Application of collagen mRNA-LNP in preparation of skin injury repairing medicine

Abstract

The invention discloses application of collagen mRNA-LNP in preparation of a medicine for repairing skin injury, and relates to the technical field of biomedicine. According to the invention, the mRNA for coding collagen is delivered through a specially designed LNP carrier, and is applied to an innovative scheme of preparing the skin injury repairing medicine, so that the healing speed of various skin injuries can be more effectively accelerated, and the healing period is shortened; the wound healing quality is improved, especially the formation of pathological scars is reduced or inhibited, and the regeneration of functional skin tissues is promoted. According to the invention, the safety problem is solved by utilizing the non-integration and transient expression characteristics of mRNA, the genome integration risk is avoided, and the immunogenicity is low; the efficiency problem is solved by means of the efficient delivery capacity of the LNP, and the protein expression level is high; moreover, the process is controllable, the action time is short, administration can be carried out according to needs, high safety is met, meanwhile, the cost is low, the blank of related technologies is perfectly filled up, and breakthrough significance is achieved.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the application of a collagen mRNA-LNP in the preparation of skin damage repair drugs. Background Technology

[0002] The skin is the largest organ in the human body and the first line of defense against external physical, chemical, and biological attacks. When the integrity of the skin is compromised due to trauma, burns, surgery, or disease (such as diabetes), the body initiates a complex and orderly biological process—wound healing. This process can be roughly divided into four overlapping phases: a) Hemostasis: Vasoconstriction, platelet aggregation to form a thrombus, and sealing the wound; b) Inflammation: Immune cells such as neutrophils and macrophages enter the wound, clearing bacteria and necrotic tissue, and releasing various cytokines; c) Proliferation: Fibroblasts proliferate and synthesize the extracellular matrix (mainly collagen), forming granulation tissue; simultaneously, endothelial cells proliferate to form new capillaries (angiogenesis), and epidermal cells migrate from the wound edge to the center to cover the wound surface (re-epithelialization); d) Remodeling: Granulation tissue gradually transforms into scar tissue, collagen fibers remodel, and their strength increases. This process may last for months or even years. However, in many cases, this natural healing process can be hindered or become abnormal. Acute wounds (such as surgical incisions) usually heal smoothly, but chronic wounds (such as diabetic foot ulcers, venous ulcers, pressure sores, etc.) may remain stagnant in the inflammatory phase for a long time, failing to enter the proliferative phase. This causes patients immense pain and a heavy financial burden. Furthermore, even with normal healing, the final healing product is often scar tissue that is inferior to normal skin in both function and appearance.

