol or other structural lipid. In someembodiments, the LNP comprises a neutral phospholipid. In some embodiments, the LNPcomprises a free Polyethylene glycol (PEG) lipid. In some embodiments, the LNP comprisesthe nucleic acid. In some embodiments, an aspect of the disclosure relates to an LNP or a pharmaceutical composition containing thereof, as disclosed herein, for use in a method of targeting the delivery of a nucleic acid to an immune cell of a subject. Such a method may be for the treatment of a disease or disorder as disclosed hereafter. In some embodiments, a method as disclosed herein can comprise contacting in vitro or ex vivo the immune cell of a subject with a lipid nanoparticle (LNP). In some embodiments, the LNP is an LNP as described herein in the present disclosure. In some embodiments, the LNP provides at least one of the following benefits:(i) increased specificity of targeted delivery to the immune cell compared to areference LNP;(ii) increased half-life of the nucleic acid or a polypeptide encoded by the nucleic acidin the immune cell compared to a reference LNP;(iii) increased transfection rate compared to a reference LNP; and(iv) a low level of dye accessible mRNA (<15%) and high RNA encapsulation efficiencies, wherein at least 80% mRNA was recovered in final formulation relative to the total RNA used in LNP batch preparation. In some aspect, provided are methods of expressing a polypeptide of interest in atargeted immune cell of a subject. In some embodiments, the method comprises contacting theimmune cell with a lipid nanoparticle (LNP). In some embodiments, the LNP comprises anionizable cationic lipid. In some embodiments, the LNP comprises a conjugate comprising thefollowing structure: [Lipid] – [optional linker] – [immune cell targeting group]. In someembodiments, the LNP comprises a sterol or other structural lipid. In some embodiments, theLNP comprises a neutral phospholipid. In some embodiments, the LNP comprises a freePolyethylene glycol (PEG) lipid. In some embodiments, the LNP comprises a nucleic acidencoding the polypeptide. In some embodiments, an aspect of the disclosure relates to an LNP or a pharmaceutical composition containing thereof, as disclosed herein, for use in a method of expressing a polypeptide of interest in a targeted immune cell of a subject. Such a methodmay be for the treatment of a disease or disorder as disclosed hereafter. In some embodiments,a method as disclosed herein can comprise contacting in vitro or ex vivo the immune cell of a subject with a lipid nanoparticle (LNP). In some embodiments, the LNP provides at least one of the following benefits: (i) increased expression level in the immune cell compared to a reference LNP; (ii) increased specificity of expression in the immune cell compared to a reference LNP; (iii) increased half-life of the nucleic acid or a polypeptide encoded by the nucleic acid in the immune cell compared to a reference LNP; (iv) increased transfection rate compared to a reference LNP; and (v) a low level of dye accessible mRNA (<15%) and high RNA encapsulation efficiencies, wherein at least 80% mRNA was recovered in final formulation relative to the total RNA used in LNP batch preparation. In some aspects, provided are methods of modulating cellular function of a targetimmune cell of a subject. In some embodiments, the method comprises administering to thesubject a lipid nanoparticle (LNP). In some embodiments, the LNP comprises an ionizablecationic lipid. In some embodiments, the LNP comprises a conjugate comprising the followingstructure: [Lipid] – [optional linker] – [immune cell targeting group]. In some embodiments,the LNP comprises a sterol or other structural lipid. In some embodiments, the LNP comprisesa neutral phospholipid. In some embodiments, the LNP comprises a free Polyethylene glycol(PEG) lipid. In some embodiments, the LNP comprises a nucleic acid encoding a polypeptidefor modulating the cellular function of the immune cell. In some embodiments, an aspect of the disclosure relates to an LNP or a pharmaceutical composition containing thereof, as disclosed herein, for use in a method of modulating cellular function of a targeted immune cell of a subject. Such a method may be for the treatment of a disease or disorder as disclosed hereafter. In some embodiments, a method as disclosed herein can comprise contacting in vitro or ex vivo the immune cell of a subject with a lipid nanoparticle (LNP). In some embodiments, the LNP provides at least one of the following benefits: (i) increased expression level in the immune cell compared to a reference LNP; (ii) increased specificity of expression in the immune cell compared to a reference LNP; (iii) increased half-life of the nucleic acid or a polypeptide encoded by the nucleic acid in the immune cell compared to a reference LNP; (iv) increased transfection rate compared to a reference LNP; (v) the LNP can be administered at a lower dose compared to a reference LNP to reach the same biologic effect in the immune cell; and (vi) a low level of dye accessible mRNA (<15%) and high RNA encapsulation efficiencies, wherein at least 80% mRNA was recovered in final formulation relative to the total RNA used in LNP batch preparation. In some embodiments, the modulation of cell function comprises reprogrammingthe immune cells to initiate an immune response. In some embodiments, the modulation of cellfunction comprises modulating antigen specificity of the immune cell. In some aspect, provided are methods of treating, ameliorating, or preventing asymptom of a disorder or disease in a subject in need thereof. In some embodiments, the methodcomprises administering to the subject a lipid nanoparticle (LNP) for delivering a nucleic acidinto an immune cell of the subject. In some embodiments, the LNP comprises an ionizablecationic lipid. In some embodiments, the LNP comprises a conjugate comprising the followingstructure: [Lipid] – [optional linker] – [immune cell targeting group]. In some embodiments,the LNP comprises a sterol or other structural lipid. In some embodiments, the LNP comprisesa neutral phospholipid. In some embodiments, the LNP comprises a free Polyethylene glycol(PEG) lipid. In some embodiments, the LNP comprises the nucleic acid.In some embodiments, the nucleic acid modulates the immune response of the immune cell, therefore to treat or ameliorate the symptom. In some embodiments, an aspect of the disclosure relates to an LNP or a pharmaceutical composition containing thereof, as disclosed herein, for use in a method of treating, ameliorating, or preventing a symptom of a disorder or disease in a subject in need thereof. A disease or disorder may be as disclosed hereafter. In some embodiments, a method as disclosed herein can comprise contacting in vitro or ex vivo the immune cell of a subject with a lipid nanoparticle (LNP). In some embodiments, the LNP provides at least one of the following benefits: (i) increased specificity of delivery of the nucleic acid into the immune cell compared to a reference LNP; (ii) increased half-life of the nucleic acid or a polypeptide encoded by the nucleic acid in the immune cell compared to a reference LNP; (iii) increased transfection rate compared to a reference LNP; (iv) the LNP can be administered at a lower dose compared to a reference LNP to reach the same treatment efficacy; (v) increased level of gain of function by an immune cell compared to a reference LNP; and (vi) a low level of dye accessible mRNA (<15%) and high RNA encapsulation efficiencies, wherein at least 80% mRNA was recovered in final formulation relative to the total RNA used in LNP batch preparation. In some embodiments, the disorder is an immune disorder, an inflammatorydisorder, or cancer. In some embodiments, the nucleic acid encodes an antigen for use in atherapeutic or prophylactic vaccine for treating or preventing an infection by a pathogen. In some embodiments, no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or10% of non-immune cells are transfected by the LNP. In some embodiments, no more than1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of undesired immune cells that are not meant to be the destination of the delivery are transfected by the LNP. In some embodiments, the half- life of the nucleic acid delivered by the LNP to the immune cell or a polypeptide encoded by the nucleic acid delivered by the LNP is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times, or longer than the half-life of nucleic acid delivered by a reference LNP to the immune cell or a polypeptide encoded by the nucleic acid delivered by the reference LNP. In some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more immune cells that are meant to be the destination of the delivery are transfected by the LNP. In some embodiments, expression level of the nucleic acid delivered by the LNP is at least 5%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, at least 10%, 1.5 time, 2 times, 3 times, 4 times, 5 times, 10 times, 15 times, 20 times or more higher than expression level of nucleic acid in the same immune cells delivered by a reference LNP. In some aspects, provided are methods of targeting the delivery of a nucleic acid to an immune cell of a subject. In some embodiments, the method comprises contacting the immune cell with a lipid nanoparticle (LNP) provided herein. In some embodiments, the method is for targeting NK cells. In some embodiments, the immune cell targeting group binds to CD56. In some embodiments, the method is for targeting both T cells and NK cells simultaneously. In some embodiments, the immune cell targeting group binds to CD7, CD8, or both CD7 and CD8. In some embodiments, the method is for targeting both CD4+ and CD8+ T cells simultaneously. In some embodiments, the immune cell targeting group comprises a polypeptide that binds to CD3 or CD7. In some aspects, provided are methods of expressing a polypeptide of interest in a targeted immune cell of a subject. In some embodiments, the method comprises contacting the immune cell with a lipid nanoparticle (LNP) provided herein. In some aspect, provided are method of modulating cellular function of a target immune cell of a subject. In some embodiments, the method comprises administering to the subject a lipid nanoparticle (LNP) provided herein. In some aspects, provided are method of treating, ameliorating, or preventing a symptom of a disorder or disease in a subject in need thereof. In some embodiments, the method comprises administering to the subject a lipid nanoparticle (LNP) provided herein. In some aspects, provided are methods of treating a disease or disorder related to CD8 in a subject. In some embodiments, the method comprises administering a pharmaceutical composition described herein to the subject. In some embodiments, the disease or disorder is cancer. LNPs disclosed in the present disclosure and as claimed are suitable for the methodsdescribed above.VIII. KITS FOR USE IN MEDICAL APPLICATIONSAnother aspect of the invention provides a kit for treating a disorder. The kitcomprises: an ionizable cationic lipid, a lipid-immune cell targeting group conjugate, a lipid nanoparticle composition comprising an ionizable cationic lipid and / or a lipid-immune celltargeting group conjugate with or without an encapsulated payload (e.g., an mRNA), andinstructions for treating a medical disorder, such as, cancer or a microbial or viral infection.ENUMERATED EMBODIMENTSThe following enumerated embodiments are representative of some aspects of theinvention. It will be understood that reference to an embodiment number refers to all subembodiments, unless specified otherwise. For example, “embodiment 20” refers tosubembodiments 20A to 20F, unless specified otherwise.1. A compound of Formula (I):(I), or a salt thereof, wherein: R1and R2are each C1-3 alkylene; R3is C1-3 alkylene or a bond; R1Aand R2Aare each a bond or C1-10 alkylene; R3Ais a bond or C1-3 alkylene; R1A1, R2A1, R3A1, and R3A2are each H; R1A2and R2A2are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2; R1A3and R2A3are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2; R3A3is -C(O)ORa1; Ra1and Ra2are each independently C1-20alkyl; R3Bis ; R3B1is C4-6 alkylene; and R3B2and R3B3are each C1-3 alkyl.2. The compound of embodiment 1, or a salt thereof, wherein R1 and R2 are each methylene. 3. The compound of embodiment 1 or 2, or a salt thereof, wherein R1Aand R2Aare each a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9- , or -(CH2)10-. 4. The compound of embodiment 3, or a salt thereof, wherein R1Aand R2Aare each a bond, - (CH2)2-, -(CH2)5-, -(CH2)7-, or -(CH2)9-. 5. The compound of any one of embodiments 1 to 4, or a salt thereof, wherein R3Ais a bond, -CH2-, or -(CH2)2-. 6. The compound of embodiment 5, or a salt thereof, wherein R3Ais -CH2-. 7. The compound of any one of embodiments 1 to 6, or a salt thereof, wherein R1A2and R2A2are each -OC(O)(C1-15 alkyl), -C(O)O(C1-15 alkyl), -OC(O)CH(C1-10 alkyl)(C1-10 alkyl), - C(O)OCH(C1-10 alkyl)(C1-10 alkyl), -(CH2)C(O)O(C1-10 alkyl), or -(CH2)OC(O)(C1-10 alkyl). 8. The compound of embodiment 7, or a salt thereof, wherein R1A2and R2A2are each - OC(O)(C1-10 alkyl), -C(O)O(C1-10 alkyl), -OC(O)CH(C6 alkyl)(C8 alkyl), -C(O)OCH(C2-3 alkyl)(C5-6 alkyl), or -(CH2)C(O)O(C10 alkyl). 9. The compound of embodiment 8, or a salt thereof, wherein R1A2and R2A2are each , , , , , , , , or . 10. The compound of any one of embodiments 1 to 9, or a salt thereof, wherein R1A3and R2A3are each H, -OC(O)(C1-15 alkyl), or -C(O)O(C1-15 alkyl). 11. The compound of embodiment 10, or a salt thereof, wherein R1A3and R2A3are each H, - OC(O)(C5-10 alkyl), -C(O)O(C6-10 alkyl), or -(CH2)C(O)O(C10 alkyl). 12. The compound of embodiment 11, or a salt thereof, wherein R1A3and R2A3are each H, , , , , , , , , , , or . 13. The compound of any one of embodiments 1 to 12, or a salt thereof, wherein R3A3is - C(O)OCH(C1-5 alkyl)(C1-10 alkyl). 14. The compound of embodiment 13, or a salt thereof, wherein R3A3is -C(O)OCH(C3 alkyl)(C6 alkyl). 15. The compound of embodiment 14, or a salt thereof, wherein R3A3is . 16. The compound of any one of embodiments 1 to 15, or a salt thereof, wherein R3B1is - (CH2)4-. 17. The compound of any one of embodiments 1 to 16, or a salt thereof, wherein R3B2and R3B3are each methyl. 18. The compound of any one of embodiments 1 to 15 and 17, or a salt thereof, wherein is , , or . 19. The compound of embodiment 1, or a salt thereof, wherein the compound is selected from Table 1. 20A. The compound of embodiment 1, or a salt thereof, wherein the compound is . 20B. The compound of embodiment 1, or a salt thereof, wherein the compound is . 20C. The compound of embodiment 1, or a salt thereof, wherein the compound is . 20D. The compound of embodiment 1, or a salt thereof, wherein the compound is

