COMPOSIÇÕES E MÉTODOS PARA INIBIÇÃO DE KRAS PARA O TRATAMENTO DE DOENÇA

Abstract

The present disclosure provides pharmaceutical compositions comprising a peptide- polynucleotide complex, wherein the peptide comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; and wherein the polynucleotide is a small interfering RNA (siRNA) targeting human KRAS mRNA, wherein the target sequence of human KRAS mRNA does not encode G12, G13, or Q61 with reference to SEQ ID NO: 4 or a mutant amino acid at position 12, 13, or 61 with reference to SEQ ID NO: 4.

Description

1 / 93 COMPOSITIONS AND METHODS FOR INHIBITING KRAS FOR THE TREATMENT OF DISEASE 1. CROSS-REFERENCE WITH RELATED ORDERS

[001] This application claims priority over U.S. Provisional Application No. 63 / 486,339, filed February 22, 2023, and U.S. Provisional Application No. 63 / 624,088, filed January 23, 2024; each of which is incorporated herein by reference in its entirety. 2. DESCRIPTION OF THE TEXT FILE SENT ELECTRONICALLY

[002] The contents of the electronic sequence listing (AURS_010_02WO_ListSeq_ST26.xml; Size: 2,214,874 bytes; and Creation Date: February 10, 2024) are incorporated herein by reference in their entirety. 3. FIELD OF THE INVENTION

[003] The present invention relates generally to pharmaceutical compositions for the reduction / inhibition (knocking down) of KRAS. The present invention also relates to the treatment of a disease or disorder in an individual using the pharmaceutical compositions described in this report. 4. BASIS OF THE INVENTION

[004] The KRAS gene provides instructions for the production of a protein called KRAS, which plays important roles in cell division, cell differentiation, and cell self-destruction (apoptosis). Mutational activation of KRAS is a common oncogenic event. 5. SUMMARY OF THE INVENTION

[005] In one aspect, this report describes a pharmaceutical composition comprising a peptide-polynucleotide complex, wherein the peptide comprises a sequence of Petition 870260073661, dated 07 / 24 / 2026, page 6 / 207 2 / 93 amino acids with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% ideomentity to the amino acid sequence of ID SEQ NO: 1, ID SEQ NO: 2, or ID SEQ NO: 3; and wherein the polynucleotide is a small interfering RNA (siRNA) targeting human KRAS mRNA, in which the target human KRAS mRNA sequence does not encode G12, G13, or Q61 with reference to ID SEQ NO: 4 or a mutant amino acid at position 12, 13, or 61 with reference to ID SEQ NO: 4. In some embodiments, the peptide is non-lytic, non-cytotoxic, and capable of affecting the release of the polynucleotide from an endosome of a cell. In some embodiments, the peptide comprises two or more contiguous basic amino acids (a cationic region) and one or more histidine residues located adjacent to the cationic region. In some embodiments, the peptide comprises an amino acid sequence of ID SEQ NO: 1, ID SEQ NO: 2, or ID SEQ NO: 3.In some embodiments, siRNA comprises a sense strand and an antisense strand. In some embodiments, the sense strand and the antisense strand are each 16 to 24 bases long. In some embodiments, the sense strand is 19 bases long. In some embodiments, the antisense strand is 21 bases long. In some embodiments, the sense strand and the antisense strand are modified. In some embodiments, the modifications are selected from the group consisting of 2'-methoxy (2'OMe), 2'-fluorine (2'-F), 2'-O-methoxyethyl (2'-O-MOE), 5'-vinylphosphonate, phosphorothioate (PTO), blocked nucleic acid (LNA), blocked nucleic acid (UNA), glycol nucleic acid (GNA), and deoxyribonucleic acid (DNA). In some embodiments, the sense strand modifications comprise: PTO at positions 1 and 2; 2'-F in positions 3, 7-9, 12 and 17; and 2'-OMe in positions 1, 2, 4-6, 10, 11, 13-16, 18 and 19. In some modalities, the antisense tape modifications include: PTO. Petition 870260073661, dated 07 / 24 / 2026, p. 7 / 207 3 / 93 at positions 1, 2, 19, and 20; 2'-F at positions 2 and 14; and 2'-OMe at positions 1, 3-13, and 15-21. In some embodiments, the last nucleotide of the sense strand is adenine (A). In some embodiments, the first nucleotide of the antisense strand is uracil (U). In some embodiments, the sense strand comprises a nucleotide sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity with the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity with the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2.In some embodiments, the peptide-to-polynucleotide ratio is about 6:1 to about 18:1, wherein the ratio is the proportion of positively charged polymer amine groups to negatively charged nucleic acid phosphate groups. In some embodiments, the charge ratio between peptide and polynucleotide is about 12:1. In some embodiments, the peptide-to-polynucleotide ratio is about 2:1 to about 3500:1, wherein the ratio is the molar ratio. In some embodiments, the molar ratio of peptide to polynucleotide is about 4:1 to about 1000:1. In some embodiments, the molar ratio between peptide and polynucleotide is about 5:1 to about 200:1. In some embodiments, the molar ratio between peptide and polynucleotide is about 50:1 to about 200:1. In some embodiments, the molar ratio between peptide and polynucleotide is approximately 5:1. In some embodiments, the molar ratio between peptide and polynucleotide is approximately 100:1.In some embodiments, the peptide-polynucleotide complex is a nanoparticle with a diameter of about 10 nm to about 300 nm. In some... Petition 870260073661, dated 07 / 24 / 2026, page 8 / 207 In 4 / 93 embodiments, the peptide-polynucleotide complex is coated with albumin and / or hyaluronic acid. In some embodiments, the pharmaceutical composition additionally comprises a pharmaceutically acceptable carrier.

[006] In another aspect, this report provides a method of treating a disease or disorder in an individual, which method comprises administering to the individual a therapeutically effective amount of the pharmaceutical composition described in this report. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is blood cancer or solid tumor cancer. 6. BRIEF DESCRIPTION OF THE FIGURES

[007] Fig. 1 shows an exemplary siRNA modification pattern described in this report. 2'-methoxy is referred to as 2'-OMe, 2'-fluorine is referred to as 2'-F, and phosphorothioate is referred to as PTO.

[008] Figures 2A-2F show the knockdown of KRAS in NCI-H23 cells carrying a KRAS G12C mutation by two exemplary siRNAs: XD-39946 and XD-39966. Figure 2A shows the dose-response curve of XD-39946; Figure 2B shows the dose-response curve of XD-39966; Figure 2C shows the relative mRNA expression level of KRAS at different concentrations of XD-39946 and XD-39966; Figure 2D shows the relative mRNA expression level of GAPDH at different concentrations of XD-39946 and XD-39966; Figure 2E shows the original data regarding the mRNA expression levels of KRAS and GAPDH at different concentrations of XD-39946 and XD-39966. Figure 2F shows the bar graphs of the original data in Figure 2E.

[009] Figures 3A-3C show the knockdown of KRAS in cell lines harboring wild-type or mutant KRAS by two exemplary siRNAs: XD-39951 and XD-39947. Figure Petition 870260073661, dated 07 / 24 / 2026, page 9 / 207 5 / 93 Figure 3A shows the knockdown of KRAS in SW480 cells (G12V mutation). Figure 3B shows the knockdown of KRAS in HT-29 cells (wild type). Figure 3C shows the knockdown of KRAS in LS174T cells (G12D mutation).

[0010] Figures 4A-4B show the knockdown of KRAS in more cell lines carrying additional KRAS mutations by siRNA specimen XD-39951 and its effect on cell viability. Figure 4A shows the knockdown of KRAS in PDAC / ACP, NSCLC / CNPC, and CRC cells carrying different KRAS mutations. Figure 4B shows cell viability after the knockdown of KRAS in PDAC / ACP, NSCLC / CNPC, and CRC cells. 7. DETAILED DESCRIPTION OF THE INVENTION

[0011] This report describes pharmaceutical compositions comprising a peptide-polynucleotide complex for KRAS inhibition for the treatment of diseases. 7.1. Definitions

[0012] The terms polypeptide, peptide, and protein are used interchangeably in this report to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residues are an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers, those containing modified residues, and non-naturally occurring amino acid polymers.

[0013] The terms homologous, identical, or percentage identity with respect to two or more peptides refer to two or more sequences or subsequences that exhibit a specified percentage of amino acid residues that are identical (i.e., approximately 60% identity, approximately 70%, approximately 75 ... Petition 870260073661, dated 07 / 24 / 2026, p. 10 / 207 6 / 93 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99% or greater identity in a specified region, when compared and aligned for maximum match in a designated comparison window or region) as measured using BLAST or BLAST 2.0 sequence comparison algorithms with standard parameters described below, or by manual alignment and visual inspection (see, for example, the NCBI website www.ncbi.nlm.nih.gov / BLAST / or similar). The definition also includes sequences that exhibit deletions and / or additions, as well as those that exhibit substitutions, as well as those that occur naturally, e.g., polymorphic or allelic variants, and artificial variants. As described below, the algorithms may take gaps and the like into account.

[0014] The terms isolated, purified, or biologically pure refer to material that is substantially or essentially free of components that normally accompany it, as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. A protein or nucleic acid that is the predominant species present in a preparation is substantially purified. The term purified, in some embodiments, denotes that a nucleic acid or protein gives rise to essentially one band on an electrophoretic gel; this means that the nucleic acid or protein is at least 85% pure, at least 95% pure, and at most at least 99% pure. Purify or purification, in other embodiments, means removing at least one contaminant from the composition to be purified.In this sense, purification does not require that the purified compound be homogeneous, for example, 100% pure. Petition 870260073661, dated 07 / 24 / 2026, page 11 / 207 7 / 93

[0015] The term target sequence refers to a nucleotide sequence found in the mRNA of a target gene (e.g., the KRAS gene). Such a nucleotide sequence is complementary to the antisense strand of an siRNA described in this report. 7.2. Peptide-Polynucleotide Complex

[0016] One aspect of the present invention involves a peptide-polynucleotide complex. A peptide-polynucleotide complex of the invention is capable of efficient transfection of a peptide-associated polynucleotide into the cytoplasm of a cell. The peptide, the polynucleotide, the peptide-polynucleotide complex, and the cell are described below. 7.2.1. Peptide

[0017] In one aspect, a peptide-polynucleotide complex of the invention comprises a peptide. In general, and as described in the examples, a peptide of the invention is derived from melittin and modified to attenuate its cytotoxicity while maintaining its propensity to interact with membrane bilayers. Furthermore, the peptide is substantially non-lytic and non-cytotoxic to cells. A peptide-polynucleotide complex of the invention comprises a peptide that (1) has a function substantially similar to a peptide with an amino acid sequence of ID SEQ NO: 1 (VLTTGLPALISWIRRRHRRHC), ID SEQ NO: 2 (VLTTGLPALISWIRRRHRRHG) or ID SEQ NO: 3 (VLTTGLPALISWIKRKRQHRWRRRR), and (2) has an amino acid sequence with similarity or identity to the amino acid sequence of ID SEQ NO: 1, ID SEQ NO: 2 or ID SEQ NO: 3.

[0018] As used in this report, the expression functions substantially similarly to a peptide comprising ID SEQ NO: 1, 2 or 3 refers to a substantially non-lytic and / or non-cytotoxic peptide that is capable of affecting the release of a polynucleotide. Petition 870260073661, dated 07 / 24 / 2026, page 12 / 207 8 / 93 from an endosome. In some embodiments, a peptide of the invention is non-lytic. The term non-lytic means that the lipid bilayer of a cell is not normally compromised upon contact with the peptide. The integrity of the lipid bilayer can be assessed by the inappropriate entry or exit of cellular or extracellular components into a cell. For example, proteins and / or cellular organelles may leak out of a cell with a compromised lipid bilayer. Alternatively, extracellular components (i.e., those that do not normally enter through gap junctions, for example) may enter a cell with a compromised lipid bilayer. It should be noted, however, that the peptide may penetrate the lipid bilayer of a cell and enter the interior of the cell, but in doing so, the integrity of the lipid bilayer is not affected. In other embodiments, a peptide of the invention is substantially non-cytotoxic.The term non-cytotoxic indicates that the cell is not normally killed upon contact with the peptide. Typically, a peptide of the invention decreases cell viability by no more than about 10%, no more than about 7%, no more than about 5%, or no more than about 3%. In certain embodiments, a peptide of the invention is both non-lytic and non-cytotoxic.

[0019] A peptide of the invention is capable of associating with a polynucleotide. Thus, in one aspect, a peptide of the invention comprises at least one cationic region that interacts with a polynucleotide. Typically, a cationic region has 2 or more contiguous basic amino acids. Importantly, a peptide of the invention also possesses an endosomolytic capacity, which allows it to affect the release of a polynucleotide from an endosome into the cytoplasm of a cell. The term endosomolytic can be used to describe substances that initiate or facilitate the lysis of endosomes. As described in the Examples, protonation Petition 870260073661, dated 07 / 24 / 2026, page 13 / 207 9 / 93 of histidine residues of a peptide of the invention promotes the disassembly of the peptide-polynucleotide complex, which releases the peptide to permeabilize the endosomal membrane for the release of the polynucleotide. Thus, in another aspect, a peptide of the invention comprises one or more histidine residues located adjacent to or within at least one cationic region of the peptide.By way of non-limiting example, if a peptide of the invention comprises three cationic regions, the peptide may have at least one histidine adjacent to or within the first cationic region of the peptide, at least one histidine adjacent to or within the second cationic region of the peptide, at least one histidine adjacent to or within the third cationic region of the peptide, at least one histidine adjacent to or within each of the first and second cationic regions of the peptide, at least one histidine adjacent to or within each of the first and third cationic regions of the peptide, at least one histidine adjacent to or within each of the second and third cationic regions of the peptide, or at least one histidine adjacent to or within each of the first, second and third cationic regions of the peptide. A histidine residue adjacent to a cationic region may be positioned before or after the cationic region.In some embodiments, a histidine residue adjacent to a cationic region is immediately adjacent to the region. In other embodiments, a histidine residue adjacent to a cationic region is not immediately adjacent to the region. For example, the histidine residue may be about 2, 3, 4, or 5 positions away from the cationic region. In other embodiments, a histidine residue is within a cationic region. The endosomolytic capacity of a peptide of the invention eliminates the need for additional endosomolytic agents, such as chloroquine, fusogenic peptides, inactivated adenoviruses, and polyethyleneimine, to release transfected polynucleotides from endosomes to ad. Petition 870260073661, dated 07 / 24 / 2026, page 14 / 207 10 / 93 administration into the cytoplasm of a cell. Such known endosomal lytic agents have negative effects on cells and may increase cytotoxicity during transfection.

[0020] In some embodiments, a peptide of the invention comprises ID SEQ NO: 1. In other embodiments, a peptide of the invention consists of ID SEQ NO: 1. In certain embodiments, a peptide of the invention is a variant of ID SEQ NO: 1, wherein the variant comprises at least 10 contiguous amino acids of ID SEQ NO: 1 and functions substantially similarly to a peptide comprising ID SEQ NO: 1. For example, a peptide of the invention may encompass at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids of ID SEQ NO: 1.

[0021] In some embodiments, a peptide of the invention comprises ID SEQ NO: 2. In other embodiments, a peptide of the invention consists of ID SEQ NO: 2. In certain embodiments, a peptide of the invention is a variant of ID SEQ NO: 2, wherein the variant comprises at least 10 contiguous amino acids of ID SEQ NO: 2 and functions substantially similarly to a peptide comprising ID SEQ NO: 2. For example, a peptide of the invention may comprise at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids of ID SEQ NO: 2.

[0022] In some embodiments, a peptide of the invention comprises ID SEQ NO: 3. In other embodiments, a peptide of the invention consists of ID SEQ NO: 3. In certain embodiments, a peptide of the invention is a variant of ID SEQ NO: 3, wherein the variant comprises at least 10 contiguous amino acids of ID SEQ NO: 3 and functions substantially similarly to a peptide comprising ID SEQ NO: 3. For example, a peptide of the invention may comprise at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids of ID SEQ NO: 3. Petition 870260073661, dated 07 / 24 / 2026, p. 15 / 207 11 / 93

[0023] In some embodiments, a peptide of the invention comprises an amino acid sequence that exhibits at least 80% identity to ID SEQ NO: 1, wherein the peptide is non-lytic and is capable of affecting the release of a polynucleotide from an endosome of a cell. The peptide comprising an amino acid sequence showing at least 80% identity with ID SEQ NO: 1 may show approximately 80%, approximately 85%, approximately 90%, or approximately 95% identity with the amino acid sequence of ID SEQ NO: 1. A peptide of the invention comprising an amino acid sequence showing at least 80% identity with ID SEQ NO: 1 may comprise one or more amino acids that have been conservatively substituted.For example, one, two, three, four, five, six, seven, eight, nine or more of nine amino acids may be conservatively substituted, provided that the resulting peptide functions substantially similarly to a peptide comprising ID SEQ NO: 1.

[0024] In some embodiments, a peptide of the invention comprises an amino acid sequence that exhibits at least 80% identity with ID SEQ NO: 2, wherein the peptide is non-lytic and is capable of affecting the release of a polynucleotide from an endosome of a cell. The peptide comprising an amino acid sequence showing at least 80% identity with ID SEQ NO: 2 may exhibit approximately 80%, approximately 85%, approximately 90%, or approximately 95% identity with the amino acid sequence of ID SEQ NO: 2. A peptide of the invention comprising an amino acid sequence showing at least 80% identity with ID SEQ NO: 2 may comprise one or more amino acids that have been conservatively substituted. For example, one, two, three, four, five, six, seven, eight, nine, or more than nine amino acids may be conservatively substituted, provided that the peptide re Petition 870260073661, dated 07 / 24 / 2026, p. 16 / 207 12 / 93 resulting function substantially similarly to a peptide comprising ID SEQ NO: 2.

[0025] In some embodiments, a peptide of the invention comprises an amino acid sequence that exhibits at least 80% identity with ID SEQ NO: 3, wherein the peptide is non-lytic and is capable of affecting the release of a polynucleotide from an endosome of a cell. The peptide comprising an amino acid sequence showing at least 80% identity with ID SEQ NO: 3 may exhibit approximately 80%, approximately 85%, approximately 90%, or approximately 95% identity with the amino acid sequence of ID SEQ NO: 3. A peptide of the invention comprising an amino acid sequence showing at least 80% identity with ID SEQ NO: 3 may comprise one or more amino acids that have been conservatively substituted.For example, one, two, three, four, five, six, seven, eight, nine or more amino acids may be conservatively substituted, provided that the resulting peptide functions substantially similarly to a peptide comprising ID SEQ NO: 3.

[0026] A peptide of the invention can be produced using a variety of techniques known in the state of the art. Peptides can be isolated using standard techniques, can be synthesized using standard techniques, or can be acquired or obtained from a repository.

[0027] When a peptide of the invention contains a C-terminal thiol in the form of a cysteine ​​residue, a peptide of the invention may be able to form a disulfide bond with another free thiol group, for example, with a free thiol group of the same peptide or of a different peptide. One skilled in the art can readily determine whether the formation of dimers improves or not the transfer of plasmid DNA. Without being bound by theory, the form Petition 870260073661, dated 07 / 24 / 2026, page 17 / 207 13 / 93 Dimerization can improve the transfer of plasmid DNA to certain peptides of the invention due to enhanced DNA condensation. Dimerization can be induced by incubating the free peptide in 20% DMSO for 24 to 72 hours, or by other methods known in other states of the art. As a non-limiting example, free thiols can be quantified by colorimetric assays using Ellman's reagent.