[0003] In related technologies, to address the aforementioned issues, researchers have explored various strategies, including passive or traditional approaches, as well as active approaches, to develop methods or products that can actively intervene in the healing process, accelerate wound closure, and improve healing quality (i.e., achieve regenerative repair rather than scarring). These strategies have demonstrated some effectiveness and practicality, improving wound healing to a certain extent, but all have significant drawbacks. For example, passive or traditional approaches mainly include: traditional dressings, such as gauze and medicated gauze, which primarily protect and absorb exudate but lack the function of actively promoting healing; and functional dressings, such as hydrogels, foam dressings, and alginate dressings, which provide a moist healing environment for the wound, but their healing-promoting effect remains limited. Active approaches mainly include: 1) exogenous growth factor / protein therapy: This is the most direct approach, applying purified recombinant growth factors directly to the wound, for example... The gel's active ingredient is recombinant human platelet-derived growth factor (rhPDGF); other growth factors under investigation include fibroblast growth factor (FGF) and epidermal growth factor (EGF). However, this approach has several drawbacks: poor stability and short half-life; the harsh wound environment, rich in proteases, makes exogenous proteins highly susceptible to degradation, leading to rapid loss of biological activity; low delivery efficiency and high cost; maintaining effective concentrations requires high doses and frequent administration, while the production cost of recombinant proteins is inherently high, significantly increasing treatment costs; and unsatisfactory pharmacokinetics, making it difficult to maintain a long-term, stable therapeutic window on the wound. 2) Cell therapy: using autologous or allogeneic cells to promote healing, such as skin transplantation and stem cell (especially mesenchymal stem cells, MSCs) therapy. However, this approach is complex to prepare and extremely costly: the isolation, culture, identification, and storage of cells are complex, difficult to standardize, and costly, hindering its widespread application; furthermore, there are safety and consistency issues: risks of immune rejection, tumorigenesis, and batch-to-batch functional inconsistencies exist. 3) Gene therapy (early forms): For example, plasmid DNA (pDNA) therapy involves directly injecting plasmid DNA encoding healing-promoting factors (such as VEGF and PDGF) into the wound; viral vector therapy uses adenovirus, adeno-associated virus (AAV), or retrovirus as vectors to deliver therapeutic genes to wound cells. Gene therapy also has significant drawbacks: plasmid DNA (pDNA) therapy has extremely low delivery efficiency; naked DNA has difficulty crossing the cell membrane, let alone entering the cell nucleus for transcription, resulting in very low protein expression levels and difficulty achieving therapeutic effects. Furthermore, there are safety risks; although the risk is relatively low, plasmid DNA still has the potential to randomly integrate into the host genome, which may lead to the activation of proto-oncogenes or the inactivation of tumor suppressor genes, causing cancer (i.e., insertion mutations). Viral vector therapy, on the other hand, is highly immunogenic. The human immune system recognizes and attacks the viral vector, triggering a strong inflammatory response. This not only reduces the effectiveness of treatment but may also harm the patient. Pre-existing immunity can also hinder the efficacy of the treatment. Moreover, it carries high safety risks. Integrating viruses (such as retroviruses) have a high risk of genome integration, and even non-integrating viruses pose a risk of generating replicating active viruses during the production process. In addition, this approach is complex and expensive to produce. Clinical-grade viral vectors have complex, costly, and time-consuming preparation processes.

[0004] Therefore, it is of great significance to address the current skin damage repair strategies' inability to simultaneously achieve high efficiency, stability, safety, and low cost, and to provide a skin damage repair strategy that can simultaneously satisfy the advantages of high safety (no risk of genome integration, low immunogenicity), high efficiency (high protein expression level), controllable action (short duration of action, can be administered on demand), and convenient production. Summary of the Invention

[0005] This invention aims to address at least one of the technical problems existing in the prior art. To this end, this invention proposes the application of collagen mRNA-LNP in the preparation of skin damage repair drugs, aiming to solve the problem that current skin damage repair strategies struggle to simultaneously achieve high efficiency, stability, safety, low cost, and convenient production.

[0006] An embodiment of the first aspect of the present invention provides the application of collagen mRNA-LNP in the preparation of skin damage repair drugs.

[0007] According to the first aspect of the present invention, the application has at least the following beneficial effects: The present invention proposes and verifies for the first time an innovative scheme for delivering collagen-encoding mRNA via a specially designed LNP (lipid nanoparticle) carrier in the preparation of skin damage repair drugs. Its mechanism of action is as follows: When a drug containing collagen mRNA-LNP is applied to the skin injury site, the LNP can protect the collagen mRNA from degradation and efficiently deliver it to skin cells (such as fibroblasts) at the skin injury site. Skin cells utilize their own translation system to temporarily and locally express large amounts of collagen. As a key component of the extracellular matrix, collagen can optimize the structure of newly formed tissues, regulate cell behavior, thereby significantly accelerating wound closure, improving healing quality, and potentially reducing scar formation. This invention applies mRNA-LNP technology to the development of drugs for treating skin injuries. It addresses safety concerns by utilizing the non-integrative and transient expression characteristics of mRNA, eliminating the risk of genomic integration and exhibiting low immunogenicity. Furthermore, it leverages the high-efficiency delivery capability of LNPs to overcome efficiency issues, resulting in high protein expression levels. The process is controllable, with a short duration of action, allowing for on-demand dosing and meeting high safety requirements while maintaining low cost. This innovation perfectly fills a gap in related technologies and is of groundbreaking significance. Ultimately, the innovative approach of applying collagen mRNA-LNP to the preparation of skin injury repair drugs proposed in this invention can more effectively accelerate the healing speed of various skin injuries, shorten the healing cycle, improve wound healing quality, particularly reducing or inhibiting the formation of pathological scars and promoting the regeneration of functional skin tissue. Moreover, this approach can synergistically promote wound healing through multiple targets and pathways, rather than targeting only a single stage of the healing process. In addition, this approach has the advantages of good safety, low cost, and ease of application, enabling the further development of various new skin injury treatment products and wide application in various types of skin injuries, including acute trauma and chronic, difficult-to-heal wounds caused by various reasons.