[0009] . 20E. The compound of embodiment 1, or a salt thereof, wherein the compound is . 20F. The compound of embodiment 1, or a salt thereof, wherein the compound is . 21. A lipid nanoparticle (LNP) comprising a lipid blend for targeted delivery of a nucleic acid into an immune cell, the lipid blend comprising: (a) a lipid-immune cell targeting group conjugate comprising the compound of Formula (II): [Lipid] – [optional linker] – [immune cell targeting group], (b) an ionizable cationic lipid, and (c) a nucleic acid, wherein the nucleic acid is encapsulated in the LNP. 22. The LNP of embodiment 21, wherein the ionizable cationic lipid comprises the compound of any one of embodiments 1 to 20. 23. The LNP of embodiment 21 or 22, wherein the immune cell targeting group comprises an antibody that binds a macrophage antigen, a monocyte antigen, and / or a dendritic antigen. 24. The LNP of embodiment 23, wherein the immune cell targeting group comprises an antibody that binds a macrophage antigen. 25. The LNP of embodiment 23 or 24, wherein the macrophage comprises an M1 macrophage, an M2 macrophage, or both. 26. The LNP of any one of embodiments 23 to 25, wherein the macrophage comprises an M2a macrophage, an M2b macrophage, an M2c macrophage, or any combination thereof. 27. The LNP of embodiment 23, wherein the macrophage antigen comprises CDIIB, CD68, CD80, CD86, TRL-2, TRL-4, iNOS, MHC-II, CD163, CD206, CD209, FIZZ1, or Ym1 / 2, or any combination thereof. 28. The LNP of embodiment 27, wherein the macrophage antigen comprises CD206. 29. The LNP of embodiment 23, wherein the immune cell targeting group comprises an antibody that binds a monocyte antigen. 30. The LNP of embodiment 29, wherein the monocyte antigen comprises CD14, CCR2, CCR5, CD62L, HLA, CD68, CXCR1, CXCR3, CD11c, or any combination thereof. 31. The LNP of any one of embodiments 21 to 30, wherein the immune cell targeting group is covalently coupled to a lipid in the lipid blend via a polyethylene glycol (PEG) containing linker. 32. The LNP of embodiment 31, wherein the lipid covalently coupled to the immune cell targeting group via a PEG containing linker is distearoylglycerol (DSG), distearoyl- phosphatidylethanolamine (DSPE), dimyrstoyl-phosphatidylethanolamine (DMPE), distearoyl-glycero-phosphoglycerol (DSPG), dimyristoyl-glycerol (DMG), dipalmitoyl- phosphatidylethanolamine (DPPE), dipalmitoyl-glycerol (DPG), or ceramide. 33. The LNP of embodiment 31 or 32, wherein the PEG is PEG 2000 or PEG 3400. 34. The LNP of any one of embodiments 21 to 33, wherein the lipid-immune cell targeting group conjugate is present in the lipid blend in a range of 0.001 to 0.5 mole percent (e.g., 0.002-0.2 mole percent). 35. The LNP of any one of embodiments 21 to 34, wherein the lipid blend further comprises one or more of a structural lipid (e.g., a sterol), a neutral phospholipid, and a free PEG- lipid. 36. The LNP of any one of embodiments 21 to 35, wherein the ionizable cationic lipid is present in the lipid blend in a range of 30-70 (e.g., 40-60) mole percent. 37. The LNP of embodiment 35, wherein the sterol is present in the lipid blend in a range of 20-70 (e.g., 30-50) mole percent. 38. The LNP of embodiment 35 or 37, wherein the sterol is cholesterol. 39. The LNP of any one of embodiments 35 to 38, wherein the neutral phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), and sphingomyelin. 40. The LNP of any one of embodiments 35 to 39, wherein the neutral phospholipid is present in the lipid blend in a range of 5-15 mole percent. 41A. The LNP of any one of embodiments 35 to 40, wherein the free PEG-lipid is selected from the group consisting of PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG- modified diacylglycerols, and PEG-modified dialkylglycerols. For example, a PEG lipid may be PEG- dioleoylgylcerol (PEG-DOG), PEG-dimyristoyl-glycerol (PEG-DMG), PEG-dipalmitoyl-glycerol (PEG-DPG), PEG-dilinoleoyl-glycero-phosphatidyl ethanolamine (PEG-DLPE), PEG-dimyrstoyl-phosphatidylethanolamine (PEG-DMPE), PEG-dipalmitoyl- phosphatidylethanolamine (PEG-DPPE), PEG-distearoylglycerol (PEG-DSG), PEG-diacylglycerol (PEG-DAG, e.g., PEG-DMG, PEG-DPG, and PEG- DSG), PEG-ceramide, PEG-distearoyl-glycero-phosphoglycerol (PEG-DSPG), PEG- dioleoyl-glycero-phosphoethanolamine (PEG-DOPE), 2-[(polyethylene glycol)-2000]- N,N-ditetradecylacetamide, or a PEG-distearoyl-phosphatidylethanolamine (PEG-DSPE) lipid. 41B. The LNP of any one of embodiments 35 to 40, wherein the free PEG-lipid is DSG-PEG. 41C. The LNP of any one of embodiments 35 to 40, wherein the free PEG-lipid is DPG-PEG. 42. The LNP of any one of embodiments 35 to 40, wherein the free PEG-lipid comprises a diacylphosphatidylethanolamine comprising Dipalmitoyl (C16) chain or Distearoyl (C18) chain, and optionally the free PEG-lipid comprises PEG-DPG and PEG-DMG. 43A. The LNP of any one of embodiments 35 to 42, wherein the free PEG-lipid is present in the lipid blend in a range of 1-4 mole percent. 43B. The LNP of any one of embodiments 35 to 42, wherein the free PEG-lipid is present in the lipid blend in a range of about 1 to about 2 mole percent. 43C. The LNP of any one of embodiments 35 to 42, wherein the free PEG-lipid is present in the lipid blend in a concentration of about 1.5 mole percent. 43D. The LNP of any one of embodiments 35 to 42, wherein the free PEG-lipid is present in the lipid blend in a range of about 3 to about 4 mole percent. 43E. The LNP of any one of embodiments 35 to 42, wherein the free PEG-lipid is present in the lipid blend in a concentration of about 3.5 mole percent. 44. The LNP of any one of embodiments 35 to 43, wherein the free PEG-lipid comprises the same or a different lipid as the lipid in the lipid-immune cell targeting group conjugate. 45. The LNP of any one of embodiments 21 to 44, wherein the LNP has a mean diameter in the range of 50-200 nm. 46. The LNP of embodiment 45, where the LNP has a mean diameter of about 100 nm. 47. The LNP of any one of embodiments 21 to 46, wherein the LNP has a polydispersity index in a range from 0.01 to 0.1. 48. The LNP of any one of embodiments 21 to 47, wherein the LNP has a zeta potential of from about +0 mV to about +10 mV at pH 5.5, or from about -5 mV to about 0 mV at pH 7.4. 49. The LNP of any one of embodiments 21 to 48, wherein the nucleic acid is DNA or RNA. 50. The LNP of embodiment 49, wherein the RNA is an mRNA. 51. The LNP of embodiment 50, wherein the mRNA encodes a receptor, a growth factor, a hormone, a cytokine, an antibody, an antigen, an enzyme, or a vaccine. 52. The LNP of embodiment 50, wherein the mRNA encodes a polypeptide capable of regulating immune response in the immune cell. 53. The LNP of embodiment 50, wherein the mRNA encodes a polypeptide capable of reprogramming the immune cell. 54. The LNP of embodiment 53, wherein the mRNA encodes polypeptide capable of reprogramming an M2 macrophage to an M1 macrophage. 55. The LNP of any one of embodiments 21 to 54, wherein the immune cell targeting group comprises an antibody, and the antibody is a Fab or an immunoglobulin single variable domain (e.g., a VHH). 56. The LNP of any one of embodiments 21 to 54, wherein the immune cell targeting group comprises a Fab, F(ab’)2, Fab’-SH, Fv, or scFv fragment. 57. The LNP of embodiment 55 or embodiment 56, wherein the immune cell targeting group comprises a Fab that is engineered to knock out the natural interchain disulfide bond at the C-terminus. 58. The LNP of embodiment 57, wherein the Fab comprises a heavy chain fragment that comprises C233S substitution, and a light chain fragment that comprises C214S substitution, numbering according to Kabat. 59. The LNP of any one of embodiments 56 to 58, wherein the immune cell targeting group comprises a Fab that has a non-natural interchain disulfide bond (e.g., an engineered, buried interchain disulfide bond). 60. The LNP of embodiment 59, wherein the Fab comprises F174C substitution in the heavy chain fragment, and S176C substitution in the light chain fragment, numbering according to Kabat. 61. The LNP of embodiments 56 to 60, wherein the immune cell targeting group comprises a Fab that comprises a cysteine at the C-terminus of the heavy or light chain fragment. 62. The LNP of embodiment 61, wherein the Fab further comprises one or more amino acids between the heavy chain fragment of the Fab and the C-terminal cysteine. 63. The LNP of embodiment 55, wherein the immune cell targeting group comprises an immunoglobulin single variable domain. 64. The LNP of embodiment 55 or 63, wherein the immunoglobulin single variable domain comprises a cysteine at the C-terminus. 65. The LNP of embodiment 64, wherein the immunoglobulin single variable domain comprises a VHH domain and further comprises a spacer comprising one or more amino acids between the VHH domain and the C-terminal cysteine. 66. The LNP of any one of embodiments 56 and 63 to 65, wherein the immune cell targeting group comprises two or more VHH domains. 67. The LNP of embodiment 66, wherein the two or more VHH domains are linked by an amino acid linker. 68. The LNP of embodiment 66, wherein the immune cell targeting group comprises a first VHH domain linked to an antibody CH1 domain and a second VHH domain linked to an antibody light chain constant domain, and wherein the antibody CH1 domain and the antibody light chain constant domain are linked by one or more disulfide bonds. 