[0028] A peptide of the invention can be labeled. Non-limiting examples of suitable markers include fluorescent markers, chemiluminescent markers, radioactive markers, colorimetric markers, and resonance markers. Methods of labeling peptides are well known in the state of the art.

[0029] A peptide may be linked to a cargo complex. As used in this report, the term cargo complex may refer to any molecule or agent that can be transported or linked to the peptide, in addition to a polynucleotide of the invention. Otherwise stated, a peptide of the invention may be linked to a cargo complex in addition to a polynucleotide of the invention. For example, a cargo complex may be an imaging cargo, a therapeutic cargo, a cytotoxic cargo, or a targeting cargo.

[0030] Non-limiting examples of molecules and loading agents for imaging may include any molecule, agent, or material that has a detectable physical or chemical property. Such loads for imaging have been well developed in the field of fluorescent imaging, magnetic resonance imaging, positron emission tomography, Raman imaging, optical coherence tomography, photoacoustic imaging, Fourier transform infrared imaging, or immunoassays, and in general, almost all useful markers in such methods can be applied to the present. Petition 870260073661, dated 07 / 24 / 2026, p. 18 / 207 14 / 93 invention. For a review of various marking or signal-making systems that may be used, see U.S. Patent No. 4,391,904, incorporated herein by reference in its entirety.

[0031] Non-limiting examples of therapeutic load may include any substance that exhibits biological activity, such as pharmacological agents.Such a therapeutic load may include analgesics, antipyretics, antiasthmatics, antibiotics, antidepressants, antidiabetics, antifungal agents, antihypertensive agents, anti-inflammatory agents, including non-steroidal and steroidal anti-inflammatory drugs, antineoplastics, anxiolytic agents, immunosuppressive agents, antimigraine agents, sedatives, hypnotics, antianginal agents, antipsychotic agents, antimanic agents, antiarrhythmics, antiarthritic agents, antigout agents, anticoagulants, thrombolytic agents, antifibrinolytic agents, hemorheological agents, antiplatelet agents, anticonvulsants, antiparkinsonian agents, antihistamines, anti-restenosis agents, antipruritics, agents useful for calcium regulation, antibacterial agents, antiviral agents, antimicrobials, anti-infectives, bronchodilators, steroidal compounds and hormones, and combinations thereof.Alternatively, a cargo complex may be in the form of components of pharmacologically acceptable molecular complexes or salts.

[0032] Cytotoxic payload refers to a molecule or agent that is harmful (e.g., kills or damages) a cell. Examples may include antimicrotubule drugs such as taxols (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine). For example, examples may include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracine didna, mitoxantrone, mithramycin, actinomycin D, 1 Petition 870260073661, dated 07 / 24 / 2026, page 19 / 207 15 / 93 dihydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol and puromycin and analogues or homologues thereof.

[0033] A targeting payload can be any molecule or agent that directs a peptide-polynucleotide complex of the invention to a cell. A targeting payload can be directed to a eukaryotic target cell or a prokaryotic target cell. Non-limiting examples of targeting agents may include an antibody or antibody fragment, a receptor ligand, a small molecule, a peptide, a polypeptide, a lipid, a carbohydrate, a nucleic acid, a siRNA, a shRNA, an antisense RNA, a dendrimer, a microbubble, or an aptamer.

[0034] The means by which a cargo complex binds to a peptide of the invention can and will vary depending on the embodiment. A cargo complex can be linked to a peptide of the invention by any means known in the prior art, including covalently or non-covalently. 7.2.2. Polynucleotide

[0035] In another aspect, a peptide-polynucleotide complex of the invention comprises a polynucleotide. A polynucleotide may be single-stranded, double-stranded, or a combination thereof. In some embodiments, a polynucleotide is double-stranded. In other embodiments, a polynucleotide is single-stranded. In still other embodiments, a polynucleotide is a combination of single-stranded and double-stranded.

[0036] A polynucleotide of the invention may comprise a ribonucleic acid (RNA), a deoxyribonucleic acid (DNA), or a combination of RNA and DNA. Additionally, a polynucleotide may comprise modified nucleic acid bases, such as modified DNA bases or modified RNA bases. The modifications may occur, but are not limited to, the 2' position of the sugar, the C-5 position of pyrimidines, and the 8' position of purines. Examples of ba Petition 870260073661, dated 07 / 24 / 2026, page 20 / 207 Suitable modified DNA or RNA sequences include 2'-fluoronucleotides, 2'-aminonucleotides, 5'-aminoallyl-2'-fluoronucleotides, and phosphorothioate nucleotides (monothiophosphate and dithiophosphate). Alternatively, a polynucleotide may be a nucleotide mimic. Examples of nucleotide mimics include locked nucleic acids (LNA), peptide nucleic acids (PNA), and morpholino phosphorodiamidate (PMO) oligomers.

[0037] In some embodiments, a polynucleotide of the invention is a combination of RNA and DNA. In other embodiments, a polynucleotide comprises DNA. When a polynucleotide is DNA, the polynucleotide may comprise an expression cassette. As used in this report, an expression cassette is a nucleic acid construct comprising a nucleic acid sequence encoding a protein or peptide operatively linked to a promoter. In certain embodiments, a nucleic acid construct further comprises additional regulatory sequences. A non-limiting example of an additional regulatory sequence includes a transcription termination sequence. Other additional regulatory sequences are known in the art. As used in this report, the term promoter may mean a synthetic or naturally occurring molecule capable of conferring or activating the expression of a target nucleic acid sequence in a cell.A promoter can be the promoter normally associated with a DNA polynucleotide of the invention or it can be a heterologous promoter. A heterologous promoter can be derived from sources such as viruses, bacteria, fungi, plants, insects, and animals. A promoter can regulate the expression of a DNA sequence constitutively or differentially with respect to the cell, tissue, or organ in which the expression occurs. Or, a promoter can regulate expression with respect to the developmental stage or in response to external stimuli, such as stress. Petition 870260073661, dated 07 / 24 / 2026, page 21 / 207 17 / 93 physiological, pathogenic, metal ions, or inducing or activating agents (i.e., an inducible promoter). Representative, non-limiting examples of promoters may include the bacteriophage T7 promoter, the bacteriophage T3 promoter, the SP6 promoter, the basal HSP70 promoter, the lac operator-promoter, the tac promoter, the late SV40 promoter, the early SV40 promoter, the RSV-LTR promoter, the CMV IE promoter, a promoter comprising the tetracycline response element (TRE) nucleic acid sequence, and the CMV IE promoter. In some alternatives of these embodiments, a DNA polynucleotide of the invention is incorporated into a vector. One skilled in the state of the art would be able to construct a vector by means of standard recombinant techniques (see, for example, Sambrook et al., 2001 and Ausubel et al., 1996, both incorporated herein by reference).Vectors include, but are not limited to, plasmids, cosmids, transposable elements, viruses (bacteriophages, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs), such as retroviral vectors (e.g., derived from Moloney murine leukemia virus (MoMLV), MSCV, SFFV, MPSV, SNV, etc. vectors), lentiviral vectors (e.g., derived from HIV-1, HIV-2, SIV, BIV, FIV, etc.), adenoviral (Ad) vectors, including replication-competent, replication-deficient, and gutless forms thereof, adeno-associated viral (AAV) vectors, simian virus 40 (SV-40) vectors, bovine papillomavirus vectors, Epstein-Barr virus, herpesvirus vectors, vaccinia virus vectors, Harvey murine sarcoma virus vectors, murine mammary tumor virus vectors, and Rous sarcoma virus vectors.

[0038] In still other embodiments, a polynucleotide comprises RNA. Non-limiting examples of RNA sequences may include mRNA capable of encoding a protein and non-coding RNA, such as tRNA, rRNA, snoRNAs, microRNAs, siRNAs, saRNAs, pi Petition 870260073661, dated 07 / 24 / 2026, p. 22 / 207 18 / 93 RNAs and long non-coding RNA (IncRNA). For example, a nucleic acid may comprise mRNA. In some embodiments, when a nucleic acid comprises mRNA, the mRNA molecule may be encapsulated in 5', polyadenylated, or encapsulated and polyadenylated. Alternatively, an mRNA molecule may comprise internal ribosomal entry sites (IRES) for translation of an internal open reading frame of mRNA.

[0039] In certain embodiments, a polynucleotide comprises noncoding RNA capable of regulating or inhibiting the expression of a nucleic acid sequence expressed in a cell. Non-limiting examples of noncoding RNA capable of regulating or inhibiting the expression of a nucleic acid sequence expressed in a cell include microRNAs (also known as miRNAs), siRNAs, piRNAs, and lncRNAs. In general, transfection of a cell with a noncoding RNA capable of regulating or inhibiting the expression of a nucleic acid sequence may lead to cleavage of the nucleic acid sequence, may enhance, prevent, or stop the translation of the nucleic acid sequence into a protein, or may regulate the transcription of a nucleic acid sequence.

[0040] In some embodiments, a polynucleotide of the invention comprises a non-coding RNA capable of interrupting the expression of a nucleic acid sequence expressed in a cell. As used in this report, interrupting the expression of a nucleic acid sequence can be used to describe any decrease in the expression level of a nucleic acid sequence, or of a protein translated from the nucleic acid sequence, when compared to an expression level of the nucleic acid sequence in a cell that has not been treated with a peptide-polynucleotide complex of the invention. In some alternative embodiments, a polynucleotide comprises a short interfering RNA. Petition 870260073661, dated 07 / 24 / 2026, page 23 / 207 19 / 93 (siARN).

[0041] In general, an siRNA comprises a double-stranded RNA molecule ranging from about 15 to about 29 nucleotides in length. In some embodiments, the siRNA may be 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 nucleotides in length. In other embodiments, the siRNA may be about 16 to about 18, about 17 to about 19, about 21 to about 23, about 24 to about 27, or about 27 to about 29 nucleotides in length. In some embodiments, the siRNA may be about 21 nucleotides in length. An siRNA may optionally further comprise one or two single-stranded overhangs, for example, a 5' overhang at one or both ends, a 3' overhang at one or both ends, or a combination thereof. The siRNA may be formed from two RNA molecules that hybridize with each other or, alternatively, it may be generated from a short hairpin RNA (shRNA) (see below).In some embodiments, the two strands of siRNA may be completely complementary, such that there are no mismatches or overhangs in the duplex formed between the two sequences. In other embodiments, the two strands of siRNA may be substantially complementary, such that one or more mismatches and / or overhangs may exist in the duplex formed between the two sequences. In certain embodiments, one or both of the 5' ends of the siRNA may have a phosphate group, while in other embodiments, one or both of the 5' ends do not have a phosphate group. In other embodiments, one or both of the 3' ends of the siRNA may have a hydroxyl group, while in other embodiments one or both of the 5' ends do not have a hydroxyl group.

[0042] One strand of siRNA, called the antisense strand or guide strand, includes a portion that hybridizes with a target transcript. A Petition 870260073661, dated 07 / 24 / 2026, page 24 / 20720 / 93 target transcript refers to a nucleic acid sequence expressed by a cell whose expression is to be interrupted. In the context of a therapeutic composition of the invention, interrupting the expression of a target transcript can produce a beneficial effect. In some embodiments, the antisense strand of the siRNA may be completely complementary to a region of the target transcript, i.e., it hybridizes with the target transcript without a single mismatch or overhang over a target region between about 15 and about 29 nucleotides in length, at least 16 nucleotides in length, and about 18 to 20 nucleotides in length. In other embodiments, the antisense strand may be substantially complementary to the target region, i.e., one or more mismatches and / or overhangs may exist in the duplex formed by the antisense strand and the target transcript. Typically, siRNAs are directed to exonic sequences of the target transcript.Those versed in the state of the art are familiar with commercial programs, algorithms, and / or services that design siRNAs for target transcripts. A prime example is the Rosetta siRNA Design Algorithm (Rosetta Inpharmatics, North Seattle, Washington), siRNA MISSION® (Sigma-Aldrich, St. Louis, MO), and siRNA siGENOME (Thermo Scientific). siRNA can be synthesized enzymatically in vitro using methods well-known to those versed in the state of the art. Alternatively, siRNA can be synthesized chemically using oligonucleotide synthesis techniques that are well-known in the state of the art.

[0043] In some embodiments, a polynucleotide of the invention comprises a non-coding RNA capable of interrupting the expression of a nucleic acid sequence encoding KRAS. In some embodiments, the non-coding RNA is siRNA. In some embodiments, the target human KRAS mRNA sequence does not encode G12, G13, or Q61 with reference to the human KRAS protein of type Petition 870260073661, dated 07 / 24 / 2026, p. 25 / 207 21 / 93 wild type or a mutant amino acid at position 12, 13, or 61 with reference to the wild type human KRAS protein. In some embodiments, the amino acid sequence of the wild type human KRAS protein is: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDG ETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHY REQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIE TSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM (ID SEQ NO: 4).

[0044] Exemplary siRNAs compatible with the polypeptide-polynucleotide complex described in this report are shown in Table 1 below. Table 1 selected siARNs Name of sense tape sequence (5'-3') ID SEQ NO. Antisense tape sequence (5'-3') ID SEQ NO. 66 CGGCUCGGCCAGUA CUCCC 5 GGGAGUACUGGCC GAGCCG 101 245 UUGACGAUACAGCU AAUUC 6 GAAUUAGCUGUAUC GUCAA 102 246 UGACGAUACAGCUA AUUCA 7 UGAAUUAGCUGUAU CGUCA 103 247 GACGAUACAGCUAA UUCAG 8 CUGAAUUAGCUGUA UCGUC 104 248 ACGAUACAGCUAAU UCAGA 9 UCUGAAUUAGCUGU AUCGU 105 250 GAUACAGCUAAUUC AGAAU 10 AUUCUGAAUUAGCU GUAUC 106 277 GGACGAAUAUGAUC CAACA 11 UGUUGGAUCAUAUU CGUCC 107 278 GACGAAUAUGAUCC AACAA 12 UUGUUGGAUCAUAU UCGUC 108 279 ACGAAUAUGAUCCA ACAAU 13 AUUGUUGGAUCAUA UUCGU 109 Petition 870260073661, dated 07 / 24 / 2026, page 26 / 207 22 / 93 SEQ ID NO. Sequência de fita antisenseno (5'-3') ID SEQ NO. 280 CGAAUAUGAUCCAA CAAUA 14 UAUUGUUGGAUCAU AUUCG 110 342 GUCUCUUGGAUAUU CUCGA 15 UCGAGAAUAUCCAA GAGAC 111 349 GGAUAUUCUCGACA CAGCA 16 UGCUGUGUCGAGAA UAUCC 112 386 GCAAUGAGGGACCA GUACA 17 UGUACUGGUCCCUC AUUGC 113 387 CAAUGAGGGACCAG UACAU 18 AUGUACUGGUCCCU CAUUG 114 463 AGAUAUUCACCAUU AUAGA 19 UCUAUAUAUGGUGAA UAUCU 115 464 GAUAUUCACCAUUA UAGAG 20 CUCUAUAUAUAGGUGA AUAUC 116 465 AUAUUCACCAUUAU AGAGA 21 UCUCUAUAUAUAUGGUG AAUAU 117 466 UAUUCACCAUUAUA GAGAA 22 UUCUCUAUAUGGU GAAUA 118 517 ACCUAUGGUCCUAG UAGGA 23 UCCUACUAGGACCA UAGGU 119 583 GGACUUAGCAAGAA GUUAU 24 AUAACUUCUUGCUA AGUCC 120 656 UUCUAUAACAUUAGU UCGAG 25 CUCGAACUAAUGUA UAGAA 121 659 UAUACAUUAGUUCG AGAAA 26 UUUCUCGAACUAAU GUAUA 122 663 CAUUAGUUCGAGAA AUUCG 27 CGAAUUUCUCGAAC UAAUG 123 664 AUUAGUUCGAGAAA UUCGA 28 UCGAAUUUCUCGAA CUAAU 124 665 UUAGUUCGAGAAAU UCGAA 29 UUCGAAUUUCUCGA ACUAA 125 Petition 870260073661, dated 07 / 24 / 2026, p. 27 / 207 23 / 93 Sense strand sequence name (5'-3') SEQ ID NO. Antisense strand sequence (5'-3') SEQ ID NO. 667 AGUUCGAGAAUUC GAAAA 30 UUUUCGAAUUUCUC GAACU 126 673 AGAAUUCGAAAAC AUAAA 31 UUUUCGAA UUUCU 127 676 AAUUCGAAAACAUA AAGAA 32 UUCUUUGAAUGUU8UU8 ACUUA 33 WOOD 129 1033 GCAGUACAUCACUA CUUAU 34 WATER ACUGC 130 1102 WATER2 CUGUG1 G 35 WATER GCAUCAUGUCUAU AGUUU 36 AAACUAUAGGACAAU GAUGC 132 1312 AUGUST 37 AUGUST 133 1315 UGCAUCAUUAUAGAUAG GUCAC 38 AAACUAUAGAUGUACUAA134 UAGCUCAU 39 AUAGUAAUUUAUCU AUGUST 135 1482 AGUAUGAAAUGGGG AUUAU 40 AUAAUCCCCAUUUC AUACU 136 1508 ACCAUUUUGGGGGCU AUAUU 41 AUAUAGCCGACAAAAAU67UGCUUGUUGU 135 42 AAGCUAUAACUGGC CCAAA 138 1912 GGUCCUGCUGACAA AUCAA 43 UUGAUUUGUCAGCA GGACC 139 2070 ACAAUCUCUAGGUA UGGCU 44 ACAUCAUACUAGGUAG AUUGU 140 UUGCU45076 SUSPICIOUS 141 Petition 870260073661, dated 07 / 24 / 2026, p. 28 / 207 24 / 93 Sense strand sequence name (5'-3') SEQ ID NO. Antisense strand sequence (5'-3') SEQ ID NO. 2081 CUUAA 46 CAAAC 142 2083 UAACA 47 GCCAA 143 2234 CUUAA 48 WATER 48 2235 WATER 49 WATER WATER CCAUG 145 2272 WATER STORAGE 50 WATER WATER 146 2273 STORAGE WATER 51 WATER 51 WATER 51 AGGACAUCACUUAC UAUCC 52 GGAUAGUAAGUGAU GUCCU 148 2417 GGAUACAUCAUUUU GUCAA 53 UAUCC 149 2457 UUUAACCUAUGUUA CACCA 54 UGGUGUUAAACAUA 54 UGGUGUAAAACAUA UUAACCUAUGUUAC ACCAU 55 AUGGUGUAACAUAG GUUAA 151 2492 UGGGCAAAAUUGUG CAAGA 56 UCUUGCACAAUUUU GCCCA 152 2524 UUUGAAUCCAUUU CUCGU 57 ACGAAUCCAU615 GAUUU 58 AAAUCUUAUGGUUA GGGGA 154 2631 CCCCUAACCAUAAG AUUUA 59 UAAAUCUUAUGGUU AGGGG 155 2632 CCCUAACCAUAAGA UUUAC 60 GUAAUCAUCCAUGAAUGGU UAGCUAUGAUGGU35UAGGAAUGGU 61 AGUAAAUCUUAUGG UUAGG 157 Petition 870260073661, dated 07 / 24 / 2026, p. 29 / 207 25 / 93 Sense strand sequence name (5'-3') SEQ ID NO. Antisense strand sequence (5'-3') SEQ ID NO. 2753 AUCAC 62 GUGAUUAGGUCAAA UCCCU 158 2760 UGACCUAAUCACUA AUUUU 63 AAAAUUAGUGAGUCAU UCCUCA 64 UCCCUUGA064 2813 UGCCAUCCAUCCAUUA GCGAC 65 ​​GUCGCUAAUGGAUU GGGCA 161 2814 GCCCAAUCCAUUAG CGACA 66 UGUCGCUAAUGGAU UGGGC 162 2815 CCCAAUCCAUUAGC GACCG 6827 CUGAU CCAAUCCAUUAGCG ACAGU 68 ACUGUCGCUAAUGG AUUGG 164 2817 CAAUCCAUUAGCGA CAGUA 69 UACUGUCGCUAAUG GAUUG 165 2819 AUCCAUUAGCGACA GUAGG2 70 CCUACUUCGCUAA12 CAUUAGCGACAGUA GGAUU 71 AUUCCUACUGUCGC UAAUG 167 2851 CAUUCAUGACAGUAGACA GAACC 72 CAUACCAUUCACCC UAUCC 73 CAUUCAUGAUCAGUUCUG36 UAUC36 UAAUG4 AUACA 74 UGUAUUACUGUAAC CAGGA 170 3755 ACAAA 75 UUUGUACCCAGAUA AAACU 171 3880 GUAGGGUGUUAAGA CUUAC 76 GUAAGUCUUACU CAGCUGAAC CUUAC69272 77 AAGAGGCCUAAAUA UCCCC 173 Petition 870260073661, dated 07 / 24 / 2026, p. 30 / 207 26 / 93 Sense strand sequence name (5'-3') SEQ ID NO. Antisense strand sequence (5'-3') SEQ ID NO. 4181 CUUAGGCAUUAACA UGUUU 78 AAACAUGUUAAUGC CUAAG 174 4303 CCUAACUUUUAUAG GUUAU 79 AUAACCUAUAAAAAG UUAGG 175 4722 GAAUAGCAUAACU21 AGAUCUUA UUCAUGUU 80 CAUAACUAGAUUAA GAUCU 81 AGAUCUUAAUCUAG UUAUG 177 4781 GGGAUAAUGAUAGG UAAUU 82 AAUUACCUAUCAUU AUCCC 178 4782 GGAUAAUGAUAGGU AAUUU 83 AAUCAUUACCU8A 909 UUAUCCCUA GUGUUUUAUCCGAA AGUUU 84 AAACUUUCGGAAUA AACAC 180 4891 UGUUUUAUCCGAAA GUUUC 85 GAAACUUUCGGAUA AAACA 181 4896 UAUCCGAAAGUUUC CAAUU 86 AAUUCU982GGAAACUA CCGAAAGUUUCCAA UUCCA 87 UGGAAUUGGAAACU UUCGG 183 4967 GCCAAUUUCUUACU AGUAC 88 GUACUAGUAAGAAA UUGGC 184 4968 CCAAUUUCUUACUA GUACU55U15GUACUACUA CCAUCAUUUGGUUG CGCUG 90 CAGCCACCAAAU GAUGG 186 5118 UUCAUUUGGUUGCGC UGACC 91 GGUCAGCGCCAACCA AAUGA 187 5134 ACCUAGGAAUGUUG GUCAU 92 AUGACCAGUGAACAUUCC8 UGACCAUCC UCAUA 93 UAUGACCAACAUUC CUAGG 189 Petition 870260073661, dated 07 / 24 / 2026, p. 31 / 207 27 / 93 Name of sense tape sequence (5'-3') ID SEQ NO. Antisense tape sequence (5'-3') ID SEQ NO. 5136 CUAGGAAUGUUGGU CAUAU 94 AUAUGACCAACAUU CCUAG 190 5137 UAGGAAUGUUGGUC AUAUC 95 GAUAUUGACCAACAU UCCUA 191 5139 GGAAUGUUGGUCAU AUCAA 96 UUGAUAUGACCAAC AUUCC 192 5258 ACUGUACUACUCCU AAUUA 97 UAAUUAGGAGUAGU ACAGU 193 5259 CUGUACUACUCCUA AUUAU 98 AUAAUUAGGAGUAG UACAG 194 5260 UGUACUACUCCUAA UUAUU 99 AAUAAUUAGGAGUA GUACA 195 5261 GUACUACUCCUAAU UAUUG 100 CAAUAAUUAGGAGU AGUAC 196