[0008] In some embodiments of the present invention, the collagen mRNA-LNP comprises an LNP vector loaded with at least one collagen mRNA.

[0009] In some embodiments of the present invention, the ratio of the LNP vector to mRNA is (4-10):1.

[0010] In some embodiments of the present invention, the LNP carrier includes at least one of ionizable amino lipids, PEG lipids, phospholipids, and cholesterol, but is not limited thereto.

[0011] In some embodiments of the present invention, the ionizable amino lipids refer to a class of lipid molecules containing an amino group (-NH2 or -NR2, where R is an alkyl group) and capable of ionization under specific conditions, including but not limited to ALC0315 or SM102.

[0012] In some embodiments of the present invention, the PEG lipid (polyethylene glycol-modified lipid) is a type of lipid molecule modified with polyethylene glycol (PEG), including but not limited to ALC0159 (DMG-PEG2000).

[0013] In some embodiments of the present invention, the phospholipids are a class of lipids containing phosphoric acid and are the main components of biological membranes, including but not limited to glycerophospholipids, sphingomyelins, or other phospholipids.

[0014] In some embodiments of the present invention, the glycerophospholipids include, but are not limited to, lecithin (phosphatidylcholine), cephalin (phosphatidylethanolamine), serine phospholipids (phosphatidylserine), inositol phospholipids (phosphatidylinositol), or phosphatidylglycerol.

[0015] In some specific embodiments of the present invention, the phospholipid is selected from glycerophospholipids, the glycerophospholipid is selected from lecithin (phosphatidylcholine), and the lecithin (phosphatidylcholine) is selected from DSPC (disteaaroylphosphatidylcholine).

[0016] In some embodiments of the present invention, the collagen mRNA comprises one or more chemical modifications. Preferably, the chemical modification includes replacing uridine with N1-methylpseudouridine.

[0017] To improve stability and expression efficiency, this invention modifies collagen mRNA in one or more ways. For example, uridine is replaced with N1-methylpseudouridine, and A, C, and G are conventional NTPs.

[0018] In some embodiments of the present invention, the collagen mRNA comprises one or more structural elements. Preferably, the structural elements comprise: a 5' cap structure (Cap 1), optimized 5' and 3' untranslated regions (UTRs), and a 3' poly(A) tail.

[0019] In some embodiments of the present invention, the collagen includes at least one of COL11A1, COL1A1, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL6A6, COL12A1, COL17A1, COL18A1, COL28A1, or COLGALT1. The collagen family is the most abundant protein in mammals, widely distributed in the dermis, accounting for 70% of the skin's composition. It possesses both protective functions and appropriate elasticity and firmness.

[0020] In some embodiments of the present invention, the skin injury includes chronic healing injury or acute healing injury.

[0021] In some embodiments of the present invention, the chronically healing injury includes at least one of diabetic foot ulcers, pressure ulcers, or venous ulcers, but is not limited thereto.