69. The LNP of any one of embodiments 55 and 63 to 65, wherein the immune cell targeting group comprises a VHH domain linked to an antibody CH1 domain, and wherein the antibody CH1 domain is linked to an antibody light chain constant domain by one or more disulfide bonds. 70. The LNP of embodiment 68 or 69, wherein the CH1 domain comprises F174C and C233S substitutions, and the light chain constant domain comprises S176C and C214S substitutions, numbering according to Kabat. 71. The LNP of any one of embodiments 21 to 70, wherein the LNP comprises: (a) the ionizable cationic lipid; (b) the conjugate comprising the compound of the following formula: [Lipid] – [optional linker] – [immune cell targeting group]; (c) a sterol or other structural lipid; (d) a neutral phospholipid; (e) a free Polyethylene glycol (PEG) lipid; and (f) the nucleic acid. 72. The LNP of any one of embodiments 21 to 71, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the immune cell is a macrophage, and the immune cell targeting group comprises an antibody that binds CD206. 73. The LNP of any one of embodiments 21 to 71, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the immune cell targeting group comprises an antibody that binds CD206, and the free PEG lipid is DMG-PEG or PEG-DPG. 74. The LNP of any one of embodiments 21 to 73, wherein the immune cell targeting group comprises an antibody, and the antibody is a Fab or an immunoglobulin single variable domain. 75. The LNP of embodiment 73, wherein the Fab is engineered to knock out the natural interchain disulfide at the C-terminus. 76. The LNP of embodiment 75, wherein the Fab comprises a heavy chain fragment that comprises C233S substitutions, and a light chain fragment that comprises C214S substitutions. 77. The LNP of embodiment 75, wherein the Fab comprises a non-natural interchain disulfide. 78. The LNP of embodiment 75, wherein the Fab comprises F174C substitution in the heavy chain fragment, and S176C substitution in the light chain fragment. 79. The LNP of embodiment 74, wherein the antibody is an immunoglobulin single variable (ISV) domain, and the ISV domain is a VHH. 80. The LNP of embodiment 79, wherein the free PEG lipid comprises a PEG having a molecular weight of at least 2000 daltons. 81. The LNP of embodiment 80, wherein the PEG has a molecular weight of about 3000 to 5000 daltons. 82. The LNP of embodiment 74, wherein the antibody is a Fab. 83. The LNP of embodiment 82, wherein the Fab binds CD206, and the free PEG lipid in the LNP comprises a PEG having a molecular weight of about 2000 daltons. 84. The LNP of embodiment 82, wherein the Fab is an anti-CD206 antibody, and the free PEG lipid in the LNP comprises a PEG having a molecular weight of about 3000 to 3500 daltons. 85. The LNP of embodiment 74, wherein the immune cell targeting group comprises two or more VHH domains. 86. The LNP of embodiment 85, wherein the two or more VHH domains are linked by an amino acid linker. 87. The LNP of embodiment 86, wherein the immune cell targeting group comprises a first VHH domain linked to an antibody CH1 domain and a second VHH domain linked to an antibody light chain constant domain. 88. The LNP of any one of embodiments 21 to 71, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the LNP binds a first macrophage antigen, and also binds a second macrophage antigen. 89. The LNP of embodiment 88, wherein the LNP comprises two conjugates, wherein the first conjugate comprises an antibody that binds the first macrophage antigen, and the second conjugate comprises an antibody that binds the second macrophage antigen. 90. The LNP of embodiment 88, wherein the LNP comprises one conjugate, and the conjugate comprises a bispecific antibody that binds both the first macrophage antigen and the second macrophage antigen. 91. The LNP of embodiment 90, wherein the bispecific antibody is an immunoglobulin single variable domain or Fab-ScFv. 92. The LNP of any one of embodiments 21 to 71, wherein the LNP binds to a first antigen on the surface of the first type of immune cell, and also binds to a second antigen on the surface of the second type of immune cell. 93. The LNP of embodiment 92, wherein the first type of immune cell is a first macrophage, and the second type of immune cell is a second macrophage, a T-cell, or an NK cell. 94. The LNP of embodiment 92 or 93, wherein the LNP comprises two conjugates, and the first conjugate comprises a first antibody that binds to the first antigen of the first type of immune cell, and the second conjugate comprises a second antibody that binds to the second antigen of the second type of immune cell. 95. The LNP of embodiment 92 or 93, wherein the LNP comprises one conjugate, and the conjugate comprises a bispecific antibody, and the bispecific antibody binds to both the first antigen on the first type of immune cell, and the second antigen on the second type of immune cells. 96. The LNP of any one of embodiments 21 to 71, wherein the bispecific antibody is an immunoglobulin single variable domain or a Fab-ScFv. 97. The LNP of any one of embodiments 21 to 71, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the immune cell targeting group comprises a single antibody that binds to CD206. 98. The LNP of any one of embodiments 21 to 71, wherein the LNP is for delivering a nucleic acid into both a macrophage and a T-cell or both a macrophage and an NK cell, wherein the immune cell targeting group binds to both (i) CD206 and (ii) one of CD3, CD7, CD8, and CD56. 99. The LNP of any one of embodiments 72 to 98, wherein the LNP has a mean diameter in the range of 50-200 nm. 100. The LNP of embodiment 99, where the LNP has a mean diameter of about 100 nm. 101. The LNP of any one of embodiments 72 to 98, wherein the LNP has a polydispersity index in a range from 0.01 to 0.1. 102. The LNP of any one of embodiments 72 to 101, wherein the LNP has a zeta potential of from about +0 mV to about +10 mV at pH 5.5, or from about -5 mV to about 0 mV at pH 7.4. 103. The LNP of any one of embodiments 72 to 102, wherein the nucleic acid is DNA or RNA. 104. The LNP of embodiment 103, wherein the RNA is an mRNA. 105. The LNP of embodiment 104, wherein the mRNA encodes a receptor, a growth factor, a hormone, a cytokine, an antibody, an antigen, an enzyme, or a vaccine. 106. The LNP of embodiment 104, wherein the mRNA encodes a polypeptide capable of regulating immune response in the immune cell. 107. The LNP of embodiment 106, wherein the mRNA encodes a polypeptide capable of reprogramming the immune cell. 108. The LNP of embodiment 107, wherein the mRNA encodes polypeptide capable of reprogramming an M2 macrophage to an M1 macrophage. 109. The LNP of any one of embodiments 21 to 71, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the immune cell targeting group comprises a Fab lacking the native interchain disulfide bond. 110. The LNP of embodiment 109, wherein the Fab is engineered to replace one or both cysteines on the native constant light chain and the native constant heavy chain that form the native interchain disulfide with a non-cysteine amino acid, therefor to remove the native interchain disulfide bond in the Fab. 111. A lipid nanoparticle (LNP) comprising a lipid blend for targeted delivery of a nucleic acid into a macrophage, the lipid blend comprising: (a) a lipid-macrophage targeting group conjugate comprising the compound of Formula (II-m): [Lipid] – [optional linker] – [macrophage targeting group]; and (b) a nucleic acid, wherein the nucleic acid is encapsulated in the LNP. 112. The LNP of embodiment 111, wherein the macrophage is an M2 macrophage. 113. The LNP of embodiment 111 or 112, wherein the macrophage targeting group binds CD206. 114. The LNP of any one of embodiments 111 to 113, wherein the nucleic acid is mRNA, and the mRNA encodes polypeptide capable of reprogramming an M2 macrophage to an M1 macrophage. 115. The LNP of any one of embodiments 111 to 114, wherein the LNP further comprises an ionizable cationic lipid. 116. The LNP of embodiment 115, wherein the ionizable cationic lipid comprises the compound of any one of embodiments 1 to 20. 117. A method of targeting the delivery of a nucleic acid to an immune cell of a subject, comprising contacting the immune cell with the LNP of any one of embodiments 21 to 116, wherein the LNP comprises the nucleic acid. 118. A method of expressing a polypeptide of interest in a targeted immune cell of a subject, comprising contacting the immune cell with the LNP of any one of embodiments 21 to 116, wherein the LNP comprises a nucleic acid encoding the polypeptide. 119. A method of modulating cellular function of a target immune cell of a subject, comprising administering to the subject the LNP of any one of embodiments 21 to 116, wherein the LNP comprises a nucleic acid modulates the cellular function of the immune cell. 120. A method of treating, ameliorating, or preventing a symptom of a disorder or disease in a subject in need thereof, comprising administering to the subject an LNP for delivering a nucleic acid into an immune cell of the subject, wherein the LNP is any one of embodiments 21 to 116, wherein the LNP comprises the nucleic acid. 121. The method of embodiment 120, wherein the disorder is an immune disorder, an inflammatory disorder, or cancer. 122. The method of embodiment 120, wherein the nucleic acid encodes an antigen for use in a therapeutic or prophylactic vaccine for treating or preventing cancer. 123. The method of any one of embodiments 117 to 122, wherein the immune cell targeting group comprises an antibody that binds a macrophage antigen. 