[0045] In some age groups, the siRNAs described in this report- The thorium compounds are modified. In some embodiments, the modifications are selected from the group consisting of 2'-methoxy (2'-OMe), 2'-fluorine (2'F), 2'-O-methoxyethyl (2-O-MOE), 5'-vinylphosphonate, phosphorothioate (PTO), locked nucleic acid (LNA), locked nucleic acid (UNA), glycol nucleic acid (GNA), and DNA.

[0046] In some embodiments, the sense tape modifications comprise PTO in positions 1 and / or 2. In some embodiments, the sense tape modifications comprise 2'-F in one or more positions of 3, 7-9, 12 and 17. In some embodiments, the sense tape modifications comprise 2'-OMe in one or more positions of 1, 2, 4-6, 10, 11, 13-16, 18 and 19. In some embodiments, the antisense tape modifications comprise PTO in one or more positions of 1, 2, 19 and 20. In some embodiments, the antisense tape modifications comprise 2'-F in positions 2 and / or 14. In some embodiments, the antisense tape modifications comprise 2'-OMe in any position of 1, 3-13 and 15-21. Petition 870260073661, dated 07 / 24 / 2026, p. 32 / 207 28 / 93

[0047] In some embodiments, the last nucleotide of the sense strand is adenine (A). In some embodiments, the first nucleotide of the antisense strand is uracil (U). In some embodiments, the last nucleotide of the sense strand is uracil (U). In some embodiments, the first nucleotide of the antisense strand is adenine (A). In some embodiments, the last nucleotide of the sense strand is cytosine (C). In some embodiments, the first nucleotide of the antisense strand is guanine (G). In some embodiments, the last nucleotide of the sense strand is guanine (G). In some embodiments, the first nucleotide of the antisense strand is cytosine (C).

[0048] The exemplary modified siRNAs compatible with the polypeptide-polynucleotide complex described in this report are shown in Table 2 below. RNA n=2'O-methyl, RNA Nf=2'-fluor, s=phosphorothioate. Table 2 Modification of selected siARNs Name of sense tape sequence (5'-3') ID SEQ NO. Antisense tape sequence (5'-3') ID SEQ NO. 66 csgsGfcucGfGfCfcaGf uacuCfca 197 usGfsgaguacuggccGfa gccgscsc 293 245 ususGfacgAfUfAfcaGfc uaaUfua 198 usAfsauuagcuguauCfg ucaasgsg 294 246 usgsAfcg aUfAfCfagCfu aauUfca 199 usGfsaauuagcuguaUfc gucasasg 295 247 gsasCfgauAfCfAfgcUfa auuCfaa 200 usUfsgaauuagcuguAfu cgucsasa 296 248 ascsGfauaCfAfGfcuAf auucAfga 201 usCfsugaauuagcugUfa ucguscsa 297 250 gsasUfacaGfCfUfaaUf ucagAfaa 202 usUfsucugaauuagcUfg uaucsgsu 298 277 gsgsAfcgaAfUfAfugAfu ccaAfca 203 usGfsuuggaucauauUfc guccsasc 299 278 gsasCfgaaUfAfUfgaUf ccaaCfaa 204 usUfsguuggaucauaUfu cgucscsa 300 Petition 870260073661, dated 07 / 24 / 2026, page 33 / 207 29 / 93 Name of sense tape sequence (5'-3') ID SEQ NO. Antisense tape sequence (5'-3') ID SEQ NO. 279 ascsGfaauAfUfGfauCf caacAfaa 205 usUfsuguuggaucauAfu ucguscsc 301 280 csgsAfauaUfGfAfucCfa acaAfua 206 usAfsuuguuggaucaUfa uucgsusc 302 342 gsusCfucuUfGfGfauAf uucuCfga 207 usCfsgagaauauccaAfg agacsasg 303 349 gsgsAfuauUfCfUfcgAfc acaGfca 208 usGfscugugucgagaAfu auccsasa 304 386 gscsAfaugAfGfGfgaCf caguAfca 209 usGfsuacuggucccuCfa uugcsasc 305 387 csasAfu gaGfGfGfacCf waterCfaa 210 usUfsguacuggucccUfc auugscsa 306 463 asgsAfuau UfCfAfccAfu uauAfga 211 usCfsuauaauggugaAfu aucususc 307 464 gsasUfauuCfAfCfcaUf uauaGfaa 212 usUfscuauaauggugAfa uaucsusu 308 465 asusAfu u cAfCfCfa uUfa uagAfga 213 usCfsucuauaaugguGfa auauscsu 309 466 usasUfucaCfCfAfuuAfu agaGfaa 214 usUfscucuauaauggUfg aauasusc 310 517 ascsCfuauGfGfUfccUf waterGfga 215 usCfscuacuaggaccAfu aggusasc 311 583 gsgsAfcuuAfGfCfaaGf aaguUfaa 216 usUfsaacuucuugcuAfa guccsusg 312 656 ususCfuauAfCfAfuuAfg uucGfaa 217 usUfscgaacuaauguAfuagaasgsg 313 659 usasUfacaUfUfAfguUfc gagAfaa 218 usUfsucucgaacuaaUfg uauasgsa 314 663 csasUfuagUfUfCfgaGf aaauUfca 219 usGfsaauuucucgaaCfu aaugsusa 315 664 asusUfaguUfCfGfagAf aauuCfga 220 usCfsgaauuucucgaAfc uaausgsu 316 Petition 870260073661, dated 07 / 24 / 2026, page 34 / 207 30 / 93 Name of sense tape sequence (5'-3') ID SEQ NO. Antisense tape sequence (5'-3') ID SEQ NO. 665 usu sAfg uu CfGfAfg aAf auucGfaa 221 use asgsAfaauUfCfGfaaAf acauAfaa 223 usUfsuauguuuucgaAfu uucuscsg 319 676 asasUfucgAfAfAfacAfu aaaGfaa 224 usUfscuuuauguuuuCfg aauususc 320 808 usgsUfacaUfUfAfcaCfu aaaUfua 225 usAfsauuuaguguaaUfg uacasasa 321 1033 gscsAfguuGfAfUfuaCf uucuUfaa 226 usUfsaagaaguaaucAfa cugcsasu 322 1102 gsasAfucaUfCfCfcuAfu ucuGfua 227 usAfscagaauagggaUfg auucsasa 323 1239 gscsAfucaUfGfUfccUfa uagUfua 228 usAfsacuauaggacaUfg augcscsu 324 1312 csasCfugcUfAfUfuaGf ucauGfga 229 usCfscaugacuaauaGfc agugsgsa 325 1315 usgsCfuauUfAfGfucAf ugguCfaa 230 usUfsgaccaugacuaAfu agcasgsu 326 1426 ascsAfuuaGfAfUfaaAfu uacUfaa 231 usUfsaguaauuuaucUfa augusgsa 327 1482 asgsUfaugAfAfAfugGf ggauUfaa 232 usUfsaauccccauuuCfa uacusgsg 328 1508 ascsCfauuUfUfGfggGf cuauAfua 233usAfsuauagccccaaAfa uggususg 329 1706 ususUfggg CfCfAfg uUf auagCfua 234 usAfsgcuauaacuggCfc caaasusa 330 1912 gsgsUfccu GfCfUfgaCf aaauCfaa 235AugUgaugAugCfua gaccsasc 331 2070 ascsAfaucUfCfUfagGf uuugGfca 236 usGfsccaaaccuagaGfa uugusasa 332 Petition 870260073661, of 24 / 07 / 2026, p. 35 / 207 31 / 93 Sense tape sequence name (5'-3') ID SEQ NO. antisense ribbon sequence (5'-3') SEQ ID NO. 2076 uscsUfaggUfUfUfggCf uaguUfca 237 usGfsaacuagccaaaCfc uagasgsa 333 2081 gsusUfuggCfUfAfguUf cucuUfaa 238 usUfsaagagaacuagCfc aaacscsu 20834 ususGfgcuAfGfUfucUf cuuaAfca 239 usGfsuuaagagaacuAfg ccaasasc 335 2234 gscsAfuggUfGfAfggUf gaaaGfua 240 u sAfscu uu caccu caCfc augcscsa 335 uu caccu caCfc augcscsa 335 c62fGg Gf aaagUfaa 241 usUfsacuuucaccucAfc caugscsc 337 2272 gsusGfacuUfAfGfguUf cuagAfua 242 usAfsucuagaaccuaAfg ucacscsu 338 2273 usgsAfcu uAf CfGfua ufa 2433 usUfsaucuagaaccuAfa gucascsc 339 2316 asgsGfacaUfCfAfcuUf acuaUfca 244 usGfsauaguaagugaUfg uccuscsa 340 2417 gsgsAfuacAfCfUfuaUfu uguCfaa 245Gfuaccsc 341 2457 ususUfaacCfUfAfugUf uacaCfca 246 usGfsguguaacauagGfu uaaasasa 342 2458 ususAfaccUfAfUfguUfa cacCfaa 247 usUfsgguguaacauaGfg uuaasasa 334 usGfAfgAfgAfgAfgAcauagGfu uGf ugcaAfga 248 usCfsuugcacaauuuUfg cccasasg 344 2524 ususUfgaaUfAfUfccAfu ucuCfga 249usCfsgagaauggauaUfu caaasusa 345 2630 uscsCfccuAfAfCfcaUfa agaUfua 250 usAfsaucuuaugguuAfg gggasasu 346 2631 cscsCfcu aAfCfCfauAfa gauUfua 251 usAfsaaucuuaugguUfa ggggsasa 347 2632 cscsCfuaaCfCfAfuaAfg auuUfaa 252 usUfsaaaucuuauggUfu agggsgsa 348 Petition 870260073661, dated 07 / 24 / 2026, page 36 / 207 32 / 93 Name of sense tape sequence (5'-3') ID SEQ NO. Antisense tape sequence (5'-3') ID SEQ NO. 2633 cscsUfaacCfAfUfaaGfa uuuAfca 253 usGfsuaaaucuuaugGfu uaggsgsg 349 2753 asgsGfgauUfUfGfacCf uaauCfaa 254 usUfsgauuaggucaaAfu cccususu 350 2760 usgsAfccuAfAfUfcaCfu aauUfua 255 usAfsaauuagugauuAfg gucasasa 351 2812 csusGfcccAfAfUfccAfu uagCfga 256 usCfsgcuaauggauuGfg gcagscsa 352 2813 usgsCfccaAfUfCfcaUfu agcGfaa 257 usUfscgcuaauggauUfg ggcasgsc 353 2814 gscsCfcaaUfCfCfauUf agcgAfca 258 usGfsucgcuaauggaUfu gggcsasg 354 2815 cscsCfaauCfCfAfuuAfg cgaCfaa 259 usUfsgucgcuaauggAfu ugggscsa 355 2816 cscsAfaucCfAfUfuaGfc gacAfga 260 usCfsugucgcuaaugGfa uuggsgsc 356 2817 csasAfuccAfUfUfagCfg acaGfua 261 usAfscugucgcuaauGfg auugsgsg 357 2819 asusCfcauUfAfGfcgAfc aguAfga 262 usCfsuacugucgcuaAfu ggaususg 358 2822 csasUfuag CfGfAfcaGf uaggAfua 263 u sAfsuccuacugucgCfu aaugsgsa 359 2851 gsgsUfaugAfAfUfagAfc agaAfca 264 usGfsuucugucuauuCfa uaccsasg 360 2857 asasUfagaCfAfGfaaCf ccuaUfca 265usGfsauaggguucugUfc uauuscsa 361 2943 uscsCfuggUfAfAfcaGfu aauAfca 266 usGfsuauuacuguuaCfc aggasgsu 362 3755 asgsUfuuuAfUfCfugGf guacAfaa 267 usUfsuguacccagauAfa aacusasu 363 3880 gsusAfg gg UfGfUfu aAf gacuUfaa 268 usUfsaagucuuaacaCfc cuacscsu 364 Petition 870260073661, dated 07 / 24 / 2026, page 37 / 207 33 / 93 Sense tape sequence name (5'-3') ID SEQ NO. antisense ribbon sequence (5'-3') SEQ ID NO. 3962 gsgsGfgauAfUfUfuaGf gccuCfua 269 usAfsgaggccuaaauAfu ccccsusc 365 4181 csusUfaggCfAfUfuaAfc augUfua 270 usAfsacauguuaaugCfc uagsusc 4363 cscsUfaacUfUfUfuaUfa gguUfaa 271 usUfsaaccuauaaaaGfu uaggsusu 367 4722 gsasAfuagUfCfAfuaAfc uagAfua 272 usAfsucuaguaugaCfu auucsusu 368 4729 csasAfaacUfUfUfUfUfUfUca 273 usGfsaucuuaaucuaGfu uaugsasc 369 4781 gsgsGfauaAfUfGfauAf gguaAfua 274 usAfsuuaccuaucauUfa ucccsasa 370 4782 gsgsAfuaaUfGfAfuaGf guaaUfuaUfuaUsauAfuaUcaUca auccscsa 371 4890 gsusGfuuuUfAfUfccGf aaagUfua 276 u sAfsacu uucggau aAfa acacsusg 372 4891 usgsUfuuuAfUfCfcgAfa aguUfua 277 usAfsaacuucggauAfa afa 493838csuc usasUfccgAfAfAfg u Ufu ccaAfua 278 usAfsuuggaaacuuuCfg gauasasa 374 4899 cscsGfaaaGfUfUfucCf aauuCfca 279 usGfsgaauuggaaacUfu ucggsasu 375 4967CUfCfu g uAfc uagUfaa 280 usUfsacuaguaagaaAfu uggcsasc 376 4968 cscsAfauuUfCfUfuaCfu aguAfca 281usGfsuacuaguaagaAfa uuggscsa 377 5115 cscsAfucaUfUfUfggUfu gcgCfua 282 usAfsgcgcaaccaaaUfg auggsasa 378 5118 uscsAfu uu GfGfUfu g Cf gcugAfca 283 usGfsucagcgcaaccAfa augasusg 379 5134 ascsCfuagGfAfAfugUf ugguCfaa 284 usUfsgaccaacaucCfu agguscsa 380 Petition 870260073661, of 24 / 07 / 2026, p. 38 / 207 34 / 93 Sense tape sequence name (5'-3') ID SEQ NO. antisense ribbon sequence (5'-3') SEQ ID NO. 5135 cscsUfaggAfUfguUfg gucAfua 285 usAfsugaccaacauCfc uaggsusc 381 5136 csu sAfg g aAfUfGfu uGf gucaUfaa 286 usUfsaugaccaacauUfc cuags 3872515 usasGfgaaUfGfUfugGf ucauAfua 287 usAfsuaugaccacaUfu ccuasgsg 383 5139 gsgsAfaug UfUfGfg u Cf auauCfaa 288 usUfsgauaugaccaaCfa uuccsusa 384 528 ascsUfguaCfUfAfcuCfc uaaUfua 289 usAfsauuaggaguagUfa cagususc 385 5259 csusGfuacUfAfCfucCfu aauUfaa 290 usUfsaauuaggaguaGfu acagsusu 386 5260 usgsUfacc usAfsuaauuaggaguAfg uacasgsu 387 5261 gsusAfcuaCfUfCfcuAfa uuaUfua 292 usAfsauaauuaggagUfa guacsasg 388

[0049] In some embodiments, the sense strand comprises a nucleotide sequence with at least 80% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. In some embodiments, the sense strand comprises a nucleotide sequence with at least 85% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. In some embodiments, the sense strand comprises a nucleotide sequence with at least 90% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. In some embodiments, the sense strand comprises a nucleotide sequence with at least 95% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. In some embodiments, the sense strand comprises a nucleotide sequence with at least 98% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. identity with the sequence of Petition 870260073661, dated 07 / 24 / 2026, page 39 / 207 35 / 93 nucleotides from any of the sense strands listed in Table 1 and Table 2. In some embodiments, the sense strand comprises a nucleotide sequence with at least 99% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2. In some embodiments, the sense strand comprises a nucleotide sequence with 100% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2.