[0022] In some embodiments of the present invention, the acute healing injury includes at least one of burns, surgical incisions, or trauma, but is not limited thereto.

[0023] The collagen mRNA-LNP protocol of this invention can be applied to treat various chronic, slow-healing wounds (such as diabetic foot ulcers, pressure sores, and venous ulcers) and can accelerate the healing of acute wounds (such as burns, surgical incisions, and external injuries). In addition, the aforementioned collagen mRNA-LNP protocol can also be applied in the field of medical aesthetics to improve skin repair after laser treatments, microneedling, and other procedures. This protocol not only actively intervenes in the healing process, accelerating the healing speed of various skin wounds and shortening the healing cycle, but also improves the quality of healing, particularly reducing or inhibiting the formation of pathological scars, promoting the regeneration of functional skin tissues, and achieving regenerative repair rather than scarring.

[0024] In some embodiments of the present invention, the skin damage repair agent includes, but is not limited to, at least one of topical preparations, injections, skin dressings, or biomaterial complexes.

[0025] Specifically, the topical preparation includes, but is not limited to, gels or sprays.

[0026] Specifically, the skin dressing includes, but is not limited to, foam dressings, alginate dressings, or other commonly used dressings.

[0027] In some embodiments of the present invention, the skin damage repair drug is administered topically.

[0028] In some embodiments of the present invention, the administration method of the skin damage repair drug includes at least one of intradermal injection, injection around the skin damage wound, or direct contact with the skin damage wound.

[0029] Specifically, direct contact with the skin injury includes applying directly to the skin injury, directly covering the skin injury, or other reasonable methods of administration.

[0030] In some embodiments of the present invention, the administration regimen of the skin damage repair drug includes single or multiple administrations, and the administration frequency can be adjusted according to the type and severity of the skin damage, for example, once every 3 to 7 days.

[0031] In one specific embodiment of the present invention, an application of COL11A1 mRNA-LNP in the preparation of a skin damage repair drug is provided.

[0032] Collagen type XI, alpha 1 (COL11A1) is a member of the collagen family. This invention proposes and validates for the first time an innovative approach to deliver COL11A1 mRNA via an LNP vector for the preparation of drugs to repair skin injuries. The mechanism of action is as follows: When a drug containing COL11A1 mRNA-LNP is applied to the site of skin injury, the LNP protects the COL11A1 mRNA from degradation and efficiently delivers it to skin cells (such as fibroblasts) at the wound site. Skin cells then temporarily and locally express large amounts of collagen COL11A1 using their own translation system. As a key component of the extracellular matrix, COL11A1 protein can optimize the structure of newly formed tissue, regulate cell behavior, thereby significantly accelerating wound closure, improving healing quality, and potentially reducing scar formation. This invention applies mRNA-LNP technology to the development of drugs for treating skin wounds. It solves the safety problem by utilizing the non-integrative and transient expression characteristics of mRNA, with no risk of genome integration and low immunogenicity. It also solves the efficiency problem by leveraging the high-efficiency delivery capability of LNP, resulting in high protein expression levels. Moreover, the process is controllable, the duration of action is short, and it can be administered on demand, meeting the requirements of high safety and low cost. It perfectly fills the gap in related technologies and has groundbreaking significance.

[0033] The innovative approach proposed in this invention for applying COL11A1 mRNA-LNP to the preparation of skin damage repair drugs has the following beneficial effects:

[0034] 1) Significant healing-promoting effect: The COL11A1 gene and its products of the present invention can promote the key links of wound healing through multiple pathways and synergistically, thereby significantly accelerating wound closure and shortening healing time. It shows superior therapeutic potential, especially for chronic and difficult-to-heal wounds that are difficult to treat by traditional methods.

[0035] 2) Improve healing quality and reduce scar formation: COL11A1 not only accelerates healing, but more importantly, it can regulate ECM remodeling, promote more orderly collagen deposition and tissue regeneration, thereby potentially significantly reducing excessive scar formation, improving the appearance and function of the skin after healing, and improving the patient's quality of life.