124. The method of embodiment 123, wherein the macrophage antigen comprises CDIIB, CD68, CD80, CD86, TRL-2, TRL-4, iNOS, MHC-II, CD163, CD206, CD209, FIZZ1, or Ym1 / 2, or any combination thereof. 125. The method of any one of embodiments 117 to 124, wherein the antibody is a human or humanized antibody. 126. The method of any one of embodiments 117 to 125, wherein the immune cell targeting group is covalently coupled to a lipid in the lipid blend via a polyethylene glycol (PEG) containing linker. 127. The method of embodiment 126, wherein the lipid covalently coupled to the immune cell targeting group via a PEG containing linker is distearoylglycerol (DSG), distearoyl- phosphatidylethanolamine (DSPE), dimyrstoyl-phosphatidylethanolamine (DMPE), distearoyl-glycero-phosphoglycerol (DSPG), dimyristoyl-glycerol (DMG), dipalmitoyl- phosphatidylethanolamine (DPPE), dipalmitoyl-glycerol (DPG), or ceramide. 128. The method of embodiment 126 or 127, wherein the PEG is PEG 2000. 129. The method of any one of embodiments 117 to 128, wherein the lipid-immune cell targeting group conjugate is present in the lipid blend in a range of 0.002-0.2 mole percent. 130. The method of any one of embodiments 117 to 129, wherein the ionizable cationic lipid is present in the lipid blend in a range of 40-60 mole percent. 131. The method of embodiment 117 to 130, wherein the sterol is cholesterol. 132. The method of any one of embodiments 117 to 131, wherein the sterol is present in the lipid blend in a range of 30-50 mole percent. 133. The method of clam 117 to 132, wherein the neutral phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, distearoyl-sn- glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-sn- glycero-3-phosphocholine (DOPC), sphingomyelin (SM). 134. The method of embodiment 117 to 133, wherein the neutral phospholipid is present in the lipid blend in a range of 5-15 mole percent. 135. The method of any one of embodiments 117 to 134, wherein the free PEG-lipid is selected from the group consisting of PEG-modified phosphatidylethanolamines, PEG- modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, and PEG-modified dialkylglycerols. For example, a PEG lipid may be PEG- dioleoylgylcerol (PEG-DOG), PEG-dimyristoyl-glycerol (PEG- DMG), PEG-dipalmitoyl-glycerol (PEG-DPG), PEG-dilinoleoyl-glycero-phosphatidyl ethanolamine (PEG-DLPE), PEG-dimyrstoyl-phosphatidylethanolamine (PEG-DMPE), PEG-dipalmitoyl- phosphatidylethanolamine (PEG-DPPE), PEG-distearoylglycerol (PEG-DSG), PEG-diacylglycerol (PEG-DAG, e.g., PEG-DMG, PEG-DPG, and PEG- DSG), PEG-ceramide, PEG-distearoyl-glycero-phosphoglycerol (PEG-DSPG), PEG- dioleoyl-glycero-phosphoethanolamine (PEG-DOPE), 2-[(polyethylene glycol)-2000]- N,N-ditetradecylacetamide, or a PEG-distearoyl-phosphatidylethanolamine (PEG-DSPE) lipid. 136. The method of embodiments 117 to 134, wherein the free PEG-lipid comprises a diacylphosphatidylethanolamines comprising dimyristoyl (C14) chain, Dipalmitoyl (C16) chain or Distearoyl (C18) chain. 137. The method of any one of embodiments 117 to 136, wherein the free PEG-lipid is present in the lipid blend in a range of 0.5-2.5 mole percent. 138. The method of any one of embodiments 117 to 137, wherein the free PEG-lipid comprises the same or a different lipid as the lipid in the lipid-immune cell targeting group conjugate. 139. The method of embodiments 117 to 138, wherein the LNP has a mean diameter in the range of 50-200 nm. 140. The method of embodiment 139, where the LNP has a mean diameter of about 100 nm. 141. The method of embodiments 117 to 140, wherein the LNP has a polydispersity index in a range from 0.01 to 0.1. 142. The method of embodiments 117 to 141, wherein the LNP has a zeta potential of from about +0 mV to about +10 mV at pH 5.5, or from about -5 mV to about 0 mV at pH 7.4. 143. The method of embodiments 117 to 142, wherein the nucleic acid is DNA or RNA. 144. The method of embodiment 143, wherein the RNA is an mRNA, tRNA, siRNA, gRNA, or microRNA. 145. The method of embodiment 144, wherein the mRNA encodes a receptor, a growth factor, a hormone, a cytokine, an antibody, an antigen, an enzyme, or a vaccine. 146. The method of embodiment 144, wherein the mRNA encodes a polypeptide capable of regulating immune response in the immune cell. 147. The method of embodiment 144, wherein the mRNA encodes a polypeptide capable of reprogramming the immune cell. 148. The method of embodiment 144, wherein the mRNA encodes polypeptide capable of reprogramming an M2 macrophage to an M1 macrophage. 149. The method of any one of embodiments 117 to 148, wherein the immune cell targeting group comprises an antibody, and the antibody is a Fab or an immunoglobulin single variable domain. 150. The method of any one of embodiments 117 to 149, wherein the immune cell targeting group comprises an antibody fragment selected from the group consisting of a Fab, F(ab’)2, Fab’-SH, Fv, and scFv fragment. 151. The method of embodiment 142 or 150, wherein the immune cell targeting group comprises a Fab that comprises one or more interchain disulfide bonds. 152. The method of embodiment 151, wherein the Fab comprises a heavy chain fragment that comprises F174C and C233S substitutions, and a light chain fragment that comprises S176C and C214S substitutions, numbering according to Kabat. 153. The method of any one of embodiments 149 to 152, wherein the immune cell targeting group comprises a Fab that comprises a cysteine at the C-terminus of the heavy or light chain fragment. 154. The method of embodiment 153, wherein the Fab further comprises one or more amino acids between the heavy chain fragment of the Fab and the C-terminal cysteine. 155. The method of any one of embodiments 149 to 154, wherein the Fab comprises a heavy chain variable domain linked to an antibody CH1 domain and a light chain variable domain linked to an antibody light chain constant domain, wherein the CH1 domain and the light chain constant domain are linked by one or more interchain disulfide bonds, and wherein the immune cell targeting group further comprises a single chain variable fragment (scFv) linked to the C-terminus of the light chain constant domain by an amino acid linker. 156. The method of embodiment 149, wherein the immune cell targeting group comprises an immunoglobulin single variable domain. 157. The method of embodiment 149 or 156, wherein the immunoglobulin single variable domain comprises a cysteine at the C-terminus. 158. The method of embodiment 157, wherein the immunoglobulin single variable domain comprises a VHH domain and further comprises a spacer comprising one or more amino acids between the VHH domain and the C-terminal cysteine. 159. The method of any one of embodiments 149 and 156 to 158, wherein the immune cell targeting group comprises two or more VHH domains. 160. The method of embodiment 159, wherein the two or more VHH domains are linked by an amino acid linker. 161. The method of embodiment 159, wherein the immune cell targeting group comprises a first VHH domain linked to an antibody CH1 domain and a second VHH domain linked to an antibody light chain constant domain, and wherein the antibody CH1 domain and the antibody light chain constant domain are linked by one or more disulfide bonds. 162. The method of any one of embodiments 149 and 156 to 158, wherein the immune cell targeting group comprises a VHH domain linked to an antibody CH1 domain, and wherein the antibody CH1 domain is linked to an antibody light chain constant domain by one or more disulfide bonds. 163. The method of embodiment 161 or 162, wherein the CH1 domain comprises F174C and C233S substitutions, and the light chain constant domain comprises S176C and C214S substitutions, numbering according to Kabat. 164. The method of any one of embodiments 117 to 163, wherein no more than 5% non- immune cells are transfected by the LNP. 165. The method of any one of embodiments 117 to 164, wherein half-life of the nucleic acid delivered by the LNP or a polypeptide encoded by the nucleic acid delivered by the LNP is at least 10% longer than half-life of nucleic acid delivered by a reference LNP or a polypeptide encoded by the nucleic acid delivered by the reference LNP.166. The method of any one of embodiments 117 to 165, wherein at least 10% immunecells are transfected by the LNP.167. The method of any one of embodiments 117 to 166, wherein expression level of thenucleic acid delivered by the LNP is at least 10% higher than expression level of nucleic acid delivered by a reference LNP. 168. A method of targeting delivery of a nucleic acid to a non-liver cell, the method comprising contacting the non-liver cell with an LNP of any one of embodiments 21 to 116, wherein the LNP comprises about 1 to about 2 mol% of free PEG-lipid. 169. The method of embodiment 168, wherein the LNP comprises about 1.5 mol% of free PEG-lipid. 170. A method of targeting delivery of a nucleic acid to a liver cell, the method comprising contacting the liver cell with an LNP of any one of embodiments 21 to 116, wherein the LNP comprises about 2 to about 4 mol% of free PEG-lipid. 171. The method of embodiment 170, wherein the LNP comprises about 3.5 mol% of free PEG-lipid. EXAMPLES The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.EXAMPLE 1. PREPARATION OF IONIZABLE CATIONIC LIPIDSThis Example describes the synthesis of various cationic lipids.Synthesis of head group intermediates 8, 8’, 9 and 9’