[0050] In some embodiments, the antisense strand comprises a nucleotide sequence with at least 80% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence with at least 85% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence with at least 90% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence with at least 95% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2.In some embodiments, the antisense strand comprises a nucleotide sequence with at least 98% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence with at least 99% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence with 100% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2. Petition 870260073661, dated 07 / 24 / 2026, page 40 / 207 36 / 93 identity with the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2.

[0051] In general, promoters used to direct the in vivo expression of one or more siRNA or shRNA transcription units can be RNA polymerase III (Pol III) promoters. Certain Pol III promoters, such as U6 or H1 promoters, do not require cis-acting regulatory elements within the transcribed region and are therefore present in certain modalities. In other modalities, Pol II promoters can be used to direct the expression of one or more siRNA or shRNA transcription units. In some modalities, tissue-specific, cell-specific, or inducible Pol II promoters can be used.

[0052] A construct that provides a template for siRNA or shRNA synthesis can be produced using standard recombinant DNA methods and inserted into any one of a wide variety of different vectors suitable for expression in eukaryotic cells. Guidelines can be found in Current Protocols in Molecular Biology (Ausubel et al., John Wiley & Sons, New York, 2003) or Molecular Cloning: A Laboratory Manual (Sambrook & Russell, Cold Spring Harbor Press, Cold Spring Harbor, NI, 3rd edition, 2001). Those versed in the state of the art also recognize that vectors may comprise additional regulatory sequences (e.g., termination sequence, translational control sequence, etc.) as well as selectable marker sequences. DNA plasmids are known in the state of the art, including those based on pBR322, PUC, and so forth.Since many expression vectors already contain one or more suitable promoters, it may only be necessary to insert the nucleic acid sequence encoding the RNAi agent of interest at an appropriate location relative to the promoter(s). Viral vectors can also be used. Petition 870260073661, dated 07 / 24 / 2026, page 41 / 207 37 / 93 to provide intracellular expression of RNAi agents. Suitable viral vectors include retroviral vectors, lentiviral vectors, adenoviral vectors, adeno-associated virus vectors, herpes virus vectors, and so forth. In some embodiments, the RNAi expression vector is a lentiviral shARNA-based vector or a lentiviral particle, such as that provided in shARNA MISSION® TRC products (Sigma-Aldrich).

[0053] The nucleic acid sequences of the invention can be obtained using a variety of different techniques known in the art. Nucleotide sequences, as well as homologous sequences, can be isolated using standard techniques, can be synthesized using standard techniques, or can be acquired or obtained from a repository. Once the nucleotide sequence is obtained, it can be amplified for use in a variety of applications using methods known in the art. 7.2.3. Polypeptide-Polynucleotide Complex

[0054] In another aspect of the invention, a polypeptide and a polynucleotide of the invention associate to form a complex. As used in this report, the term associate may refer to the interaction of a peptide and a polynucleotide through non-covalent bonds, or to the covalent bonding of a peptide and a polynucleotide. In some embodiments, a polypeptide and a polynucleotide of the invention associate through non-covalent bonds, such as a hydrogen bond, an ionic bond, a Van der Waals-based bond, a hydrophobic bond, or electrostatic interactions. For example, a peptide of the invention may have an overall net positive charge, which may allow the peptide to associate with a polynucleotide of the invention through electrostatic interactions to form a complex of the invention. Methods for forming a complex Petition 870260073661, dated 07 / 24 / 2026, page 42 / 207 38 / 93 polypeptide-polynucleotide complex of the invention are known in the prior art and further described in this report.

[0055] The peptide-to-polynucleotide ratio at which a peptide of the invention associates with a polynucleotide of the invention may vary and will vary depending on the peptide, the composition of the polynucleotide, or the size of the polynucleotide, and can be determined experimentally. In essence, a suitable molar ratio of a peptide of the invention to a polynucleotide of the invention may be a molar ratio at which the peptide completely complexes the polynucleotide while minimizing an individual's exposure to the peptide.

[0056] In some embodiments, the ratio is the molar ratio. In some embodiments, the molar ratio is from about 2:1 to about 3500:1. In some embodiments, the molar ratio of peptide to polynucleotide is from about 4:1 to about 1000:1. In some embodiments, the molar ratio of peptide to polynucleotide is from about 10:1 to about 500:1. In some embodiments, the molar ratio of peptide to polynucleotide is from about 5:1 to about 200:1. In some embodiments, the molar ratio of peptide to polynucleotide is from about 50:1 to about 200:1. In some embodiments, the molar ratio of peptide to polynucleotide is from about 100:1. In some embodiments, the molar ratio of peptide to polynucleotide is from about 5:1.

[0057] In some embodiments, the ratio is the ratio of positively charged polymeric amine groups to negatively charged nucleic acid phosphate groups. In some embodiments, the peptide-to-polynucleotide charge ratio is about 6:1 to about 18:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 6:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 7:1. In al Petition 870260073661, dated 07 / 24 / 2026, page 43 / 207 In some embodiments, the peptide-to-polynucleotide charge ratio is about 8:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 9:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 10:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 11:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 12:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 13:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 14:1. In some embodiments, the peptide-to-polynucleotide charge ratio is about 15:1. In some embodiments, the peptide-to-polynucleotide charge ratio is approximately 16:1. In some embodiments, the peptide-to-polynucleotide charge ratio is approximately 17:1.In some embodiments, the peptide-to-polynucleotide charge ratio is approximately 18:1.

[0058] Methods for determining the ratio at which the peptide is able to fully complex the polynucleotide are known in the art and may include gel retardation assays, as described in the examples. Methods for determining a molar ratio at which an individual's exposure to the peptide is minimized are known in the art and may include cytotoxicity measurements using increasing doses of the polypeptide.

[0059] A peptide-polynucleotide complex of the invention may have a diameter of about 10 nm to about 500 nm. In some embodiments, the diameter of the peptide-polynucleotide complex is about 10 nm to about 300 nm. In some embodiments, the diameter of the peptide-polynucleotide complex is at least about 10 nm. In some embodiments, the diameter of the peptide-polynucleotide complex is at most about 300 nm. In some Petition 870260073661, dated 07 / 24 / 2026, p. 44 / 207 40 / 93 modalities, the diameter of the peptide-polynucleotide complex is from about 10 nm to about 50 nm, about 10 nm to about 100 nm, about 10 nm to about 150 nm, about 10 nm to about 200 nm, about 10 nm to about 250 nm, about 10 nm to about 300 nm, about 50 nm to about 100 nm, about 50 nm to about 150 nm, about 50 nm to about 200 nm, about 50 nm to about 250 nm, about 50 nm to about 300 nm, about 100 nm to about 150 nm, about 100 nm to about 200 nm, about 100 nm to about 250 nm, about 100 nm to about 300 nm, about 150 nm to about 200 nm, about 150 nm to about 250 nm, about 150 nm to about 300 nm, about 200 nm to about 250 nm, about 200 nm to about 300 nm, or about 250 nm to about 300 nm. In some embodiments, the diameter of the peptide-polynucleotide complex is about 10 nm, about 50 nm, about 100 nm, about 150 nm, about 200 nm, about 250 nm, or about 300 nm.

[0060] A nanoparticle of the invention can be further modified to enhance its stability. For example, a nanoparticle of the invention can be coated with albumin and / or hyaluronic acid to enhance its stability. A nanoparticle of the invention coated with albumin can be about 5 to about 90 nm or more in diameter.

[0061] The size and / or charge of particles can be evaluated using methods known in the state of the art. Non-limiting examples of methods for measuring particle size may include dynamic light scattering, light scattering, multi-angle light scattering, field flux fractionation systems, laser diffraction, electrozone (electrical detection zone), light obscuring—also known as photozone—and single particle optical sensing (SPOS), sieve analysis, medi Petition 870260073661, dated 07 / 24 / 2026, page 45 / 207 41 / 93 aerodynamic measurements, air permeability diameter, sedimentation, nanoparticle tracking analysis, electron microscopy, atomic force microscopy, small-angle X-ray scattering, flow cytometry, particle zeta potential measurement, analytical ultracentrifugation, or combinations thereof. In some methods, particle size is assessed by dynamic light scattering. In some methods, particle charge is assessed by measuring the particle zeta potential. In still other methods, particle size and / or charge are assessed by dynamic light scattering or by measuring the particle zeta potential.

[0062] A nanoparticle of the invention may have a zeta potential of about -15 to about 20 mV, about 0 mV or more. For example, a nanoparticle may have a zeta potential of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19 or about 20 mV or more. In some embodiments, a nanoparticle has a zeta potential of about 1, about 2, about 3, about 4 or about 5 mV. In other embodiments, a nanoparticle has a zeta potential of about 10, 11, 12, 13, or about 14 mV. In still other embodiments, a nanoparticle has a zeta potential of about 11, about 12, about 13, about 14, or about 15 mV. In an exemplary embodiment, a nanoparticle has a zeta potential of about 1, about 2, about 3, about 4, or about 5 mV.In other embodiments, a nanoparticle has a zeta potential of about 10, about 11, 12, about 13, or about 14 mV. In one exemplary embodiment, a nanoparticle has a zeta potential of about 3.72 mV. In another exemplary embodiment, a nanoparticle has a zeta potential of about 12 mV. In yet another exemplary embodiment, a nanoparticle has a potential... Petition 870260073661, dated 07 / 24 / 2026, p. 46 / 207 42 / 93 zeta of about 13.1 mV.

[0063] A peptide-polynucleotide complex is capable of efficiently releasing the polynucleotide into the cytoplasm of a cell. A peptide-polynucleotide complex may also be able to protect the polynucleotide from degradation after administration to an individual. Thus, a peptide-polynucleotide nanoparticle of the invention can remain stable in the presence of serum. A nanoparticle can remain stable in the presence of serum for approximately 10, 20, 30, 40, 50, 60 minutes, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 hours, approximately 1, 2, 3, 4, 5, 6, 7 days or more. A nanoparticle can remain stable in the presence of approximately 5, 10, 15, 25, 50, 100, 150, 200, or approximately 300 μg / ml or more of human serum albumin.The stability of a nanoparticle can be determined by measuring its ability to maintain the activity of a polynucleotide in the peptide-polynucleotide complex of the nanoparticle or by measuring changes in the size of a nanoparticle over time. Methods for measuring the size of a nanoparticle can be as described in this section.

[0064] The methods for preparing a peptide-polynucleotide complex of the invention generally comprise contacting a peptide of the invention with a polynucleotide of the invention to form a peptide-polynucleotide complex. Typically, a peptide and a polynucleotide are brought into contact by incubation under conditions suitable for the formation of a peptide-polynucleotide complex. The conditions suitable for the formation of a peptide-polynucleotide complex may be as described in the examples. Typically, such conditions may comprise a temperature of about 30°C to about 40°C, and incubation times of between about 20 seconds to about 60 minutes or more. Petition 870260073661, dated 07 / 24 / 2026, page 47 / 207 43 / 93 Suitable temperatures may also be lower than about 30°C. For example, incubation may occur on ice. Those skilled in the art will appreciate that the duration and temperature of incubation may and will vary depending on the peptide and polynucleotide, and may be determined experimentally.

[0065] A nanoparticle comprising a peptide-polynucleotide complex of the invention can be further modified to enhance its stability. For example, a peptide-polynucleotide complex of the invention can be crosslinked to enhance the stability of the nanoparticles. One skilled in the art would recognize that a suitable crosslinker can vary, and will vary, depending on the composition of the nanoparticle and the antibody or antibody fragment. In some respects, a peptide-polynucleotide complex of the invention can be chemically crosslinked using chemical crosslinkers such as glutaraldehyde, bis-carboxylic acid spacers, active bis-carboxylic acid esters, using a carbodiimide amine / bis-ligand coupling protocol, or using a click chemistry, carbodiimide coupling chemistry, acylation, active ester coupling, or alkylation protocol.

[0066] Alternatively, a peptide-polynucleotide complex of the invention can be coated with a compound capable of enhancing the stability of the nanoparticles. Methods of modifying a nanoparticle to enhance stability are known in the art and can be described in Nicolas et al., 2013 Acta Biomater. 9: 4754-4762, the description of which is incorporated herein by reference in its entirety.

[0067] As used in this report, the term coating may refer to the interaction of a peptide-polynucleotide complex with a compound via non-covalent bonds, or to the covalent bonding of a peptide complex. Petition 870260073661, dated 07 / 24 / 2026, p. 48 / 207 44 / 93 polynucleotide and a compound. In some embodiments, a peptide-polynucleotide complex of the invention and a coating compound associate via non-covalent bonds, such as a hydrogen bond, an ionic bond, a Van der Waals-based bond, a hydrophobic bond, or electrostatic interactions. For example, a peptide-polynucleotide complex of the invention may have an overall net positive charge, and a coating compound may have an overall negative charge, which may allow the peptide-polynucleotide complex and the compound to associate via electrostatic interactions to form a complex of the invention.

[0068] Non-limiting examples of compounds that can be used to coat a nanoparticle to enhance its stability include albumin, fatty acids such as oleic acid, polyethylene glycol, polysaccharides such as chitosan, heparin or heparans and other glycosaminoglycans, or other coating materials published and known to those skilled in the art. In some embodiments, the stability of a peptide-polynucleotide complex of the invention can be enhanced by coating the nanoparticles with a fatty acid. In other embodiments, the stability of a peptide-polynucleotide complex of the invention can be enhanced by coating the nanoparticles with a polysaccharide.

[0069] In some embodiments, the stability of a nanoparticle comprising a peptide-polynucleotide complex of the invention can be enhanced by coating the nanoparticles with albumin. Albumins are globular proteins with a negative charge commonly found in blood serum. While not to be limited to theory, it is believed that coating the nanoparticles of the invention with albumin can enhance the stability of the nanoparticles. Petition 870260073661, dated 07 / 24 / 2026, page 49 / 207 45 / 93 In the nanoparticles, avoiding flocculation, albumins that can be used to coat a nanoparticle comprising a peptide-polynucleotide complex of the invention are serum albumins, and may include bovine serum albumin and human serum albumin. In exemplary embodiments, the stability of a nanoparticle comprising a peptide-polynucleotide complex of the invention can be enhanced by coating the nanoparticles with human serum albumin.

[0070] In essence, a nanoparticle is coated with albumin by incubating the nanoparticle with a solution comprising albumin. The nanoparticles can be incubated in a solution comprising approximately 0.1; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9; 1.0; 1.2; 1.4; 1.6; 1.8; 2.0; 2.2; 2.4; 2.6; 2.8; 3.0; 3.2; 3.4; 3.6; 3.8; 4.0; 4.2; 4.4; 4.6; 4.8; 5.0 mg / ml or more of albumin. In some embodiments, the nanoparticles comprising a peptide-polynucleotide complex of the invention can be incubated in a solution comprising approximately 0.1, 0.3, 0.5, 0.7, or 0.9 mg / ml of albumin. In other embodiments, the nanoparticles comprising a peptide-polynucleotide complex of the invention can be incubated in a solution comprising approximately 1.0, 1.2, 1.4, 1.6, or 1.8 mg / ml of albumin.In still other embodiments, the nanoparticles comprising a peptide-polynucleotide complex of the invention can be incubated in a solution comprising approximately 2.0, 2.2, 2.4, 2.6, or 2.8 mg / ml of albumin. In other embodiments, the nanoparticles comprising a peptide-polynucleotide complex of the invention can be incubated in a solution comprising approximately 3.0, 3.2, 3.4, 3.6, or 3.8 mg / ml of albumin. In further embodiments, nanoparticles comprising a peptide-polynucleotide complex of the invention can be incubated in a solution comprising approximately 4.0, 4.2, 4.4, 4.6, or 4.8 mg / ml of albumin. Petition 870260073661, dated 07 / 24 / 2026, page 50 / 207 46 / 93 or 5.0 mg / ml of albumin. In some embodiments, the nanoparticles comprising a peptide-polynucleotide complex of the invention can be incubated in a solution comprising about 4.0 mg / ml of albumin.

[0071] A peptide-polynucleotide complex can be incubated with albumin for about 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or about 60 minutes or more to coat the peptide-polynucleotide complex. In some embodiments, a particle comprising a peptide-polynucleotide complex of the invention is incubated with albumin for about 5, 10, 15 or about 20 minutes. In other embodiments, a particle comprising a peptide-polynucleotide complex of the invention is incubated with albumin for about 20, 25, 30 or about 35 minutes. In still other embodiments, a particle comprising a peptide-polynucleotide complex of the invention is incubated with albumin for about 35, 40, 45 or about 50 minutes. In other embodiments, a particle comprising a peptide-polynucleotide complex of the invention is incubated with albumin for about 50, 55 or about 60 minutes or more.In some embodiments, a particle comprising a peptide-polynucleotide complex of the invention is incubated with albumin for about 25, 30 or about 35 minutes.

[0072] A peptide-polynucleotide complex can be incubated with hyaluronic acid for approximately 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or about 60 minutes or more to allow the hyaluronic acid to coat the peptide-polynucleotide complex or integrate into the peptide-polynucleotide complex. A peptide-polynucleotide complex can be incubated with hyaluronic acid for approximately 1, 2, 3, 4, 5, 10, 12, 18 or 24 hours or more to allow the hyaluronic acid to coat the peptide-polynucleotide complex or integrate into the peptide-polynucleotide complex. In some fashion Petition 870260073661, dated 07 / 24 / 2026, page 51 / 207 47 / 93 In some modalities, a peptide-polynucleotide complex can be incubated with hyaluronic acid for approximately 45 minutes. Shorter times may be used in some modalities, for example, when using flow processes or microfluidic devices. 7.2.4. Cell

[0073] In another aspect of the invention, a peptide-polynucleotide complex of the invention is capable of transfecting the polynucleotide into the cytoplasm of a cell. In some embodiments, a cell is a prokaryotic cell. In some embodiments, a cell is a eukaryotic cell. A cell can be in vitro, in vivo, in situ, or ex vivo. A cell can be a single cell or it can comprise a tissue or an organ. The term cell also refers to a cell in an individual.

[0074] A peptide-polynucleotide complex of the invention can be administered to a cell in vitro by incubating a cell in the presence of a peptide-polynucleotide complex of the invention under conditions suitable for the transfection of a polynucleotide from a peptide-polynucleotide complex. The conditions suitable for the transfection of a polynucleotide into a peptide-polynucleotide complex may be as described in the examples. One skilled in the art will appreciate that the duration of incubation may vary, and will vary, depending on the peptide-polynucleotide complex and the cells. Typically, such conditions may comprise incubation times between about 10 (ten) minutes and 24 hours; the transfection conditions may comprise incubation times between about 15 minutes and 3 hours.

[0075] A peptide-polynucleotide complex of the invention can be administered to a cell in vivo (i.e., in an individual) by administering to an individual a composition comprising a peptide-polynucleotide complex of the invention. Petition 870260073661, dated 07 / 24 / 2026, page 52 / 207 48 / 93 7.3. Pharmaceutical Composition

[0076] In another aspect of the invention, a peptide-polynucleotide complex of the invention can be incorporated into pharmaceutical compositions suitable for administration. A pharmaceutical composition of the invention can be used to interrupt the expression of one or more nucleic acid sequences normally expressed in a cell. For example, a pharmaceutical composition of the invention can be used to interrupt the expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleic acid sequences normally expressed in a cell. One skilled in the art will judge that the pharmaceutical compositions can be administered to treat a disease, prevent a disease, or promote good health.As such, a pharmaceutical composition of the invention can be used to interrupt the expression of any nucleic acid sequence normally expressed in a cell, such that the interrupted expression leads to measurable and beneficial effects for the individual to whom the composition was administered (i.e., significant efficacy).

[0077] In some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence normally expressed in a cell. In some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence encoding KRAS. In some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence encoding STAT3. In some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence encoding JNK2. In still some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence encoding the p65 subunit of the canonical signaling pathway. Petition 870260073661, dated 07 / 24 / 2026, page 53 / 207 49 / 93 of NFkB. In some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence encoding the p100 / p52 subunit of the canonical NFkB signaling pathway.

[0078] In other embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of two nucleic acid sequences normally expressed in a cell. In some embodiments, a pharmaceutical composition of the invention is used to interrupt the expression of a nucleic acid sequence encoding the p65 subunit of the canonical NFkB signaling pathway and a nucleic acid sequence encoding the p100 / p52 subunit of the canonical NFkB signaling pathway.

[0079] When a pharmaceutical composition of the invention is used to interrupt the expression of more than one nucleic acid sequence normally expressed in a cell, a pharmaceutical composition may be formulated using a mixture of more than one peptide-polynucleotide complex, wherein each complex comprises a polynucleotide capable of interrupting the expression of a different nucleic acid sequence normally expressed in a cell. Alternatively, more than one polynucleotide may be used to generate a mixture of peptide-polynucleotide complexes, wherein each polynucleotide is capable of interrupting the expression of a different nucleic acid sequence normally expressed in a cell.

[0080] A pharmaceutical composition of the invention may also comprise one or more pharmaceutically acceptable and non-toxic carriers, adjuvants, excipients, and vehicles, as desired. As used in this report, the term pharmaceutically acceptable vehicle is intended to include any and all solvents, dispersing media, coatings, antibacterial and antifungal agents. Petition 870260073661, dated 07 / 24 / 2026, page 54 / 207 50 / 93 gicos, isotonic agents and absorption retardants and the like, compatible with pharmaceutical administration. The use of such means and agents for pharmaceutically active substances is well known in the state of the art. Except to the extent that any conventional means or agent is incompatible with the nanoparticles of the invention, their use in the compositions is contemplated. Supplementary active compounds may also be incorporated into the compositions.

[0081] A pharmaceutical composition of the invention can be formulated to be compatible with the intended route of administration. Suitable routes of administration include parenteral, oral, pulmonary, transdermal, transmucosal, and rectal administration. The term parenteral, as used in this report, includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection or infusion techniques.

[0082] Solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, polysorbates, poloxamers, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and tonicity adjusters, such as sodium chloride, glucose, or dextrose. The pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation may be packaged in ampoules, disposable syringes, or multi-dose vials, made of glass or plastic.

[0083] Oral compositions may generally include an inert diluent or an edible vehicle. Oral compositions may be enclosed in gelatin capsules or compacted into tablets. Petition 870260073661, dated 07 / 24 / 2026, p. 55 / 207 51 / 93 For purposes of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, scotch tablets, or capsules. Oral compositions may also be prepared using a fluid vehicle for use as a mouthwash, wherein the compound in the fluid vehicle is applied orally for rinsing and expectorated or swallowed. Pharmaceutically compatible binding agents and / or excipients may be included as part of the composition.Tablets, pills, capsules, tablets and similar products may contain any of the following ingredients or compounds of a similar nature: a binder, such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient, such as starch or lactose; a disintegrating agent, such as alginic acid, Primogel or corn starch; a lubricant, such as magnesium stearate or Sterotes; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate or orange flavoring. For administration by inhalation, the compounds are administered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, for example, a gas such as carbon dioxide, or a nebulizer.

[0084] In some embodiments, a pharmaceutical composition of the invention is formulated to be compatible with parenteral administration. For example, pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions (when water-soluble) or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable vehicles include physiological saline, balanced saline solution, bacteriostatic water, Cremophor EL (BASF; Parsippany, NJ) or phosphate-buffered saline solution. Petition 870260073661, dated 07 / 24 / 2026, page 56 / 207 52 / 93 (PBS). In exemplary embodiments, a pharmaceutical composition of the invention is formulated with phosphate-buffered saline (PBS) solution.

[0085] In all cases, a composition can be sterile and fluid insofar as it is easily handled with a syringe. A composition can be stable under manufacturing and storage conditions and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the necessary particle size in the case of dispersion, and by the use of surfactants. Prevention of microbial action can be achieved by means of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.In many cases, it may include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol or sodium chloride, in the composition. Prolonged absorption of injectable compositions can be achieved by including an absorption-delaying agent in the composition, for example, aluminum monostearate and gelatin.

[0086] Sterile injectable solutions can be prepared by incorporating the active compound in the required quantity into an appropriate solvent with one, or a combination of, the ingredients listed above, as needed, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of solutions Petition 870260073661, dated 07 / 24 / 2026, page 57 / 207 53 / 93 sterile injectables, the preparation methods are vacuum drying and lyophilization, which produce a powder of the active ingredient plus any desired additional ingredient from a previously filtered sterile solution thereof.

[0087] Systemic administration can also be via transmucosal or transdermal routes. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the state of the art and may include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be performed using nasal sprays or suppositories. For transdermal administration, the active compounds are formulated in ointments, balms, gels, or creams, as generally known in the state of the art. The compounds may also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal administration.

[0088] In one embodiment, the active compounds are prepared with vehicles that will protect the compound against rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, chitosans, and polylactic acid. The methods for preparing such formulations will be evident to those skilled in the art. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0089] Additional formulations of pharmaceutical compositions po Petition 870260073661, dated 07 / 24 / 2026, page 58 / 207 54 / 93 can be found, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NI (1980). Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pa., 16th edition ISBN: 0912734-04-3, the most recent edition, incorporated in this report by reference in its entirety, provides a compendium of formulation techniques as they are generally known to practitioners.

[0090] Those skilled in the art will recognize that the concentration of a peptide-polynucleotide complex of the invention in a pharmaceutical composition can and will vary depending, in part, on the route of administration, the individual, and the reason for administration, and can be determined experimentally. Methods of experimentally determining the concentration of an active agent, such as the nanoparticles of the invention, in a pharmaceutical composition are known in the art. In general, a pharmaceutical composition can be formulated to comprise from about 0.1 nM to about 50 μM of a polynucleotide in a peptide-polynucleotide complex of the invention.For example, a pharmaceutical composition can be formulated to comprise about 0.1 nm, 0.2 nm, 0.3 nm, 0.4 nm, 0.5 nm, 0.6 nm, 0.7 nm, 0.8 nm, 0.9 nm, 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, 20 nm, 21 nm, 22 nm, 23 nm, 24 nm, 25 nm, 26 nm, 27 nm, 28 nm,29 nm, 30 nm, 31 nm, 32 nm, 33 nm, 34 nm, 35 nm, 36 nm, 37 nm,38 nm, 39 nm, 40 nm, 41 nm, 42 nm, 43 nm, 44 nm, 45 nm, 46 nm,47 nm, 48 nm, 49 nm, 50 nm, 51 nm, 52 nm, 53 nm, 54 nm, 55 nm,56 nm, 57 nm, 58 nm, 59 nm, 60 nm, 61 nm, 62 nm, 63 nm, 64 nm,65 nm, 66 nm, 67 nm, 68 nm, 69 nm, 70 nm, 71 nm, 72 nm, 73 nm,74 nm, 75 nm, 76 nm, 77 nm, 78 nm, 79 nm, 80 nm, 81 nm, 82 nm,83. Petition 870260073661, of 24 / 07 / 2026, page. 59 / 207 55 / 93 nm, 84 nm, 85 nm, 86 nm, 87 nm, 88 nm, 89 nm, 90 nm, 91 nm, 92 nm nm, 94 nm, 95 nm, 96 nm, 97 nm, 98 nm, 99 nm nm, 102 nm nm, 110 nm nm, 118 nm nm 126 nm nm 134 nm nm 142 nm nm 150 nm nm 158 nm nm 166 nm nm 174 nm nm 182 nm nm 190 nm nm 198 nm nm 206 nm nm 214 nm nm 222 nm nm 230 nm nm 238 nm nm 247 nm nm 256 nm nm 265 nm nm 274 nm nm 283 nm nm 292 nm nm 300 nm nm 308 nm nm 316 nm nm 324 nm 103 nm 111 nm 119 nm 127 nm 135 nm 143 nm 151 nm 159 nm 167 nm 175 nm 183 nm 191 nm 199 nm 207 nm 215 nm 223 nm 231 nm 239 nm 248 nm 257 nm 266 nm 275 nm 284 nm 293 nm 301 nm 309 nm 317 nm 325 nm 104 nm 112 nm 120 nm 128 nm 136 nm 144 nm 152 nm 160 nm 168 nm 176 nm 184 nm 192 nm 200 nm 208 nm 216 nm 224 nm 232 nm 241 nm 249 nm 258 nm 267 nm 276 nm 285 nm 294 nm 302 nm 310 nm 318 nm 326 nm 105 nm 113 nm 121 nm 129 nm 137 nm 145 nm 153 nm 161 nm 169 nm 177 nm 185 nm 193 nm 201 nm 209 nm 217 nm 225 nm 233 nm 242 nm 251 nm 259 nm 268 nm 277 nm 286 nm 295 nm 303 nm 311 nm 319 nm 327 nm 106 nm 114 nm 122 nm 130 nm 138 nm 146 nm 154 nm 162 nm 170 nm 178 nm 186 nm 194 nm 202 nm 210 nm 218 nm 226 nm 234 nm 243 nm 252 nm 261 nm 269 ​​nm 278 nm 287 nm 296 nm 304 nm 312 nm 320 nm 328 nm 107 nm 115 nm 123 nm 131 nm 139 nm 147 nm 155 nm 163 nm 171 nm 179 nm 187 nm 195 nm 203 nm 211 nm 219 nm 227 nm 235 nm 244 nm 253 nm 262 nm 271 nm 279 nm 288 nm 297 nm 305 nm 313 nm 321 nm 329 nm 100 nm, 101 108 nm, 109 116 nm, 117 124 nm, 125 132 140 148 156 164 172 180 188 196 204 212 220 228 236 245 254 263 272 281 289 298 306 314 322 330 nm 133 141 149 157 165 173 181 189 197 205 213 221 229 237 246 255 264 273 282 291 299 307 315 323 331 Petition 870260073661, of 24 / 07 / 2026, page. 60 / 207 56 / 93 nm 332 nm 333 nm 334 nm 335 nm 336 nm 337 nm 338 nm 339 nm 340 348 356 364 372 380 388 396 404 412 420 428 436 444 452 460 468 476 484 492 500 508 516 524 532 540 548 556 564 nm 341 349 357 365 373 381 389 397 405 413 421 429 437 445 453 461 469 477 485 493 501 509 517 525 533 541 549 557 565 nm 342 350 358 366 374 382 390 398 406 414 422 430 438 446 454 462 470 478 486 494 502 510 518 526 534 542 550 558 566 nm 343 351 359 367 375 383 391 399 407 415 423 431 439 447 455 463 471 479 487 495 503 511 519 527 535 543 551 559 567 nm 344 352 360 368 376 384 392 400 408 416 424 432 440 448 456 464 472 480 488 496 504 512 520 528 536 544 552 560 568 nm 345 353 361 369 377 385 393 401 409 417 425 433 441 449 457 465 473 481 489 497 505 513 521 529 537 545 553 561 569 nm 346 354 362 370 378 386 394 402 410 418 426 434 442 450 458 466 474 482 490 498 506 514 522 530 538 546 554 562 570 nm 347 355 363 371 379 387 395 403 411 419 427 435 443 451 459 467 475 483 491 499 507 515 523 531 539 547 555 563 571 Petition 870260073661, of 24 / 07 / 2026, page. 61 / 207 57 / 93 nm 572 nm 580 nm 588 nm 596 nm 604 nm 612 nm 620 nm 628 nm 636 nm 644 nm 652 nm 660 nm 668 nm 676 nm 684 nm 692 nm 700 nm 708 nm 716 nm 724 nm 732 nm 740 nm 748 nm 756 nm 764 nm 772 nm 780 nm 788 nm 796 nm 804 nm 573 nm 581 nm 589 nm 597 nm 605 nm 613 nm 621 nm 629 nm 637 nm 645 nm 653 nm 661 nm 669 nm 677 nm 685 nm 693 nm 701 nm 709 nm 717 nm 725 nm 733 nm 741 nm 749 nm 757 nm 765 nm 773 nm 781 nm 789 nm 797 nm 805 nm 574 nm 582 nm 590 nm 598 nm 606 nm 614 nm 622 nm 630 nm 638 nm 646 nm 654 nm 662 nm 670 nm 678 nm 686 nm 694 nm 702 nm 710 nm 718 nm 726 nm 734 nm 742 nm 750 nm 758 nm 766 nm 774 nm 782 nm 790 nm 798 nm 806 nm 575 nm 583 nm 591 nm 599 nm 607 nm 615 nm 623 nm 631 nm 639 nm 647 nm 655 nm 663 nm 671 nm 679 nm 687 nm 695 nm 703 nm 711 nm 719 nm 727 nm 735 nm 743 nm 751 nm 759 nm 767 nm 775 nm 783 nm 791 nm 799 nm 807 nm 576 nm 584 nm 592 nm 600 nm 608 nm 616 nm 624 nm 632 nm 640 nm 648 nm 656 nm 664 nm 672 nm 680 nm 688 nm 696 nm 704 nm 712 nm 720 nm 728 nm 736 nm 744 nm 752 nm 760 nm 768 nm 776 nm 784 nm 792 nm 800 nm 808 nm 577 nm, 578 nm, 579 585 nm, 586 nm, 587 593 nm, 594 nm, 595 601 609 617 625 633 641 649 657 665 673 681 689 697 705 713 721 729 737 745 753 761 769 777 785 793 801 809 nm 602 610 618 626 634 642 650 658 666 674 682 690 698 706 714 722 730 738 746 754 762 770 778 786 794 802 810 nm 603 611 619 627 635 643 651 659 667 675 683 691 699 707 715 723 731 739 747 755 763 771 779 787 795 803 811 Petition 870260073661, of 24 / 07 / 2026, page. 62 / 207 58 / 93 nm 812 nm nm 820 nm nm 828 nm nm 836 nm nm 844 nm nm 852 nm nm 860 nm nm 868 nm nm 876 nm nm 884 nm nm 892 nm nm 900 nm nm 908 nm nm 916 nm nm 924 nm nm 932 nm nm 940 nm nm 948 nm nm 956 nm nm 964 nm nm 972 nm nm 980 nm nm nm 988 nm 813 nm 821 nm 829 nm 837 nm 845 nm 853 nm 861 nm 869 nm 877 nm 885 nm 893 nm 901 nm 909 nm 917 nm 925 nm 933 nm 941 nm 949 nm 957 nm 965 nm 973 nm 981 nm 989 nm 814 nm 822 nm 830 nm 838 nm 846 nm 854 nm 862 nm 870 nm 878 nm 886 nm 894 nm 902 nm 910 nm 918 nm 926 nm 934 nm 942 nm 950 nm 958 nm 966 nm 974 nm 982 nm 990 nm 815 nm 823 nm 831 nm 839 nm 847 nm 855 nm 863 nm 871 nm 879 nm 887 nm 895 nm 903 nm 911 nm 919 nm 927 nm 935 nm 943 nm 951 nm 959 nm 967 nm 975 nm 983 nm 991 nm 816 nm 824 nm 832 nm 840 nm 848 nm 856 nm 864 nm 872 nm 880 nm 888 nm 896 nm 904 nm 912 nm 920 nm 928 nm 936 nm 944 nm 952 nm 960 nm 968 nm 976 nm 984 nm 992 nm 817 nm 825 nm 833 nm 841 nm 849 nm 857 nm 865 nm 873 nm 881 nm 889 nm 897 nm 905 nm 913 nm 921 nm 929 nm 937 nm 945 nm 953 nm 961 nm 969 nm 977 nm 985 nm 993 nm 818 nm, 819 826 nm, 827 834 nm, 835 842 nm, 843 850 nm, 851 858 nm, 859 866 nm, 867 874 nm, 875 882 nm, 883 890 nm, 891 898 nm, 899 906 nm, 907 914 nm, 915 922 nm, 923 930 nm, 931 938 nm, 939 946 nm, 947 954 nm, 955 962 nm, 963 970 nm, 971 978 nm, 979 986 nm, 987 994 nm, 995 996 nm, 997 nm, 998 nm, 999 nm, 1 µm, 2 µm, 3 µm, 4 µm, 5 µm, µm, 7 µm, 8 µm, 9 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, 20 µm, 21 µm, 22 µm, 23 µm, 24 µm, 25 µm, 26 µm, 27 µm, 28 µm, 29 µm, 30 µm, 31 µm, 32 µm, 33 µm, 34 µm, 35 µm, 36 µm, 37 µm, 38 µm, 39 µm, 40 µm, 41 µm, 42 µm, 43 µm, 44 µm, 45 µm, 46 µm, 47 µm, 48 µm, 49 µm ou cerca de 50 µm de um polinucleotídeo em um complexo de peptídeo-polynucleotídeo da Petition 870260073661, de 24 / 07 / 2026, pág. 63 / 207 59 / 93 invention. In some embodiments, a pharmaceutical composition may be formulated to comprise from about 0.1 nM to about 1.0 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise from about 1 nM to about 10 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise from about 1 nM to about 100 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise from about 1 nM to about 200 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise from about 1 nM to about 50 nM of a polynucleotide in a peptide-polynucleotide complex of the invention.In other embodiments, a pharmaceutical composition may be formulated to comprise about 10 nM to about 100 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 10 nM to about 200 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 50 nM to about 100 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 50 nM to about 200 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 100 nM to about 200 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. Petition 870260073661, dated 07 / 24 / 2026, p. 64 / 207 60 / 93 deo-polynucleotide of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 150 nM to about 200 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 200 nM to about 100 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 500 nM to about 1000 nM of a polynucleotide in a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition may be formulated to comprise about 1 μM to about 50 μM of a polynucleotide in a peptide-polynucleotide complex of the invention.The peptide concentration in a peptide-polynucleotide complex of the invention can be calculated based on the desired polynucleotide concentration and the peptide-to-polynucleotide ratio in the peptide-polynucleotide complex of the invention.

[0091] A pharmaceutical composition may also be formulated to comprise about 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650 or about 700 pg / ml or more of a peptide-polynucleotide complex of the invention. In some embodiments, a pharmaceutical composition is formulated to comprise 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 pg / ml of a peptide-polynucleotide complex of the invention. In other embodiments, a pharmaceutical composition is formulated to comprise 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or about 300 pg / ml of a peptide-polynucleotide complex of the invention. In still other embodiments, a pharmaceutical composition is formulated to comprise 300, 310, 320, 330, 340, 350, 360, 370, 380, Petition 870260073661, dated 07 / 24 / 2026, page 65 / 207 61 / 93 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or about 500 μg / ml of a peptide-polynucleotide complex of the invention. In still other embodiments, a pharmaceutical composition is formulated to comprise 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690 or about 700 μg / ml or more of a peptide-polynucleotide complex of the invention. 7.4. Method of Use

[0092] In another aspect, the invention encompasses a method for using a peptide-polynucleotide complex of the invention to transfect the polynucleotide into the cytoplasm of a cell. In some embodiments, the cell is in vitro. In other embodiments, the cell is in vivo. Thus, the present invention also provides a method for using a peptide-polynucleotide complex of the invention to transfect the polynucleotide into the cytoplasm of a cell in an individual in need thereof. Generally, a method of the invention comprises contacting a cell with a peptide-polynucleotide complex of the invention under conditions suitable for the transfection of a polynucleotide. Suitable cells and conditions are described above. In embodiments where the cell is in vivo, a method of the invention typically comprises administering a pharmaceutical composition comprising a peptide-polynucleotide complex of the invention to an individual in need thereof.Suitable pharmaceutical compositions are described in this report.