[0010] Scheme 1. General scheme for the synthesis of head group intermediates 9 and 9’

[0011] Synthesis of intermediates 9’a, 9’b, and 9’cProtection of starting material dihydroxyacetone 1 (111 mmol, 10 g, 1 eq.) usingtert-butyltrimethylsilyl chloride TBSCl (332.9 mmol, 50.2 g, 3.0 eq), TEA (554.9 mmol, 56.15g, 5 eq,) and DMAP (22.1 mmol, 2.71 g, 0.2 eq.) in 100 mL DCM at room temperature for 16 hours yielded protected intermediate 2. Crude intermediate 2 (45g) was purified using ISCO column chromatography on silica column eluting with Hexane and ethyl acetate to obtain 20g of purified intermediate 2. Intermediate 2 (6g, 18.8 mmol, 1 eq.) was reductively aminated using N,N-dimethylaminobutyl amine 15-3’, (37.7 mmol, 4.38 g, 2.0 eq.), Acetic acid (37.7 mmol, 2.26mL, 2.0 eq.), and Na(OAc)3BH (22.6 mmol, 4.79 g, 1.2 eq.), in 60 mL of dichloromethane at room temperature for 6 hours. Crude product was purified by filter column chromatography on silica column eluting with DCM and (10%MeOH in DCM + 1% NH4OH) to obtain desiredproduct yielding 5.6g (66%) pure intermediate 4a based on TLC.Intermediate 2 (3g, 9.4 mmol, 1 eq.) was reductively aminated using N,N-dimethylaminobutyl amine 15-4’, (18.8 mmol, 2.45 g, 2.0 eq.), Acetic acid (18.8 mmol, 1.13mL, 2.0 eq.), and Na(OAc)3BH (11.3 mmol, 2.39 g, 1.2 eq.), in 30 mL of dichloromethane at room temperature for 3 hours. Crude product was purified by filter column chromatography on silica column eluting with DCM and (10%MeOH in DCM + 1% NH4OH) to obtain desiredproduct yielding 2.9g (71%) pure intermediate 4b based on product mass and proton NMR.Intermediate 2 (1g, 3.1 mmol, 1 eq.) was reductively aminated using N,N-dimethylaminobutyl amine 15-5’, (37.7 mmol, 0.86 g, 2.0 eq.), Acetic acid (37.7 mmol, 1.13mL, 2.0 eq.), and Na(OAc)3BH (11.3 mmol, 2.39 g, 1.2 eq.), in 30 mL of dichloromethane at room temperature for 3 hours. Crude product was purified by filter column chromatography on silica column eluting with DCM and (10%MeOH in DCM + 1% NH4OH) to obtain desiredproduct yielding 1.1 g (78%) of pure intermediate 4c based on product mass and proton NMR.Intermediate 4a (5.2g, 12.4 mmol, 1 eq.) was reacted with previously producedintermediate 7b (4.81 g, 1.5 eq, 18.6 mmol) using EDCI (3.57 g, 1.5 eq, 18.6 mmol), DIPEA(2.41 g, 1.5 eq, 18.6 mmol) and DMAP (0.75 g, 0.5 eq, 6.2 mmol) in DCM (60 mL) at room temperature for 4 hours. Crude product was purified by filter column chromatography on silica column eluting with DCM and (10%MeOH in DCM + 1% NH4OH) to obtain desired productyielding 3.4 g (36%) of pure intermediate 8’a based on product mass and proton NMR.Intermediate 4b (3.1g, 7.1 mmol, 1 eq.) was reacted with previously producedintermediate 7b (2.77 g, 1.5 eq, 10.7 mmol) using EDCI (2.05 g, 1.5 eq, 10.7 mmol), DIPEA(1.38 g, 1.5 eq, 10.7 mmol) and DMAP (0.43 g, 0.5 eq, 3.5 mmol) in DCM (30 mL) at room temperature for 4 hours. Crude product was purified by filter column chromatography on silica column eluting with DCM and (10%MeOH in DCM + 1% NH4OH) to obtain desired productyielding 2.7 g (56%) of pure intermediate 8’b based on product mass and proton NMR. Intermediate 4c (1.1 g, 1.6 mmol, 1 eq.) was reacted with previously producedintermediate 7b (0.9 g, 1.5 eq, 2.4 mmol) using EDCI (0.7 g, 1.5 eq, 3.6 mmol), DIPEA (0.47g, 1.5 eq, 3.6 mmol) and DMAP (0.15 g, 0.5 eq, 1.2 mmol) in DCM (10 mL) at room temperature for 4 hours. Crude product was purified by filter column chromatography on silica column eluting with DCM and (10%MeOH in DCM + 1% NH4OH) to obtain desired productyielding 0.8 g (47%) of pure intermediate 8’c based on product mass and proton NMR.Intermediate 8’a (300 mg, 0.45 mmol, 1 eq.) was deprotected in HF-Pyridine (0.41 mL, 10.0 eq, 4.5 mmol) and THF (20 mL) at room temperature for 2 hours to obtain dihydroxyl intermediate 9’a. Crude product was used in subsequent reactions (as described below). Intermediate 8’b (300 mg, 0.44 mmol, 1 eq.) was deprotected in HF-Pyridine (0.40 mL, 10.0 eq, 4.4 mmol) and THF (4 mL) at room temperature for 2 hours to obtain dihydroxyl intermediate 9’b. Crude product was used in subsequent reactions (as described below). Intermediate 8’c (300 mg, 0.45 mmol, 1 eq.) was deprotected in HF-Pyridine (0.41 mL, 10.0 eq, 4.5 mmol) and THF (4 mL) at room temperature for 2 hours to obtain dihydroxyl intermediate 9’c. Crude product was used in subsequent reactions (as described below). Synthesis of intermediate 14-34’ Starting material 14-32a (4.82 g, 30.09 mmol, 1.0 eq.) was esterified with 7- carboxyhexanoic acid 14-25 (11.30 g, 44.07 mmol, 1.45 eq.) using EDCI (8.84 g, 46.11 mmol, 1.53 eq), DIPEA (8 mL, 45.93 mm0l, 1.53 eq) and DMAP (0.796 g, 6.51 mmol, 0.22 eq) in DCM (50 mL) at room temperature overnight to obtain protected intermediate 14-33a. Crude product was purified on Silica gel column using hexanes / ethyl acetate (6 / 4) mixture as eluent to yield pure compound 14-33a (7.75g, 65%) based on product mass and NMR. Protected intermediate 14-33a (4.38 g, 10.98 mmol, 1.0 eq.) was deprotected using 4N HCl in dioxane (24 mL) at room temperature overnight. Crude product was purified by column chromatography on silica column eluting with Hexanes / Ethyl acetate to obtain free acid intermediate 14-34 (3g, 80%) based on1H NMR. Intermediate 14-34 (1.86 g, 5.4 mmol) was converted to the corresponding acid chloride 14-34’ using oxalyl chloride (1.59 mL, 3.4 eq, 18.4 mmol) and DMF (200 µL) in toluene (12.0 mL) for 2 hours at room temperature. Crude product was used for the synthesis of lipids 40, 41 and 42 as described below. Synthesis of Lipid 40 Diol intermediate 9’a (0.39 g, 0.9 mmol, 1 eq.) was reacted with crude acid chloride 14-34’ (1.86 g, 6.0 eq, 5.4 mmol) using TEA (1.27 mL, 10.0 eq, 9.05 mmol) in toluene (10.0 mL), at room temperature overnight to obtain crude lipid 40. Crude product was purified on ISCO column chromatography on silica column eluting with DCM and 10% MeOH in DCM to obtain pure lipid 40 (480 mg, 49%) characterized by mass spectrometry,1H NMR, and LC- CAD (>99%). Synthesis of Lipid 41 Diol intermediate 9’b (0.195 g, 0.43 mmol, 1 eq.) was reacted with crude acid chloride 14-34’ (0.90 g, 6.0 eq, 2.6 mmol) using TEA (0.61 mL, 10.0 eq, 4.3 mmol) in toluene (5.0 mL), at room temperature overnight to obtain crude lipid 41. Crude product was purified on ISCO column chromatography on silica column eluting with DCM and 10% MeOH in DCMto obtain pure lipid 41 (245 mg, 51%) characterized by mass spectrometry, 1H NMR, and LC-CAD (>99%). Synthesis of Lipid 42 Diol intermediate 9’c (0.195 g, 0.43 mmol, 1 eq.) was reacted with crude acid chloride 14-34’ (0.90 g, 6.0 eq, 2.6 mmol) using TEA (0.61 mL, 10.0 eq, 4.3 mmol) in toluene (5.0 mL), at room temperature overnight to obtain crude lipid 41. Crude product was purified on ISCO column chromatography on silica column eluting with DCM and 10% MeOH in DCMto obtain pure lipid 42 (320 mg, 67%) characterized by mass spectrometry, 1H NMR, and LC-CAD (>99%). Synthesis of tail group Intermediate 10 Starting material 10a (3.0 g, (1.0 eq, 13.0 mmol)) was reacted with 8-(tert-Butoxy)-8-oxooctanoic acid (3.1 g, 1.5 eq, 19.5 mmol) using EDCI (3.75 g, 1.5 eq, 19.5 mmol), DMAP(728 mg, 0.5 eq, 6.5 mmol), and DIPEA (3.4 mL, 1.5 eq, 19.5 mmol) in DCM (20.0 mL) atroom temperature, overnight to obtain protected intermediate 10b. Crude product was purified by Silica column chromatography eluting with Hexanes : Ethyl Acetate to obtain pure Intermediate 10b (4.39 g, 91%) characterized by mass spectrometry and1H NMR.