[0093] In another aspect, the invention encompasses a method for treating a condition in an individual. The method comprises administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a peptide-polynucleotide complex. A complex of Petition 870260073661, dated 07 / 24 / 2026, page 66 / 207 The 62 / 93 peptide-polynucleotide complex of the invention is capable of efficiently transfecting, or transferring, the polynucleotide from the peptide-polynucleotide complex into a cell of the individual.

[0094] In some embodiments, a polynucleotide of the invention comprises non-coding RNA capable of regulating or inhibiting the expression of a nucleic acid sequence expressed in a cell. By efficiently transfecting a polynucleotide capable of regulating or inhibiting the expression of a nucleic acid sequence expressed in a cell, a method of the invention can be used to treat any condition that can be treated by regulating or inhibiting the expression of a nucleic acid sequence normally expressed in a cell. In some embodiments, the invention encompasses a method of administering a peptide-polynucleotide complex of the invention to an individual to treat an NFkB-mediated condition in the individual. In some embodiments, the invention encompasses a method of administering a peptide-polynucleotide complex of the invention to an individual to treat a condition associated with KRAS overexpression or aberrant expression in the individual.In some embodiments, the invention encompasses a method of administering to an individual a peptide-polynucleotide complex of the invention to treat a condition associated with STAT3 dysregulation in the individual. In some embodiments, the invention encompasses a method of administering to an individual a peptide-polynucleotide complex of the invention to treat a condition associated with JNK2 dysregulation in the individual.

[0095] The peptide, polynucleotide, and peptide-polynucleotide complex may be as described in this report. Pharmaceutical compositions comprising a peptide-polynucleotide complex of the invention may be as described in this report. Methods of administering a peptide complex Petition 870260073661, dated 07 / 24 / 2026, page 67 / 207 63 / 93 polynucleotide of the invention and methods of treating a condition are described below. 7.4.1. Administration to an individual in need of this

[0096] In one aspect, the present invention encompasses administering a therapeutically effective amount of a pharmaceutical composition to an individual in need thereof. As used in this report, the expression "an individual in need thereof" refers to an individual who requires preventive or therapeutic treatment. An individual may be a rodent, a human, a farm animal, a companion animal, or a zoo animal. In one embodiment, an individual may be a rodent, for example, a mouse, a rat, a guinea pig, etc. In another embodiment, an individual may be a farm animal. Non-limiting examples of suitable farm animals may include pigs, cows, horses, goats, sheep, llamas, and alpacas. In yet another embodiment, an individual may be a companion animal. Non-limiting examples of companion animals may include pets such as dogs, cats, rabbits, and birds.In yet another modality, an individual may be a zoological animal. As used in this report, a zoological animal refers to an animal that can be found in a zoo. Such animals may include non-human primates, big cats, wolves, and bears. In some modalities, the individual is a mouse. In some modalities, the individual is a human.

[0097] As described in this report, a pharmaceutical composition of the invention is formulated to be compatible with the intended route of administration. Suitable routes of administration include parenteral, oral, pulmonary, transdermal, transmucosal, and rectal administration. In some embodiments, a pharmaceutical composition of the invention is administered by injection. Petition 870260073661, dated 07 / 24 / 2026, page 68 / 207 64 / 93

[0098] Those skilled in the art will recognize that the amount and concentration of the composition administered to an individual will depend, in part, on the individual and the reason for administration. Methods for determining ideal amounts are known in the art. In general, the concentration of a peptide-polynucleotide complex of the invention in a pharmaceutical composition may be as described in this report.

[0099] The compositions of the invention are typically administered to an individual in need thereof in an amount sufficient to provide a benefit to the individual. This amount is defined as a therapeutically effective amount. A therapeutically effective amount can be determined by the efficacy or potency of the specific composition, the disorder to be treated, the duration or frequency of administration, the method of administration, and the size and condition of the individual, including the individual's specific response to treatment. A therapeutically effective amount can be determined using methods known in the art and can be determined experimentally, derived from therapeutically effective amounts determined in animal models, such as mice, or a combination thereof. Additionally, the route of administration can be considered when determining the therapeutically effective amount.In determining therapeutically effective amounts, one skilled in the art may also consider the existence, nature, and extent of any adverse effects that accompany the administration of a specific compound to a particular individual.

[00100] When a pharmaceutical composition of the invention is administered to an individual by injection, the composition may be administered to an individual as a bolus, in an amount of about 0.1 mg / kg to about 100 mg / kg or more. In some ways Petition 870260073661, dated 07 / 24 / 2026, page 69 / 207 In embodiments, a pharmaceutical composition of the invention is administered to an individual in an amount of about 0.1 mg / kg to about 5 mg / kg. In other embodiments, a pharmaceutical composition of the invention is administered to an individual in an amount of about 5 mg / kg to about 15 mg / kg. In still other embodiments, a pharmaceutical composition of the invention is administered to an individual in an amount of about 15 mg / kg to about 30 mg / kg. In other embodiments, a pharmaceutical composition of the invention is administered to an individual in an amount of about 30 mg / kg to about 45 mg / kg. In further embodiments, a pharmaceutical composition of the invention is administered to an individual in an amount of about 45 mg / kg to about 100 mg / kg or more. In some embodiments, a composition is administered to the individual as a bolus in an amount of about 0.5 to about 1.5 mg / kg.

[00101] A composition may also be administered by injecting more than one bolus into the individual over a period of time. For example, a composition may be administered by injecting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more boluses into the individual. In some embodiments, a composition is administered by injecting 1, 2, 3, 4 or 5 boluses into the individual. In other embodiments, a composition is administered by injecting 5, 6, 7, 8, 9, 10 or more boluses into the individual. In some embodiments, a composition is administered by injecting 2, 3 or 4 boluses into the individual. Bolus injections can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or approximately every 12 hours, or they can be administered every 1, 2, 3, 4, 5, 6 or approximately every 7 days. In some modalities, boluses can be administered approximately daily. 7.4.2. Cancer Treatment

[00102] In some forms, a method of invention is used. Petition 870260073661, dated 07 / 24 / 2026, pp. 70 / 207 66 / 93 tion to treat a neoplasm or cancer. The neoplasm can be malignant or benign, the cancer can be primary or metastatic; the neoplasm or cancer can be in an early or advanced stage. The cancer can be a blood cancer or a solid tumor cancer. A cancer or neoplasm can be treated by transferring a nucleic acid sequence to a cancerous tumor in an individual. The cancer or neoplasm can be treated by reducing the growth of cancerous cells, by eliminating cancerous cells, or by reducing the spread of cancerous cells to generate metastases. In some modalities, the cancerous cell expresses KRAS or a mutated version of KRAS.The present invention is particularly suitable for treating patients exhibiting one or more of a wide variety of mutations in the KRAS gene, since the nucleic acid sequences of the present invention have been carefully selected as KRAS target sites outside of known mutation hotspot regions, for example, mutations in amino acids G12, G13 and Q61. The complexes of the present invention, instead, selectively target cancer cells by nature of the complex's entry into cancerous tissues and, as a result, have been designed to target cancer cells in particular, regardless of the identity of any KRAS mutation.

[00103] In some embodiments, a polynucleotide of a peptide-polynucleotide complex of the invention can treat a cancer or neoplasm by transferring a polynucleotide from the nanoparticle to a cancer cell in an individual in vivo. In some embodiments, a polynucleotide of a peptide-polynucleotide complex of the invention can treat a cancer or neoplasm by transferring a polynucleotide from the nanoparticle to cells of the tumor microenvironment or to other cells in the vicinity of a tumor. Non-limiting examples of neoplasms or cancers that can be treated with Petition 870260073661, dated 07 / 24 / 2026, page 71 / 207 67 / 93 A method of the invention may include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas (childhood cerebellar or cerebral), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors (cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic gliomas), breast cancer, bronchial adenomas / carcinoids, Burkitt's lymphoma, carcinoid tumors (childhood, gastrointestinal), carcinoma of unknown primary cells, central nervous system lymphoma (primary), cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, Chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer,Cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma in the Ewing family of tumors, extracranial germ cell tumor (childhood), extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancers (intraocular melanoma, retinoblastoma), gallbladder cancer, gastric cancer (stomach), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumors (childhood extracranial, extragonadal, ovarian), gestational trophoblastic tumor, gliomas (adult, childhood brainstem, childhood brain astrocytoma, visual pathway and childhood hypothalamic), gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma (liver), Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma (childhood), intraocular melanoma, islet cell carcinoma, Kaposi's sarcoma,Kidney cancer (renal cell cancer), laryngeal cancer, leukemias (lymphoma, Petition 870260073661, dated 07 / 24 / 2026, page 72 / 207 68 / 93 acute phoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cavity cancer, liver cancer (primary), lung cancer (non-small cell, small cell), lymphomas (AIDS-related, Burkitt, cutaneous T-cell, Hodgkin, non-Hodgkin, primary central nervous system), macroglobulinemia (Waldenstrom), malignant fibrous histiocytoma of bone / osteosarcoma, medulloblastoma (childhood), melanoma, intraocular melanoma, Merkel cell carcinoma, mesotheliomas (malignant adult, childhood), metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome (childhood), multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, myelogenous leukemia (chronic), myeloid leukemias (acute adult, acute childhood), multiple myeloma, myeloproliferative disorders (chronic),Nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer (surface epithelial-stromal tumor), ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, pancreatic cancer (islet cell), paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma and supratentorial primitive neuroectodermal tumors (childhood), pituitary adenoma, plasma cell neoplasm, pleuropulmonary blastoma, primary lymphoma of the central nervous system, prostate cancer, rectal cancer, renal cell carcinoma (cancer kidney cancer), transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma,rhabdomyosarcoma (childhood), salivary gland cancer, sarcoma (family of tumors of, Petition 870260073661, dated 07 / 24 / 2026, page 73 / 207 69 / 93 Ewing, Kaposi, soft tissue, uterine), Sézary syndrome, skin cancers (non-melanoma, melanoma), skin carcinoma (Merkel cell), small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary (metastatic), stomach cancer, supratentorial primitive neuroectodermal tumor (childhood), T-cell lymphoma (cutaneous), T-cell leukemia and lymphoma, testicular cancer, throat cancer, thymoma (childhood), thymic thymoma and carcinoma, thyroid cancer, thyroid cancer (childhood), transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor (gestational), primary site unknown (adult, childhood), transitional cell carcinoma of the ureter and renal pelvis, urethral cancer, uterine cancer (endometrial), uterine sarcoma, vaginal cancer, visual pathway glioma and hypothalamic (childhood), vulvar cancer,Waldenstrom's macroglobulinemia and Wilms' tumor (childhood). In some embodiments, a method of the invention is used to treat T-cell leukemia and lymphoma. In an exemplary embodiment, a method of the invention is used to treat adult T-cell leukemia / lymphoma (CLL) induced by Human T-lymphotropic virus-1 (HTLV-1).

[00104] In other embodiments, a polynucleotide of a peptide-polynucleotide complex of the invention can be transferred to a cancer cell in vitro. For example, a polynucleotide of a peptide-polynucleotide complex of the invention can be transferred to a cancer cell line in vitro. A cancer cell can be a cancer cell line cultured in vitro. In some alternative embodiments, a cancer cell line can be a primary cell line that has not yet been described. The methods for preparing a primary cancer cell line utilize standard techniques known to those skilled in the art. In other alternatives, a Petition 870260073661, dated 07 / 24 / 2026, page 74 / 207 70 / 93 cancer cell line may be an established cancer cell line. A cancer cell line may be adherent or non-adherent, or a cell line may be cultured under conditions that encourage adherent, non-adherent, or organotypic growth, using standard techniques known to those skilled in the art. A cancer cell line may be contact-inhibited or non-contact-inhibited.

[00105] In some embodiments, the cancer cell line may be an established human cell line derived from a tumor. Non-limiting examples of tumor-derived cancer cell lines may include the osteosarcoma cell lines 143B, CAL-72, G-292, HOS, KHOS, MG-63, Saos-2, and U-2 OS; the prostate cancer cell lines DU145, PC3, and Lncap; the breast cancer cell lines MCF-7, MDA-MB-438, and T47D; the myeloid leukemia cell line THP-1; the glioblastoma cell line U87; the neuroblastoma cell line SHSY5Y; and the bone cancer cell line Saos-2. the colon cancer cell lines WiDr, COLO 320DM, HT29, DLD-1, COLO 205, COLO 201, HCT-15, SW620, LoVo, SW403, SW403, SW1116, SW1463, SW837, SW948, SW1417, GPC-16, HCT-8, HCT 116, NCI-H716, NCI-H747, NCIHSO8, NCI-H498, COLO 320HSR, SNU-C2A, LS 180, LS 174T, MOLT-4, LS513, LS1034, LS411N, Hs 675.T, CO 88BV59-1, Co88BV59H21-2, Co88BV59H21-2V67-66, 1116-NS-19-9, TA 99, AS 33, TS 106, Caco-2, HT-29, SK-CO-1, SNU-C2B and SW480; the non-small cell lung cancer (NSCLC) cell lines H358, H2122, H441, H727, SK-Lu-1, H2009, the melanoma cell line B16-F10, the macrophage cell line RAW264.7, the F8 cell line and the pancreatic carcinoma cell lines Panc1, PANC 10.05, CAPAN-1, CAPAN-2, PSN1. Petition 870260073661, dated 07 / 24 / 2026, page 75 / 207 71 / 93 MIA-PaCa2. In one exemplary embodiment, a peptide-polynucleotide complex of the invention can be administered to an F8 cell line. In another exemplary embodiment, a peptide-polynucleotide complex of the invention can be administered to a B16-F10 cell line. 7.5. Kit

[00106] Another aspect of the invention encompasses a kit. The kit comprises a first composition comprising a peptide of the invention and, optionally, a second composition comprising a polynucleotide. Alternatively, a polynucleotide of interest may be supplied by a user of the kit. Following the directions provided by the kit, a user of the kit may mix the composition comprising a peptide of the invention and a composition comprising a polynucleotide to form a peptide-polynucleotide complex. The kit directions may include instructions for mixing the peptide and the polynucleotide in a suitable ratio. The kit may also include suitable buffers, water, crosslinking reagents, or albumin. 8. EXAMPLES

[00107] The following is a description of various methods and materials used in the studies. These are presented in order to provide those skilled in the art with a complete disclosure and description of how to produce and use the present invention, and are not intended to limit the scope of what the inventors consider to be their invention, nor are they intended to represent that the experiments below have been performed and represent all experiments that may be performed. It should be understood that exemplary descriptions written in the present tense have not necessarily been performed, but rather that the descriptions may be performed to generate the data and similar aspects associated with the teachings of the present invention. Petition 870260073661, dated 07 / 24 / 2026, page 76 / 207 72 / 93 invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, percentages, etc.), but some experimental errors and deviations should be considered. EXAMPLE 1 - siARN targeting KRAS

[00108] siRNAs that avoid mutation-hosting sites were developed with the aim of using the same compound to reduce / inhibit KRAS, regardless of the mutation. The mutation sites that were avoided are G12, G13, and Q61.

[00109] It was initiated with an in silico evaluation. The bioinformatics approach assumed a canonical siRNA structure. Positions 2-18 (5'-3') of the sense and antisense strands were used for specificity calculations. Positions 1-19 (5'-3') of the antisense strand were used for cross-reactivity and human SNP analysis. The following parameters were evaluated. • Cross-reactivity between species for humans, cynomolgus monkeys, rhesus monkeys, and mice: Analysis based on a canonical siRNA design using 19 bases and 17 bases (excluding positions 1 and 19) for cross-reactivity. Complete matching as well as simple mismatch analyses were included. • Predicted specificity in humans, rhesus monkeys, cynomolgus monkeys, and mice. The sense and antisense strands were analyzed separately. • Similarity of the seed region of siRNAs and the seed region of known miRNAs • Analysis of the human SNP database (NCBI-DBSNP) to identify siRNAs targeting regions with known SNPs. The information included the positions of SNPs within the target sequence, as well as the frequency of the minor allele (MAF), if applicable. Petition 870260073661, dated 07 / 24 / 2026, page 77 / 207 73 / 93 the data were available. • Prediction of siRNA activity based on canonical siRNA design.

[00110] The 96 sequences were selected for the first in vitro analysis. The sequences are shown in Table 1 above.

[00111] The 96 selected sequences were further modified. The modification pattern is shown in Fig. 1. The modified sequences are shown in Table 2 above.

[00112] These 96 sequences were synthesized and tested in NCI-H23 cells carrying the KRAS G12C mutation at two different doses (0.1 and 10 nM), the results of this analysis are shown in Table 3 below. Table 3 - Two-dose analysis in NCI-H23 KRAS GAPDH KRAS GAPDH Sense Antisense MV% residual SD MV SD MV% residual SD MV SD Selected gsgsAfcuuAf GfCfaaGfaag uUfaa usUfsaacuuc uugcuAfaguc csusg 12.6 2.3 92.0 2.9 30.6 1.6 101.9 6.4 x gsusCfucuUf GfGfauAfuuc uCfga usCfsgagaau auccaAfgaga csasg 12.9 3.4 100.0 4.6 62.1 3.7 99.9 4.6 x gscsAfguuGf AfUfuaCfuuc uUfaa usUfsaagaag uaaucAfacug csasu 14.7 1.5 89.3 3.5 22.0 0.9 93.6 3.9 x asgsAfaauUf CfGfaaAfaca uAfaa usUfsuauguu uucgaAfuuuc uscsg 15.0 0.9 84.8 3.9 65.9 4.6 86.4 4.7 x asgsAfuauUf CfAfccAfuua uAfga usCfsuauaau ggugaAfuauc ususc 15.1 1.9 90.5 6.5 41.0 2.7 90.8 5.1 x gsasAfucaUf CfCfcuAfuuc uGfua usAfscagaau agggaUfgau ucsasa 15.9 1.1 95.3 1.4 47.4 2.6 96.2 2.4 x Petition 870260073661, dated 07 / 24 / 2026, page 78 / 207 74 / 93 KRAS GAPDH KRAS GAPDH Sense Antisense MV% residual SD MV SD MV% residual SD MV SD Selected ususCfuauAf CfBlowAfguu cGfaa usUfscgaacu aauguAfuaga asgsg 16.1 1.6 98.9 3.8 62.9 3.0 95.9 5.2 x gsasUfauuCf AfCfcaUfuau aGfaa usUfscuauaa uggugAfauau csusu 16.4 0.9 98.2 7.5 42.6 3.9 91.9 9.9 x usasUfucaCf CfAfuuAfuag aGfaa usUfscucuau aauggUfgaa uasusc 17.4 2.2 89.8 5.0 49.9 5.1 94.8 8.2 x ususAfguuCf GfAfgaAfauu cGfaa usUfscgaauu ucucgAfacua asusg 17.6 1.3 90.8 6.6 54.7 7.5 90.9 9.7 x csgsAfauaUf GfAfucCfaac aAfua usAfsuuguug gaucaUfauuc gsusc 17.6 1.0 74.1 6.5 30.1 1.9 94.3 3.8 x usgsAfcgaUf AfCfagCfuaa uUfca usGfsaauuag cuguaUfcguc asasg 17.9 1.1 89.7 4.4 57.5 4.5 95.9 8.7 x ascsGfauaCf AfGfcuAfau cAfga usCfsugaauu agcugUfaucg uscsa 18.6 0.9 82.0 11.6 38.7 2.5 88.1 5.4 x asusUfaguUf CfGfagAfau uCfga usCfsgaauuu cucgaAfcuaa usgsu 18.8 2.7 95.4 6.1 69.8 6.4 90.8 7.0 x gsasUfacaGf CfUfaaUfuca gAfaa usUfsucugaa uuagcUfguau csgsu 19.8 0.5 86.5 6.2 62.9 3.0 91.7 7.0 .9 x gsgsAfuauUf CfUfcgAfcac aGfca usGfscugugu cgagaAfuauc csasa 21.8 7.0 88.8 15.8 77.7 4.2 97.0 6.8 x asgsGfacaUf CfAfcuUfacu aUfca usGfsauagua agugaUfgucc uscsa 21.9 0.6 70.8 18.7 47.8 9.2 98.2 8.5 x, Petition 870260073661, dated 07 / 24 / 2026, pp. 79 / 207 75 / 93 KRAS GAPDH KRAS GAPDH Sense Antisense MV% residual SD MV SD MV% residual SD MV SD Selected cscsAfauuUf CfUfuaCfuag uAfca usGfsuacuag uaagaAfauug gscsa 24.5 3.4 95.5 6.4 33.2 4.4 87.3 3.1 x ascsBlowGf BreathBlow cUfa usUfsaguaau uuaucUfaaug usgsa 25.3 2.7 90.1 7.5 48.2 2.4 86.7 1.7 x usgsUfacaUf UfAfcaCfuaa aUfua usAfsauuuag uguaaUfguac asasa 25.8 4.4 81.4 7.8 46.0 1.9 91.0 4.5 x cscsCfuaaCf CfAfuaAfgau uUfaa usUfsaaucu uauggUfuag ggsgsa 26.1 2.0 90.2 8.5 43.1 2.6 101.1 5.7 x asgsUfaugAf AfAfugGfgga usUfsaauccc cauuuCfauac usgsg 27.3 4.7 92.0 10.7 54.8 4.7 75.1 28.7 x gscsCfaauUf UfCfuuAfcua gUfaa usUfsacuagu aagaaAfuugg csasc 29.3 5.8 79.6 19.3 39.6 4.8 86.7 5.9 x csasAfugaGf GfGfacCfagu aCfaa usUfsguacug gucccUfcauu gscsa 23.3 1.3 101.1 5.3 79.1 1.6 96.1 5.8 gsgsAfcgaAf UfAfugAfucc aAfca usGfsuuggau cauauUfcguc csasc 24.0 0.5 81.3 20.3 101.0 6.1 94.8 5.1 usGfgcuAf GfUfucUfcu aAfca usGfsuuaaga gaacuAfgcca asasc 26.0 2.2 98.9 1.5 81.8 5.9 99.9 0.2 ususUfgaaUf AfUfccAfuuc uCfga usCfsgagaau ggauaUfucaa asusa 26.3 1.4 90.2 1.0 68.9 4.6 100.1 2.2 gsgsAfuacAf CfUfuaUfuug uCfaa usUfsgacaaa uaaguGfuau ccsusu 28.1 4.1 87.2 6.7 72.9 9.7 96.6 4.9 uscsUfaggUf UfUfggCfuag uUfca usGfsaacuag ccaaaCfcuag asgsa 28.2 1.4 90.7 0.7 71.2 3.2 104.3 3.8, Petition 870260073661, dated 07 / 24 / 2026, pp. 80 / 207 76 / 93 KRAS GAPDH KRAS GAPDH Antisense Sense MV% residual SD MV SD SD SD MV% residual SD MV SD Selected based on UfucgAf AfAfAfAfuaa aGfaa usUfscuuuau guuuuCfGAa uususc,8 1,3 5,3 13,92. 91.1 6.3 usgsGfgcaAf AfAfuuGfugc aAfga usCfsuugcac aauuuUfgccc asasg 29.1 5.6 92.6 2.3 71.8 2.8 104.0 1.9 usgsAfUsauuCfuagG aaccuAfaguc ascsc 29.2 2.1 98.4 4.4 81.9 16.2 98.3 6.9 gsusAfgggUf GfUaAfgac uUfaa usUfsaagucu uaacaCfccua 30.6 40.3 85 cscsu 3,4 gsusCfgauAf UfAfguUfcuc usUfaua usUfaua 30.7 0.7 88.1 22.1 64.5 5.4 102.0 3.6 gsasCfgauAf csasa 30.8 2.4 84.5 3.1 86.9 5.4 92.8 4.9 gsgsAfuaaUf GfAfuaGfgua aUfua usAfsauuacc uaucaUfuauc cscsa 31.6 5.6 35.54 cscsa uscsCfuggUf afAfcaGfuaa uAfca usGfsuauuac uguuaCfcagg year 32.8 9.9 92.4 5.0 72.2 3.5 102.5 1.6 csusUfaggCf 33.2 4.8 97.5 8.5 50.0 3.8 98.4 4,5 gsasAfuagUf CfAfuaAfcua gAfua usAfsucuagu uaugaCfuau ucsusu 33.7 4.8 87.0 7.7 77.1 3.2 97.1 5.2 usasGfgaaUf GfUfugGfuca uAfua usAfsuaugac caacaUfuccu asgsg 33.8 2.0 69.4 23.2 39.1 1.6 89.4 2.9 ascsUfguaCf UfAfcuCfcua aUfua usAfsauuagg aguagUfacag ususc 34.0 5.6 91.1 5.2 73.3 9.0 96.0 5.2, Petition 870260073661, dated 07 / 24 / 2026, page 81 / 207 77 / 93 KRAS GAPDH KRAS GAPDH Sense Antisense MV% residual SD MV SD MV% residual SD MV SD Selected uscsAfuuuGf GfUfugCfgcu gAfca usGfsucagcg caaccAfaaug asusg 35.2 4.4 94.2 13.1 56.3 6.2 92.3 3.6 gscsAfucaUf GfUfccUfaua gUfua usAfsacuaua ggacaUfgaug cscsu 35.3 3.9 89.8 3.5 82.8 5.5 80.2 23.3 usgsCfuauUf AfGfucAfugg uCfaa usUfsgaccau gacuaAfuagc asgsu 35.5 12.1 79.4 20.2 69.6 1.3 94.2 4.1 usgsAfCfcgAfag uUfua usAfsaacuuu cggauAfaac ascsu 35.6 3.1 99.4 4.1 45.5 5.4 92.5 3.0 asgsAf UfCfugGfgua cAfaa usUfsuguacc cagauAfaaac usasu 35.6 5.9 102.8 12.0 69.7 4.4 102.7 1.4 gsusGfuuuUf AfUfccGfaaa gUfua usAfsacuuuc ggauaAfaaca csusg 36.1 5.9 87.1 4.0 51.5 3.4 99.1 4.5 asusUfacaUf CfCfauUfaua gAfaa usUfsucucga acuaaUfguau asgsa 36.2 2.8 91.6 2.5 71.1 4.0 93.2 5.6 asusAfuucAf CfCfauUfaua gAfga usCfsucuaua augguGfaau auscsu 36.3 2.2 102.2 4.9 111.3 5.5 98.6 8.1 cscsUfaacCf AfUfaaGfauu uAfca usGfsuaaauc uuaugGfuua ggsgsg 36.9 2.6 98.2 2.5 68.6 1.0 97.2 4,2 asasUfagaCf AfGfaaCfccu aUfca usGfsauaggg ucugUfcuau uscsa 38,5 12,9 83,2 7,8 77,6 4,4 100,2 5,0 csusGfuacUf AfCfucCfuaac9 agagusua gagusuaU3uGfusau uUfau 6.2 94.7 4.4 68.1 2.9 95.1 4.9 gsgsAfaugUf UfGfguCfaua uCfaua usUfsgauaug accaaCfauuc csusa 39.3 4.5 86.2 3.1 57.91.7 Petition 870260073661, dated 24 / 07 / 2026, p. 82 / 207 78 / 93 KRAS GAPDH KRAS GAPDH Sense Antisenso MV% residual SD MV SD MV% residual SD MV SD Selected cscsAfucaUf UfUfggUfugc gCfua usAfsgcgcaa ccaaaUfgaug gsasa, 72,20,30 3 11.6 90.8 5.9 asgsGfgauUf UfGfacCfuaa uCfaa usUfsgauuag writeAfuccc ususu 39.4 5.1 83.5 5.6 74.3 6.8 96.6 5.3 ususUfgausaagfgggCfa Cfa acuggCfccaa asusa 39.6 16.8 82.7 5.8 95.0 14.1 92.6 4.6 csusAfggaAf UfGfuuGfguc aUfaa usUfsaugacc aacauUfccua gsgsu 40.7 1.49 1.49 1.46 2,2 daysYearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyearyear 41.6 7.1 76.3 6.7 74.0 2.1 94.1 6.6 gsusGfacuUf afGfguA gsusGfacuUf afGfgua gsusGfacua cscsu 43.2 4.2 85.3 10.8 013.3 92.3 uscsCfccuAf AfCfcaUfaag aUfua usAfsaucuua ugguuAfgggg base 43.6 3.8 96.5 2.3 80.9 3.3 103,4 3,0 ascsCfuagGf AfAfugUfugg uCfacgaacca4usggUs5 8.9 90.0 4.4 71.3 7.7 85.4 4,5 cscsCfcuaAf CfCfauAfaga uUfua usAfsaaucuu augguUfagg ggsasa 46.0 7.5 71.9 21.5 67.1 4.0 99.4 4.1 gsgsUfccuGf CfUfgaCfaaa uCfaa usUfsgauuug ucagcAfggac csasc 46.3 8.3 84.2 9.4 69.4 4.5 97.2 4.9 cscsUfaggAf AfUfguUfggu cAfua usAfsugacca acauuCfcuag gsusc 46.4 9.6 97.5 11.0 55.3 8.4 90.2 2.4, Petition 870260073661, dated 07 / 24 / 2026, page 83 / 207 79 / 93 KRAS GAPDH KRAS GAPDH Sense Antisense MV% residual SD MV SD MV% residual SD MV SD Selected gsgsGfgauAf UfUfuaGfgcc uCfua usAfsgaggcc uaaauAfuccc csusc 48.2 8.2 93.5 10.5 496.596 4.2 usgsCfccaAf UfCfcaUfuag cGfaa usUfscgcuaa uggauUfgggc asgsc 49.5 2.6 89.9 2.1 92.4 3.8 100.4 2.2 csasUfuagUf UfCfgaGfaaa ufCfcaUfuagUuCuAuc gsusa 49.7 4.7 87.7 6.7 92.3 5.0 92.2 7.6 gsgsUfaugAf AfUfagAfcag aAfca usGfsuucugu cuauuCfauac csasg 49.7 5.5 76.6 4.4 88.24.25.96.6 gscsCfcaaUf CfCfauUfagc gAfca usGfsucgcua auggaUfugg gcsasg 51.6 8.0 77.9 6.2 99.8 12.8 86.9 19.1 csasUfuagCf GfAfcaGfuag gAfuac usAfcau gsucgsau5cgsagsa5 15.2 72.9 26.7 85.6 4.8 96.6 5.8 csasUfaacUf AfGfauUfaag aUfca usGfsaucuua aucuaGfuua ugsasc 52.7 6.5 89.4 6.6 104.0 9.1 96.6. aCfaa usUfsguugga ucauaUfucgu cscsa 53.9 2.5 78.1 8.3 112.4 8.7 91.8 8.9 gsgsGfauaAf UfGfauAfggu aAfua usAfsuuaccu aucauUfaucc csasa 53.4,97.814 82.6 7.5 95.4 4,7 ascsAfaucUf CfUfagGfuuu gGfca usGfsccaaac cuagaGfauu gusasa 55.6 15.1 77.0 15.1 88.9 3.0 99.8 2.0 ususGfacgAf UfAfcaGfcua aUfua usAfsauuagc uguauCfguca asgsg 56.7 1.9 87.1 12.0 93.5 3.2 97.7 6.8 gsusAfcuaCf UfCfcuAfauu aUfua usAfsauaauu aggagUfagu acsasg 57.5 7.7 91.2 9.7 91.7 11.6 95.7 5.3, Petition 870260073661, de 24 / 07 / 2026, pág. 84 / 207 80 / 93 KRAS GAPDH KRAS GAPDH Sense Antisense MV% residual SD MV SD MV% residual SD MV SD Selected gscsAfuggUf GfAfggUfgaa aGfua usAfscuuuca ccucaCfcaug cscsa 60.6 5.0 101.00 194.25 101.3 3.8 csasUfgguGf AfGfguGfaaa gUfaa usUfsacuuuc accucAfccau gscsc 61.1 11.3 86.0 2.0 86.6 11.0 93.6 7.6 cscsAfaucCf AfGfAugcfcgcfcg uaaugGfauu ggsgsc 61.8 14.6 82.2 16.1 95.1 5.6 97.0 3.5 gscsAfaugAf GfGfgaCfcag uAfca usGfsuacugg ucccuCfauug csasc 62.7 3.34.8 17.17.14 95.4 5.1 ascsCfauuUf UfGfggGfcua uAfua usAfsuauagc cccaaAfaugg ususg 62.8 8.0 88.2 6.6 98.0 5.7 91.6 7.9 csasCfugcUf AfUfuaGfuca uscagfGfcag uscagfcag 67.8 4.8 92.6 6.9 91.8 11.7 90.8 3.7 ascsCfuauGf GfUfccUfagu aGfga usCfscuacua ggaccAfuagg usasc 69.2 8.9 102.9 4.2 105.8 4.0 1.8 1.8 usgsUfacuAf CfUfccUfaau uAfua usAfsuaauua ggaguAfguac asgsu 69.3 13.3 83.1 9.0 94.8 12.9 89.7 7.7 usgsAfccuAf AfUfcaCfuaa uUfua usAfUfcaCfuaa uUfuaa uAfsaaAfsaaaaa 572.765 90.9 4.8 87.1 6.3 100.2 4,1 ususUfaacCf UfAfugUfuac aCfca usGfsguguaa cauagGfua asasa 78.9 6.9 92.0 1.4 99.1 10.6 98.8 4.5 cscsUfaacUf UfUfuaUsufagg usfuagg ufsaccua uUfaa 84.0 5.3 79.5 8.8 105.4 3.9 95.1 7.8 asgsUfucgAf GfAfaaUsasa 88.3 9.5 92.6 95 4.80 10.5 Petition 870260073661, dated 24 / 07 / 2026, p. 85 / 207 81 / 93 KRAS GAPDH KRAS GAPDH Senso Antissenso MV% residual SD MV SD MV% residual SD MV SD Selecionado ascsGfaauAf UfGfauCfcaa cAfaa usUfsuguugg aucauAfuucg uscsc 89,5 4,6 78,9 7,4 113,7 7,8 95,9 3,2 asusCfcauUf AfGfcgAfcag uAfga usCfsuacugu cgcuaAfugga ususg 92,0 14,8 84,4 5,6 112,3 6,0 93,4 7,1 99.2 3.0 95,6 2,2 88,9 3,0 102,2 2,6 csgsGfcucGf GfCfcaGfuac uCfca usGfsgaguac uggccGfagcc gscsc 99,5 4,9 98,0 7,0 111,8 8,2 97,4 2,1 ususAfaccUf AfUfguUfaca cCfaa usUfsggugua acauaGfguu aasasa 103,4 5,3 91,9 3,9 93,1 4,3 107,5 3,4 csasAfuccAf UfUfagCfgac aGfua usAfscugucg cuaauGfgau ugsgsg 134,5 8,9 85,6 10,6 111,4 6.8 96.5 4.2

[00113] The top 24 siRNAs were selected and a dose response was performed to assess KRAS silencing. The dose response results (IC50s and percentage of inhibition) are included in Table 4 below. Screening of these siRNAs showed dose response curves of quite diverse shapes: some reached a plateau of 100% of the target expression, while others, surprisingly, appeared to have reached maximum saturation / reduction at all doses tested. Table 4 - Dose-Response Sense Antisense CI20 [nM] CI50 [nM] CI80 [nM] Maximum inhibition [%] usgsAfcgaUfAfC fagCfuaauUfca usGfsaauuagcug uaUfcgucasasg 0.00 0.00 0.2 88.2 Petition 870260073661, dated 07 / 24 / 2026, page 86 / 207 82 / 93 Senso Antisenso CI20 [nM] CI50 [nM] CI80 [nM] Inibição máx. [%]. fucCfaacaAfua usAfsuuguuggau caUfauucgsusc 0,00 0,00 0,2 82,0 gsusCfucuUfGfG fauAfuucuCfga usCfsgagaauoc caAfgagacsasg 0,05 0,33 7,6 84,6 gsgsAfuauUfCfU fcgAfcacaGfca usGfscugugucga gaAfuauccsasa 0,30 1,19 128,0 79,7 asgsAfuauUfCfA fccAfuuauAfga usCfsuauaauggu gaAfuaucususc 0,00 0,00 0,7 85,8 gsasUfauuCfAfC fcaUfuauaaGfaa usUfscuauaaugg ugAfauaucsususu 0,00 0,01 1,7 86,2 usasUfucaCfCfA fuuAfuagaGfaa usUfscucuauau ggUfgaauasusc 0,00 0,02 4,2 82,3 gsgsAfcuuAfGfC faaGfaaguUfaa usUfsaacuucuug cuAfaguccsusg 0,00 0,05 1,8 88,1 ususCfuauAfCfA fuuAfguucGfaa usUfscgaacuaau guAfuagaasgsg 0.00 0.02 5.0 86.0 asusUfaguUfCfG fagAfaauuCfga usCfsgaauuucuc gaAfcuaausgsu 0.02 0.26 9.4 87.5 ususAfguuCfGfA fgaAfauucGfaa usUfscgaauuucu cgAfacuaasusg 0.00 0.02 0.5 86,4 asgsFaceUfCfG faaAfacauFace usUfsuauguuuuc gaAfuuucuscsg 0.00 0.02 0.9 88.7 usgsFaceFace fcaCfuaaaUfua usAfsauuuagugu aaUfguacasasa 0.00 0.06 #N / A gscsAfguuGfAfU fuaCfuucuUfaa usUfsaagaaguaa ucAfacugcsasu 0.00 0.00 0.0 89.5 gsasAfucaUfCfC fcuAfucuGfua usAfscagaauagg gaUfgauucsasa 0.00 0.04 4.2 87.1, Petition 870260073661, 07 / 24 / 2026, p. 87 / 2 83 / 9 Sense Antisense CI20 [nM] CI50 [nM] CI80 [nM] Maximum inhibition [%] ascsAfuuaGfAfU faaAfuuacUfaa usUfsaguaauuua ucUfaaugusgsa 0.01 0.12 #N / A 78.7 asgsUfaugAfAfA fugGfggauUfaa usUfsaauccccau uuCfauacusgsg 0.00 0.12 #N / A 71.0 asgsGfacaUfCfA fcuUfacuaUfca usGfsauaguaag ugaUfguccuscsa 0.02 0.23 9.6 84.6 cscsCfuaaCfCfA fuaAfgauuUfaa usUfsaaaucuuau ggUfuagggsgsa 0.00 0.06 #N / A 75.6 cscsGfaaaGfUfU fucCfaauuCfca usGfsgaauugga aacUfuucggsasu 0.07 0.51 23.6 82.3 gscsCfaauUfUfC fuuAfcuagUfaa usUfsacuaguaag aaAfuuggcsasc 0.00 0.01 #N / A 76.6 cscsAfauuUfCfU fuaCfuaguAfca usGfsuacuaguaa gaAfauuggscsa 0.00 0.01 28222.7 79.2

[00114] Two of the siARNs (shown in Table 5 below) present- They exhibited unexpectedly high activity and were tested at lower doses to reach a concentration of 0.00002 nM (20 fM). This dose-response curve also showed maximum reduction at all doses. The results of this analysis are shown in Figures 2A-2F. Table 5 Sense Antisense csgsAfauaUfGfAfucCfaacaAfua usAfsuuguuggaucaUfauucgsusc gscsAfg uu GfAfUfuaCfu ucuUfaa usUfsaagaaguaaucAfacugcsasu

[00115] Finally, two candidates (XD-39951 and XD-39947) were tested in cell lines harboring different KRAS mutations. These evaluations were performed by transfecting the siRNAs into cells carrying the KRAS wt or KRAS mutations (HT-29: wt; SW480:G12V mutation; LS174T:G12D mutation). As shown in Figures 3A-3C, both sequences were able to knock down KRAS, regardless of the mutation.