[0012] Intermediate 10b (4.39 g, 1.0 eq, 11.8 mmol) was deprotected in 4.0M HCl inDioxane / DCM (25 mL / 10 mL) at room temperature, overnight to obtain acid intermediate 10.Crude product was purified by silica column chromatography with DCM:10% MeOH in DCM + 1% NH4OH (2X) to obtain 3.24 g (92%) characterized by1H NMR and Mass Spectrometry. Synthesis of tail group intermediate 14-22 Protected starting material 14-19 (4.0 g, 1.0 eq, 15.5 mmol) was reacted with 3-hydroxydecanol 14-20 (3.7 g, 1.5 eq, 23.25 mmol) using EDCI (4.5 g, 1.5 eq, 23.25 mmol),DMAP (950 mg, 0.5 eq, 7.75 mmol) and DIPEA (4.0 mL, 1.5 eq, 23.25 mmol) in DCM (20.0 mL) at room temperature, overnight. Crude product was purified by ISCO columnchromatography on silica column eluting with DCM and 10% MeOH in DCM (X2) to obtain4.1 g of the desired product 14-21 based on1H NMR. Intermediate 14-21 (4.1 g, 1.0 eq, 10.3 mmol) was deprotected in 15 mL 4N HCl / Dioxane to yield product 14-22. Crude product was purified by ISCO column chromatography on silica eluting with Hexanes and Ethyl acetate to obtain 2.7 g (77%) of pure 14-22 based on1H NMR. Synthesis of tail group intermediate 2 Starting material 14-23 () was reacted with 14-24 (3.4 g, 1.5 eq, 26.0 mmol) using EDCI (5.0 g, 1.5 eq, 26.0 mmol), DMAP (292 mg, 0.15 eq, 2.6 mmol) and DIPEA (4.5 mL, 1.5 eq, 26.0 mmol) in DCM (100 mL), at room temperature, overnight to obtain protected intermediate 2’. Crude product was purified by Silica column chromatography eluting with Hexanes : Ethyl Acetate to obtain pure Intermediate 2’ (5.84 g, 84%) characterized by mass spectrometry and1H NMR.

[0013] Protected intermediate 2’ (5.84 g, 1.0 eq, 17.0 mmol) was deprotected in 4.0M HClin Dioxane / DCM (40 mL / 10 mL) at room temperature, overnight to obtain acid intermediate10. Crude product was purified by silica column chromatography with DCM:10% MeOH in DCM + 1% NH4OH to obtain 4.47 g (82%) characterized by1H NMR and Mass Spectrometry. Synthesis of Lipid 43 Intermediate 9’a was reacted with intermediate 10 (723 mg, 3.0 eq, 2.3 mmol) using EDCI (875 mg, 6.0 eq, 4.56 mmol), DIPEA (794 µL,6.0 eq, 4.56 mmol) and DMAP (51 mg, 0.6 eq, 0.46 mmol) in DCM (30 mL) at room temperature, overnight. Crude product was purified on silica column eluting with DCM:10% MeOH in DCM to obtain 600 mg of product with impurities. The compound was repurified on silica column eluting with Hexanes : Ethyl acetate to obtain 320 mg of purified compound based on LC-ELSD Purity>98% and UPLC-CAD purity > 90%; characterized by1H NMR and Mass Spectrometry. Synthesis of Lipid 46 Intermediate 14-22 (1.27 g, 1.0 eq, 3.72 mmol) was converted to the correspondingacid chloride 14-22’, using Oxalyl chloride (1.1 mL, 3.4 eq, 12.6 mmol) and DMF (40 µL), inToluene (5.0 mL) at room temperature, overnight. Intermediate 9’a (263 mg, 1.0 eq, 0.61 mmol) was reacted with crude 14-22’ (1.32 g, 6.0 eq, 3.66 mmol) using TEA (0.85 mL, 10.0 eq, 6.1 mmol) in Toluene (5.0 mL) at room temperature, overnight. Crude product was purified by ISCO column chromatography on silica column eluting with Hexanes and Ethyl acetate to afford pure Lipid 46 (308 mg, 47%) characterized by UPLC-CAD (>99%),1H NMR and Mass Spectrometry. Synthesis of Lipid 52 Intermediate 2 (330 mg, 1.0 eq, 0.76 mmol) was reacted with diol intermediate 9’a(786 mg (3.0 eq, 2.3 mmol) using EDCI (875 mg, 6.0 eq, 4.56 mmol), DIPEA (794 µL, 6.0 eq, 4.56 mmol) and DMAP (51 mg, 0.6 eq, 0.46 mmol) in DCM (30 mL) at room temperature,overnight. Crude product was purified on silica column eluting with Hexanes: EtOAc to obtain690 mg of product with impurities. The compound was repurified on silica column eluting with DCM:10% MeOH in DCM to obtain 600 mg of product with impurities. The compound wasrepurified on silica column eluting with Hexanes : Ethyl acetate to obtain 480 mg of purifiedLipid 52 (LC-ELSD Purity> 99%. UPLC purity > 90%) and characterized by1H NMR and MS.EXAMPLE 2. PREPARATION OF LNPS BY MICROFLUIDIC MIXING USING EXEMPLARY LIPIDSThis Example describes the production of mRNA-loaded LNPs using exemplary materials and microfluidic mixing process. LNPs encapsulating an mRNA payload were prepared by mixing an aqueous mRNA solution and an ethanolic lipid blend solution (containing the ionizable lipid, DSPC, DPG-PEG and Cholesterol at lipid ratios shown in TABLE 2) using an in-line microfluidic mixing process. The mRNA stock solution was diluted in pH 4 acetate buffer (yielding a 400 µg / mL solution of mRNA) in 65 mM pH 4 acetate buffer. The lipid components were dissolved in anhydrous ethanol at the relative ratios set forth in TABLE 2 below.TABLE 2 The mRNA and lipid solutions were mixed using a NanoAssemblr Ignite microfluidic mixing device (part no. NIN0001) and NxGen mixing cartridge (part no. NIN0002) from Precision Nanosystems Inc. (British Columbia, CA). Briefly, the mRNA and lipid solutions were each loaded into separate polypropylene syringes. A mixing cartridge was inserted into the NanoAssemblr Ignite, and the syringes were directly mounted into the luer ports of the mixing cartridge. The two solutions were then mixed at a 3:1 v / v ratio of mRNA solution (3.75 mL) to lipid solution (1.25 mL) at a total flow rate of 9 mL / min using the NanoAssemblr Ignite (the ratios, volumes, and flow rates can vary). The resulting suspension was held at room temperature for a minimum of 5 minutes before proceeding to ethanol removal and buffer exchange. Following mixing, ethanol removal and buffer exchange was performed on the resulting LNP suspension using a discontinuous diafiltration process. A centrifugal ultrafiltration device with 100,000 kDa MWCO regenerated cellulose membrane (Amicon Ultra-15, MilliporeSigma, Massachusetts, US) was sanitized with 70% ethanol solution and then washed twice with MBS exchange buffer (25 mM pH 6.5 MES buffer with 150 mM NaCl).The LNP suspension (5 mL) was then loaded into the device and centrifuged at 500 RCF untilthe volume was reduced by half (2.5 mL). The suspension was then diluted with exchange buffer (2.5 mL of MBS) to bring the suspension back to the original volume. This process of two-fold concentration and two-fold dilution was repeated five additional times for a total of six discontinuous diafiltration steps. The retentate containing the LNPs in MBS was recovered from the centrifugal ultrafiltration device, mixed with sucrose to a final sucrose concentration of 10% w / v, and then filtered using a 0.2 µm PES syringe filter. The LNPs were either used right away, or stored frozen at -80 °C until further use.EXAMPLE 3. PREPARATION OF LNPS BY MICROFLUIDIC MIXING USING EXEMPLARY LIPIDS– CHARACTERIZATION OF LNPSThis Example describes the characterization of LNPs produced in Example 2. Samples of the LNPs produced in Example 2 were characterized to determine the average hydrodynamic diameter, zeta potential, and mRNA content (total and dye-accessible mRNA). The hydrodynamic diameter was determined by dynamic light scattering (DLS) using a Zetasizer model ZEN3600 (Malvern Pananalytical, UK). The zeta potential was measured in 5 mM pH 5.5 MES buffer and 5 mM pH 7.4 HEPES buffer by laser Doppler electrophoresis using the Zetasizer. RNA content of the nanoparticles is measured using Thermo Fisher Quant-iT RiboGreen RNA Assay Kit. Dye accessible RNA, which includes both un-encapsulated RNA and accessible RNA at the LNP surface, is measured by diluting the nanoparticles toapproximately 1 µg / mL mRNA using HEPES buffered saline, and then adding Quant-iTreagent to the mixture. Total RNA content is measured by disrupting a nanoparticle suspension by dilution of the stock LNP batch (typically at ≥ 40 ug / mL RNA) in 0.5% Triton solution in HEPES buffered saline to obtain a 1 ug / mL RNA solution (final nominal concentration based on formulation input values) and subsequent heating at 60 °C for 30 minutes followed by addition of Quant-It reagent. RNA is quantified by measuring fluorescence at 485 / 535 nm, and concentration is determined relative to a contemporaneously run RNA standard curve. Exemplary results are set forth in TABLE 3. TABLE 3 EXAMPLE 4. PREPARATION OF VHH CONJUGATES TO ENABLE M2 MACROPHAGETARGETING An anti-CD206 VHH targeting moiety was conjugated to DSPE-PEG(2k)-maleimide via covalent coupling between the maleimide group and a thiol functionality of a C-terminal cysteine residue on the protein. The protein (3-4 mg / mL), after buffer exchange into pH 7.4 phosphate buffered saline (PBS 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, and 1.8 mM KH2PO4) with 5 mM ethylenediaminetetraacetic acid (EDTA), was reduced using 2 mM Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) for 1 hour at room temperature. The reduced protein was isolated using a 7 kDa molecular weight cutoff (MWCO) SEC column to remove TCEP and buffer exchanged into fresh PBS with 5 mM EDTA. The conjugation reaction was initiated by addition of a 10 mg / mL micellar suspension of DSPE-PEG2k-maleimide and 30 mg / mL DSPE-PEG2k-OCH3 (1:4 mol ratio is used) in PBS. The conjugation reaction is carried out using 2 – 4 mg / mL protein and a 1 - 2 molar excess of maleimide at 37°C for 2 hours followed by incubation at room temperature for anadditional 12 - 16 hours.The production of the resulting conjugate was monitored by HPLC and the reactionquenched in 2 mM cysteine. The resulting conjugate (DSPE-PEG-VHH) is isolated using a 100 kDa or 50 kDa MWCO Millipore Regenerated Cellulose membrane filtration using pH 7.0HEPES buffer saline (25 mM HEPES, 150 mM NaCl) and stored at 4°C prior to use. Afterquenching, the final micelle composition consists of a mixture of DSPE-PEG2k-VHH, DSPE- PEG-maleimide (cysteine terminated), and DSPE-PEG2k-OCH3. The ratio of the three components is approximately DSPE-PEG-Fab: DSPE-PEG-maleimide (cysteine terminated):DSPE-PEG- OCH3 = 1: 0 – 1.5: 4 -10 (by mol)).EXAMPLE 5. PREPARATION OF LNPS CONTAINING M2 MACROPHAGE TARGETING GROUPThis Example describes the incorporation of an M2 Macrophage targeting conjugate into preformed LNPs. aCD206 VHH sequence Indentification (SEQ ID 170): QVQLQESGGGLVQAGGSLRLSCAASGFTDDDYDIGWFRQAPGKEREGVSCISSSDGS TYYADSVKGRFTISSDNAKNTVYLQMNSLKPEDTAVYYCAADFFRWDSGSYYVRG CRHATYDYWGQGTQVTVSSTSFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEASR PAAGGAVHTRGLDFAGGCHHHHHH LNPs from Example 2 and 3 and DSPE-PEG2k-anti-CD206 VHH conjugate (SEQ ID X) (prepared using the methods described in Example 4) were combined in a 15 mL conical tube at a ratio of 0.084 g VHH conjugate per 1 g of mRNA and diluted with MBS (25 mM pH 6.5 MES buffer with 150 mM NaCl) and 49 wt% sucrose solution to a final mRNA concentration of 0.2 mg / mL and sucrose concentration of 10% w / v. The tube was placed into a ThermoMixer pre-heated to 37 °C and then mixed at 300 rpm for 4 hours at 37 °C. Theresulting targeted LNP suspension was subsequently filtered using a 0.2 µm PES syringe filterand then either used immediately or stored frozen at -80 °C. Exemplary targeted LNP properties are shown in Table 4. TABLE 4. EXAMPLE 6. METHOD FOR FREEZING (AND THAW) PROCESS FOR LNP SUSPENSION ANDLNP CHARACTERIZATION POST FREEZE-THAWLNP suspension was mixed with a solution of 49 wt% sucrose solution in water and additional storage buffer (if needed) to achieve a final sample containing LNPs at approximately 45 µg / mL and sucrose at approximately 9.6 wt%. Aliquots of approximately 0.05 mL in 1.5 mL centrifuge tubes were then prepared from the final LNP sample containing sucrose. The aliquots were then placed in a -80 °C freezer for at least 2 h to freeze the samples. After freezing, an aliquot was thawed by placing it at room temperature for at least 10 min.The aliquot was then mixed by vortexing at 2500 rpm for approximately 5 s. The thawed material was then analyzed for size by DLS as described in Example 3. EXAMPLE 7. PHYSIOCHEMICAL PROPERTIES OF LNPS BASED ON LIPIDS 15, 26, 25A, 27, 28,40 AND COMPARATOR LIPID ALC-0315 Lipids 15, 26, 25A, 27, 28, 40 and comparator lipid ALC-0315 encapsulating GFP-mRNA (T...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I): (I), or a salt thereof, wherein: R1and R2are each C1-3 alkylene; R3is C1-3 alkylene or a bond; R1Aand R2Aare each a bond or C1-10 alkylene; R3Ais a bond or C1-3 alkylene; R1A1, R2A1, R3A1, and R3A2are each H; R1A2and R2A2are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2; R1A3and R2A3are each H, -(CH2)0-5C(O)ORa1, or -(CH2)0-5OC(O)Ra2; R3A3is -C(O)ORa1; Ra1and Ra2are each independently C1-20 alkyl; R3Bis ; R3B1is C4-6 alkylene; and R3B2and R3B3are each C1-3 alkyl.