[00116] The XD-39951 candidate was further tested on Petition 870260073661, dated 07 / 24 / 2026, pp. 88 / 207 84 / 93 more cell lines harboring additional KRAS mutations. These assessments were performed by transfecting siRNAs into cells carrying the additional KRAS mutations. As shown in Figure 4A, in addition to G12V and G12D, XD-39951 is capable of knocking down the G12C, G12R, G12A, and A146T KRAS mutations. As shown in Figure 4B, knocking down KRAS leads to reduced cell viability in some cases.

[00117] The formulation allows for specific transfer to tumors. This occurs because tumors generally have permeable vasculature, allowing the extravasation of the nanoparticle described in this report due to its physicochemical characteristics.

[00118] Coating nanoparticles with albumin enriches the local concentration of nanoparticles by binding to pg60 and / or SPARC receptors. These receptors are upregulated in certain tumors.

[00119] Coating the nanoparticle with hyaluronic acid may have the same effect on other types of tumors through the CD44 receptor. EXAMPLE 2 - Materials and Methods 1.1 Analysis of KRAS knockdown in NCIH23 cells after transfection with different siRNAs Table 6 - Materials Materials Supplier NCI-H23 ATCC cells ARNiMax Invitrogene bADN ThermoFisher Methods

[00120] NCI-H23 (ATCC) cells at a density of 20,000 cells per well were transfected with increasing concentrations of KRAS siRNAs (0.00002 nM - 50 nM) using the transfection agent ARNiMax (Invitrogene) following the manufacturer's instructions. 24 Petition 870260073661, dated 07 / 24 / 2026, pp. 89 / 207 85 / 93 hours after transfection, the reduction in KRAS was analyzed using a Quantigene® branched DNA assay. 1.2 Analysis of KRAS knockdown in HT-29, SW480, and LS174T cells after transfection with different siRNAs. Table 7 - Cell line used in this study. No. Cell Line Species Category Tissue Origin Medium 1 SW480 Human Colon Tumor L-15 + 10% FBS 2 HT-29 Human Colon Tumor McCoy's 5a + 10% FBS 3 LS174T Human Colon Tumor MEM + 0.01 mM NEAA + 10% FBS Note: The cells were cultured in an incubator at 37°C with 5% CO2 and 95% air (except SW480 which was grown with 100% air). Table 8 - Reagents for cell culture and transfection. Item Supplier No. Cat. Medium L-15 Gibco 11415-064 McCoy's 5a Medium Gibco 12330-031 MEM Hyclone SH30024.01 FBS Gibco 10099-141 Trypsin EDTA 0.25% Gibco 25200-072 NEAA Gibco 11140-050 siRNA Axolabs N / A Lipofectamine ARNiMAX Invitrogen 13778150 Table 9 - Reagents for TR-RCP Reagent Supplier No. Cat. Kit RNeasy Mini Qiagen 74106 RNase-free DNase Kit TIANGEN RT411 High-throughput cDNA Reverse Transcriptase Kit ABI 4374966 TaqMan Universal CPR Standard Mixture ABI 4304437 Petition 870260073661, dated 07 / 24 / 2026, pp. 90 / 207 86 / 93 Table 10 - Probe information Gene ID of the Assay Supplier Catalog Number KRAS Hs00364282_m1 Thermo Fisher 4331182 GAPDH Hs02758991_g1 Thermo Fisher 4331182

[00121] Equipment 1) Applied Biosystems Inc. (ABI), 7900H Rapid CPR System, 384-well format Equipment ID: BEPCR0030 2) Data analysis software: ABI SDS2.4 3) Nanodrop™ 2000 Spectrophotometer Equipment ID: BENOP0020 4) Qiagen II Fabric Smoother Equipment ID: BETIS0010

[00122] Methods siRNA resuspension (Objective 1-3) a) Briefly centrifuge the screw-capped bottle at low speed (maximum 4,000 xg) to ensure that all material is collected at the bottom of the bottle or well before opening. b) Carefully remove the screw cap. c) Add nuclease-free water to achieve a stock concentration of 100 μM. d) Let the flask or plate stand for a few minutes at room temperature. e) Gently pipette up and down 5 times to resuspend. f) Repeat steps d, e, and f. (g) Divide aliquots of the resuspended siRNA into multiple tubes or plates to limit the number of freeze-thaw cycles. Store at -80°C. h) Note: the siRNA solution was on ice during the preparation of the transfection reaction. Petition 870260073661, dated 07 / 24 / 2026, pp. 91 / 207 87 / 93

[00123] Cell seeding and T0 plate reading (Objective 1-3). a) Place the cells in 96-well plates at a predetermined density in 90 μL of culture medium 24 hours before transfection (day 0). The cells should reach 30-50% confluence the following day. b) Take the T0 (1 day) group plate and add 10 μL of culture medium to each well for the T0 reading. c) Add 100 μL of CellTiter-Glo reagent to each well. d) Mix the contents for 20 minutes in an orbital shaker to facilitate cell lysis. e) Allow the plate to incubate at room temperature for 10 minutes to stabilize the luminescent signal. (Note: Irregular luminescent signal on standard plates may be caused by temperature gradients, uneven cell seeding, and edge effects on multilayer plates). f) Place a black Backseal sticker on the underside of each plate. g) Record the luminescence using the Envision Multilabel Reader.

[00124] siRNA Transfection (Objective 1-3). a) On the day of transfection (day 1), renew the culture medium with 90 μL of culture medium. b) Transfect the cells with siRNA at a final concentration range in triplicate (see Appendix). Prepare the siRNA-lipid complex as shown in Table 11 below: Table 11 Diluted siRNA Opti-MEM Medium (pL) 5 siRNA (pL) 0.1 Diluted Lipofectamine Opti-MEM Medium (pL) 5 Lipofectamine ARNiMAX Reagent (pL) 0.3 Petition 870260073661, dated 07 / 24 / 2026, pp. 92 / 207 88 / 93 c) Add 5 μL of diluted siRNA to 5 μL of diluted Lipofectamine and incubate the mixture for 5 minutes at room temperature. Add the siRNA-lipid complexes dropwise to each well and mix gently by gently rocking the plate back and forth. Incubate the cells for a specific time before the cell viability assay (see Appendix). Renew the culture medium after 24 hours of incubation, if necessary. d) To assess cell viability, add 100 μL of CellTiter-Glo reagent to each well. Mix the contents for 20 minutes on an orbital shaker to facilitate cell lysis. Incubate the plate at room temperature for 10 minutes to stabilize the luminescent signals. Place a black Backseal sticker on the bottom of each plate and measure the luminescence data using an EnVision MultiLabel label reader.

[00125] qRCP sample collection (Objective 1-3). a) Place the cells in 6-well plates at a predetermined density in 2.25 mL of culture medium 24 hours before transfection (day 0). The cells should reach 30-50% confluence the following day. b) On the day of transfection (day 1), replace the culture medium with 2.25 mL of growth medium. c) Transfect the cells with siRNA at a final concentration range (see Appendix). Prepare the siRNA-lipid complex as shown in Table 12 below: Table 12 Diluted siRNA Opti-MEM Medium (pL) 125 siRNA (pL) 2.5 Diluted Lipofectamine Opti-MEM Medium (pL) 125 Lipofectamine ARNiMAX Reagent (pL) 7.5 d) Add 125 μL of diluted siRNA to 125 μL of Lipofecção 870260073661, dated 07 / 24 / 2026, page 93 / 207 89 / 93 diluted methylammonium chloride and incubate the mixture for 5 minutes at room temperature. Add the siARNA-lipid complexes drop by drop to each well and mix gently by gently shaking the plate back and forth. Incubate the cells for a specified time before collection. Renew the culture medium after 24 hours of incubation, if necessary. e) Remove the culture medium and freeze the transfected cells in liquid nitrogen and store them at -80°C. Sample information

[00126] 366 samples were used in vitro efficacy studies to detect gene expression. Detailed information about the samples is shown in Table 13 below. Table 13 No. N Cell lines Treatment Doses Treatment time Target 1 90 SW480 463_XD-39951 342_XD-39947 Fluc (XD-11633) 200, 40, 8 nM 24, 48 and 72 h HT-29 LS174T Vehicle — Target 2 75 SW480 2 siRNAs + Fluc (XD-11633) (TBD) TBD per user (8 doses) 24, 48 or 72 h (TBD) HT-29 LS174T Vehicle — Target 3 201 SW480 10 siRNAs + Fluc (XD-11633) (TBD) TBD per user (6 doses) 24, 48 or 72 h (TBD) HT-29 LS174T Vehicle —

[00127] Total RNA extraction 1) Place a stainless steel sphere (average diameter of 5 mm) and 350 μL of RLT buffer in a 2 mL microcentrifuge tube containing cells. Place the tubes in the TissueLyser adapter, adjust, and operate the TissueLyser for 5 minutes at 20 Hz. Proceed with Petition 870260073661, dated 07 / 24 / 2026, pp. 94 / 207 90 / 93 RNA extraction. 2) Add 1 volume of 70% ethanol to the lysate and mix well by pipetting. Do not centrifuge. Proceed immediately to step 3. 3) Transfer up to 700 μL of the sample, including any precipitate, to an RNeasy Mini centrifuge column placed in a 2 mL collection tube (provided). Close the cap and centrifuge for 15 seconds at > 8,000 χ g. Discard the stream. Transfer the remaining lysate to the same tube and repeat step 3. 4) Add 350 μL of RW1 buffer to the RNeasy column. Close the lid and centrifuge for 15 seconds at 8,000 χ²g. Discard the flow. 5) Add 10 μL of DNase I stock solution to 70 μL of RDD buffer. Mix by gently inverting the tube and centrifuge briefly. 6) Add the DNase I incubation mixture (80 μL) directly to the membrane of the RNeasy column and place the tubes on the bench (20-30°C) for 15 minutes. 7) Add 350 μL of RW1 buffer to the RNeasy column. Close the lid and centrifuge for 15 seconds at 8,000 χ²g. Discard the flow. 8) Add 500 μL of RPE buffer to the centrifuge column. Gently close the lid and centrifuge for 2 minutes at 8,000 χ²g to wash the centrifuge column membrane. Discard the flow. 9) Add 500 μL of RPE buffer to the centrifuge column. Gently close the lid and centrifuge for 2 minutes at 8,000 χ g to wash the centrifuge column membrane. 10) Place the RNeasy centrifuge column in a new 1.5 mL collection tube (provided). Add 30-50 μL of free water. Petition 870260073661, dated 07 / 24 / 2026, pp. 95 / 207 91 / 93 of RNase directly onto the center of the centrifuge column membrane. Gently close the lid and centrifuge for 1 minute at maximum speed to elute the RNA.

[00128] RNA Quantification Total RNA quantification using a Nanodrop™ 2000 spectrophotometer. cDNA synthesis (Reverse Transcription, RT) 1) Configure the TR reaction as shown in Table 14: Table 14 Reagent Volume 10χ TR buffer mixture 2 μL 25χ dNTP mixture 0.8 μL 10χ Random primers TR 2 μL RNase inhibitor 1 μL 50U^L MultiScribe Reverse Transcriptase 1 μL RNA 2000 ng Nuclease / RNase-free water for 20 μL 2) TR reaction conditions in Table 15: Table 15 Temperature Time 25°C 10 minutes 37°C 120 minutes 85°C 5 minutes 4°C Forever 3) To achieve the highest cDNA yield, RT reactions of 20 μL with up to 2 μg of total RNA were performed. cDNA samples were stored at -20°C or used for real-time PCR immediately.

[00129] Real-time CPR reaction (TaqMan method) 1) Prepare real-time CPR as shown in Table 16: Petition 870260073661, dated 07 / 24 / 2026, pp. 96 / 207 92 / 93 Table 16 Reagent Volume TaqMan 2χ Universal Standard Mixture for CPR 5 μL Probe 0.5 μL RNase-free Water 2.5 μL cDNA 2 μL Total 10 μL 2) Real-time CPR procedure in Table 17: Table 17 Temperature Time Cycle 50°C 5 minutes 1 cycle 95°C 10 minutes 1 cycle 95°C 15 seconds 45 cycles 60°C 1 minute 3) ddH2O was used as a template-free control (CSM). The RNA sample was used as a non-reverse transcription (no RT) control. Each sample had three technical replicates.

[00130] Those skilled in the art have recognized that changes can be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments described, but is intended to encompass modifications within the spirit and scope of the present invention, as defined by the present description.

[00131] Several publications, articles, and patents are cited or described in the context of and throughout this descriptive report; each of these references is incorporated herein by reference in its entirety. The incorporated patents include, but are not limited to, U.S. Patent No. 9987371, U.S. Patent No. 10758627, and U.S. Patent No. 11529388. The discussion of documents, acts, materials, devices, articles, or similar items included in this descriptive report is for the purpose of providing... Petition 870260073661, dated 07 / 24 / 2026, pp. 97 / 207 93 / 93 context for the invention. Such discussion does not constitute an admission that any or all of these matters are part of the state of the art with respect to any inventions described or claimed. Petition 870260073661, dated 07 / 24 / 2026, pp. 98 / 207

Claims

1 / 4 CLAIMS 1. Pharmaceutical composition, characterized in that it comprises a peptide-polynucleotide complex, wherein the peptide comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of ID SEQ NO: 1, ID SEQ NO: 2 or ID SEQ NO: 3; and wherein the polynucleotide is a small interfering RNA (siRNA) targeting human KRAS mRNA, wherein the target human KRAS mRNA sequence does not encode G12, G13 or Q61 with reference to ID SEQ NO: 4 or a mutant amino acid at position 12, 13 or 61 with reference to ID SEQ NO:

4.

2. Pharmaceutical composition according to claim 1, characterized in that the peptide is non-lytic, non-cytotoxic and capable of affecting the release of the polynucleotide from an endosome of a cell. 3.Pharmaceutical composition, according to claim 1 or 2, characterized in that the peptide comprises two or more contiguous basic amino acids (a cationic region) and one or more histidine residues located adjacent to the cationic region.

4. Pharmaceutical composition, according to any one of claims 1 to 3, characterized in that the peptide comprises an amino acid sequence of ID SEQ NO: 1, ID SEQ NO: 2 or ID SEQ NO:

3.

5. Pharmaceutical composition, according to any one of claims 1 to 4, characterized in that the siRNA comprises a sense strand and an antisense strand.

6. Pharmaceutical composition, according to claim 5, characterized in that the sense strand and the antisense strand are each 16-24 bases in length.

7. Pharmaceutical composition, according to claim 5 or 6, characterized in that the sense strip is 19 bases long.

8. Pharmaceutical composition according to claim 5 or 6, characterized in that the antisense strand is 21 bases long.

9. Pharmaceutical composition according to any one of claims 5 to 8, characterized in that the sense and antisense strands are modified.

10. Pharmaceutical composition according to claim 9, characterized in that the modifications are selected from the group consisting of 2'-methoxy (2'-OMe), 2'-fluorine (2'-F), 2'-O-methoxyethyl (2'-O-MOE), 5'-vinylphosphonate, phosphorothioate (PTO), blocked nucleic acid (LNA), blocked nucleic acid (UNA), glycol nucleic acid (GNA) and DNA.

11. Pharmaceutical composition according to claim 10, characterized in that the modifications of the sense strand comprise: 1) PTO at positions 1 and 2; 2) 2'-F in positions 3, 7-9, 12 and 17; and 3) 2'-OMe at positions 1, 2, 4-6, 10, 11, 13-16, 18 and 19.

12. Pharmaceutical composition according to claim 10, characterized in that the modifications of the antisense strand comprise: 1) PTO at positions 1, 2, 19 and 20; 2) 2'-F at positions 2 and 14; and 3) 2'-OMe at positions 1, 3-13 and 15-21.

13. Pharmaceutical composition according to any one of claims 5 to 12, characterized in that the last nucleotide of the sense strand is adenine (A).

14. Pharmaceutical composition, according to any one of claims 5 to 12, characterized in that the first nucleotide of the antisense strand is uracil (U). 15.Pharmaceutical composition, according to any one of claims 5 to 14, characterized in that the sense strand comprises a nucleotide sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% or 100% identity to the nucleotide sequence of any of the sense strands listed in Table 1 and Table 2.

16. Pharmaceutical composition, according to any one of claims 5 to 14, characterized in that the antisense strand comprises a nucleotide sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% or 100% identity to the nucleotide sequence of any of the antisense strands listed in Table 1 and Table 2.

17. Pharmaceutical composition, according with any one of claims 1 to 16, characterized in that the peptide to polynucleotide ratio is from about 2:1 to about 3.500:1, wherein the ratio is the molar ratio.

18. Pharmaceutical composition according to claim 17, characterized in that the molar ratio of peptide to polynucleotide is from about 5:1 to about 200:

1.

19. Pharmaceutical composition according to claim 17, characterized in that the molar ratio of peptide to polynucleotide is from about 100:

1.

20. Pharmaceutical composition according to claim 17, characterized in that the molar ratio of peptide to polynucleotide is from about 5:

1.

21. Pharmaceutical composition, according to any one of claims 1 to 20, characterized in that the peptide to polynucleotide ratio is from about 6:1 to about 18:1, wherein the ratio is the ratio of positively charged polymer amine groups to negatively charged nucleic acid phosphate groups. 22.Pharmaceutical composition, according to claim 21, characterized in that the peptide-to-polynucleotide charge ratio is about 12:

1.

23. Pharmaceutical composition, according to any one of claims 1 to 22, characterized in that the peptide-polynucleotide complex is a nanoparticle with a diameter of about 10 nm to about 300 nm.

24. Pharmaceutical composition, according to any one of claims 1 to 23, characterized in that the peptide-polynucleotide complex is coated with albumin and / or hyaluronic acid.

25. Pharmaceutical composition, according to any one of claims 1 to 24, characterized in that it further comprises a pharmaceutically acceptable carrier. 26.A method for treating a disease or disorder in an individual, characterized in that the method comprises administering to an individual a therapeutically effective amount of the pharmaceutical composition, as defined in any one of claims 1 to 25.

27. A method according to claim 26, characterized in that the disease or disorder is cancer.

28. A method according to claim 27, characterized in that the cancer is blood cancer or solid tumor cancer. Petition 870260073661, dated 07 / 24 / 2026, pp. 102 / 207.

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