2. The compound of claim 1, or a salt thereof, wherein R1and R2are each methylene.

3. The compound of claim 1 or 2, or a salt thereof, wherein R1Aand R2Aare each a bond, - CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, or - (CH2)10-.

4. The compound of any one of claims 1 to 3, or a salt thereof, wherein R3Ais a bond, -CH2- , or -(CH2)2-.

5. The compound of any one of claims 1 to 4, or a salt thereof, wherein R1A2and R2A2are each -OC(O)(C1-15alkyl), -C(O)O(C1-15alkyl), -OC(O)CH(C1-10alkyl)(C1-10alkyl), - C(O)OCH(C1-10 alkyl)(C1-10 alkyl), -(CH2)C(O)O(C1-10 alkyl), or -(CH2)OC(O)(C1-10 alkyl).

6. The compound of claim 5, or a salt thereof, wherein R1A2and R2A2are each , , , , , , , , or .

7. The compound of any one of claims 1 to 6, or a salt thereof, wherein R1A3and R2A3are each H, -OC(O)(C1-15 alkyl), or -C(O)O(C1-15 alkyl).

8. The compound of claim 7, or a salt thereof, wherein R1A3and R2A3are each H, , , , , , , , , , , or . 1899. The compound of any one of claims 1 to 8, or a salt thereof, wherein R3A3is - C(O)OCH(C1-5 alkyl)(C1-10 alkyl).

10. The compound of claim 9, or a salt thereof, wherein R3A3is .

11. The compound of any one of claims 1 to 10, or a salt thereof, wherein R3B1is -(CH2)4-, - (CH2)5-, or -(CH2)6-.

12. The compound of any one of claims 1 to 11, or a salt thereof, wherein R3B2and R3B3are each methyl.

13. The compound of claim 1, or a salt thereof, wherein the compound is selected from Table 1.

14. The compound of claim 1, or a salt thereof, wherein the compound is .

15. The compound of claim 1, or a salt thereof, wherein the compound is .

16. A lipid nanoparticle (LNP) comprising a lipid blend for targeted delivery of a nucleic acid into an immune cell, the lipid blend comprising: (a) a lipid-immune cell targeting group conjugate comprising the compound of Formula (II): [Lipid] – [optional linker] – [immune cell targeting group], (b) an ionizable cationic lipid comprising the compound of any one of claims 1-15, or a salt thereof, and (c) a nucleic acid, wherein the nucleic acid is encapsulated in the LNP.

17. The LNP of claim 16, wherein the immune cell targeting group comprises an antibody that binds a macrophage antigen, a monocyte antigen, and / or a dendritic antigen.

18. The LNP of claim 17, wherein the macrophage comprises an M1 macrophage, an M2 macrophage, or both.

19. The LNP of claim 17 or 18, wherein the macrophage comprises an M2a macrophage, an M2b macrophage, an M2c macrophage, or any combination thereof.

20. The LNP of claim 17, wherein the macrophage antigen comprises CDIIB, CD68, CD80, CD86, TRL-2, TRL-4, iNOS, MHC-II, CD163, CD206, CD209, FIZZ1, or Ym1 / 2, or any combination thereof.

21. The LNP of claim 20, wherein the macrophage antigen comprises CD206.

22. The LNP of any one of claims 16 to 21, wherein the immune cell targeting group is covalently coupled to a lipid in the lipid blend via a polyethylene glycol (PEG) containing linker.

23. The LNP of any one of claims 16 to 22, wherein the lipid blend further comprises one or more of a structural lipid, a neutral phospholipid, and a free PEG-lipid.

24. The LNP of any one of claims 16 to 23, wherein the LNP has a mean diameter in the range of about 50 to about 200 nm.

25. The LNP of any one of claims 16 to 24, wherein the LNP has a polydispersity index in a range from 0.01 to 0.

1.

26. The LNP of any one of claims 16 to 25, wherein the LNP has a zeta potential of from about +0 mV to about +10 mV at pH 5.5, or from about -5 mV to about 0 mV at pH 7.

4.

27. The LNP of any one of claims 16 to 26, wherein the nucleic acid is DNA or RNA.

28. The LNP of claim 27, wherein the RNA is an mRNA.

29. The LNP of claim 28, wherein the mRNA encodes a receptor, a growth factor, a hormone, a cytokine, an antibody, an antigen, an enzyme, or a vaccine.

30. The LNP of claim 28, wherein the mRNA encodes a polypeptide capable of regulating immune response in the immune cell.

31. The LNP of claim 28, wherein the mRNA encodes a polypeptide capable of reprogramming the immune cell.

32. The LNP of claim 31, wherein the mRNA encodes polypeptide capable of reprogramming an M2 macrophage to an M1 macrophage.

33. The LNP of any one of claims 16 to 32, wherein the immune cell targeting group comprises an antibody, and the antibody is a Fab or an immunoglobulin single variable domain.

34. The LNP of any one of claims 16 to 32, wherein the immune cell targeting group comprises a Fab, F(ab’)2, Fab’-SH, Fv, or scFv fragment.

35. The LNP of any one of claims 16 to 34, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the LNP binds a first macrophage antigen, and also binds a second macrophage antigen.

36. The LNP of claim 35, wherein the LNP comprises two conjugates, wherein the first conjugate comprises an antibody that binds the first macrophage antigen, and the second conjugate comprises an antibody that binds the second macrophage antigen.

37. The LNP of claim 35, wherein the LNP comprises one conjugate, and the conjugate comprises a bispecific antibody that binds both the first macrophage antigen and the second macrophage antigen.

38. The LNP of claim 37, wherein the bispecific antibody is an immunoglobulin single variable domain or Fab-ScFv.

39. The LNP of any one of claims 16 to 34, wherein the LNP binds to a first antigen on the surface of the first type of immune cell, and also binds to a second antigen on the surface of the second type of immune cell.

40. The LNP of claim 39, wherein the first type of immune cell is a first macrophage, and the second type of immune cell is a second macrophage, a T-cell, or an NK cell.

41. The LNP of claim 39 or 40, wherein the LNP comprises two conjugates, and the first conjugate comprises a first antibody that binds to the first antigen of the first type of immune cell, and the second conjugate comprises a second antibody that binds to the second antigen of the second type of immune cell.

42. The LNP of claim 39 or 40, wherein the LNP comprises one conjugate, and the conjugate comprises a bispecific antibody, and the bispecific antibody binds to both the first antigen on the first type of immune cell, and the second antigen on the second type of immune cells.

43. The LNP of any one of claims 16 to 34, wherein the bispecific antibody is an immunoglobulin single variable domain or a Fab-ScFv.

44. The LNP of any one of claims 16 to 34, wherein the LNP is for delivering a nucleic acid into an immune cell, and wherein the immune cell targeting group comprises a single antibody that binds to CD206.

45. The LNP of any one of claims 16 to 34, wherein the LNP is for delivering a nucleic acid into both a macrophage and a T-cell or both a macrophage and an NK cell, wherein the immune cell targeting group binds to both (i) CD206 and (ii) one of CD3, CD7, CD8, and CD56.

46. A method of targeting the delivery of a nucleic acid to an immune cell of a subject, comprising contacting the immune cell with the LNP of any one of claims 16 to 45, wherein the LNP comprises the nucleic acid.

47. A method of expressing a polypeptide of interest in a targeted immune cell of a subject, comprising contacting the immune cell with the LNP of any one of claims 16 to 45, wherein the LNP comprises a nucleic acid encoding the polypeptide.

48. A method of modulating cellular function of a target immune cell of a subject, comprising administering to the subject the LNP of any one of claims 16 to 45, wherein the LNP comprises a nucleic acid modulates the cellular function of the immune cell.

49. A method of treating, ameliorating, or preventing a symptom of a disorder or disease in a subject in need thereof, comprising administering to the subject an LNP for delivering a nucleic acid into an immune cell of the subject, wherein the LNP is any one of claims 16 to 45, wherein the LNP comprises the nucleic acid.

50. The method of claim 49, wherein the disorder is an immune disorder, an inflammatory disorder, or cancer.

51. The method of claim 49, wherein the nucleic acid encodes an antigen for use in a therapeutic or prophylactic vaccine for treating or preventing cancer.