[0036] 3) Wide applicability: The solution provided by this invention can be applied to a variety of skin injuries, including acute trauma and chronic, difficult-to-heal wounds caused by various reasons.

[0037] 4) Diverse drug delivery strategies: COL11A1 can be delivered in various forms such as LNP and microneedles, and can be prepared into various local application dosage forms or combined with other treatment methods (such as biomaterial scaffolds), providing flexibility and convenience for clinical applications.

[0038] 5) Safety advantages: COL11A1 is an endogenously expressed molecule, and its exogenous supplementation or endogenous activation has good biocompatibility and low immunogenicity risk.

[0039] 6) Potential application value: This invention verifies that COL11A1, as a key regulatory factor, has a significant effect on promoting wound healing, providing a novel molecular target and treatment idea for the subsequent development of new drugs targeting wound healing disorders.

[0040] In some embodiments of the present invention, the COL11A1 mRNA-LNP comprises an LNP vector loaded with COL11A1 mRNA.

[0041] In some embodiments of the present invention, the ratio of the LNP vector to mRNA is (4-10):1.

[0042] In some embodiments of the present invention, the LNP carrier includes at least one of ionizable amino lipids, PEG lipids, phospholipids, and cholesterol, but is not limited thereto.

[0043] In some embodiments of the present invention, the COL11A1 mRNA comprises one or more chemical modifications. Preferably, the chemical modification includes replacing uridine with N1-methylpseudouridine.

[0044] To improve stability and expression efficiency, the present invention performs one or more chemical modifications on the mRNA of COL11A1. For example, uridine is replaced with N1-methylpseudouridine, and A, C, and G are conventional NTPs.

[0045] In some embodiments of the present invention, the COL11A1 mRNA comprises one or more structural elements. Preferably, the structural elements comprise: a 5' capped structure (Cap 1), optimized 5' and 3' untranslated regions (UTRs), and a 3' poly(A) tail.

[0046] In some embodiments of the present invention, the skin injury includes chronic healing injury or acute healing injury.

[0047] In some embodiments of the present invention, the chronically healing injury includes at least one of diabetic foot ulcers, pressure ulcers, or venous ulcers, but is not limited thereto.

[0048] In some embodiments of the present invention, the acute healing injury includes at least one of burns, surgical incisions, or trauma, but is not limited thereto.

[0049] In some embodiments of the present invention, the skin damage repair agent includes, but is not limited to, at least one of topical preparations, injections, skin dressings, or biomaterial complexes.

[0050] Specifically, the topical preparation includes, but is not limited to, gels or sprays.

[0051] Specifically, the skin dressing includes, but is not limited to, foam dressings, alginate dressings, or other commonly used dressings.

[0052] In some embodiments of the present invention, the skin damage repair drug is administered topically.

[0053] In some embodiments of the present invention, the administration method of the skin damage repair drug includes at least one of intradermal injection, injection around the skin damage wound, or direct contact with the skin damage wound.

[0054] Specifically, direct contact with the skin injury includes applying directly to the skin injury, directly covering the skin injury, or other reasonable methods of administration.

[0055] A second aspect of the present invention provides the use of collagen mRNA-LNP in at least one of (a1) to (a5), said use being for non-diagnostic or therapeutic purposes:

[0056] (a1) Develop and / or prepare products that promote the healing of skin wounds;

[0057] (a2) Develop and / or prepare products that promote ECM remodeling of skin cells;

[0058] (a3) Develop and / or prepare products that promote the regeneration of collagen tissue in skin cells;

[0059] (a4) Develop and / or prepare products for repairing skin scars or scar tissue;

[0060] (a5) Construct a skin damage repair model;

[0061] The collagen mRNA-LNP includes an LNP vector loaded with at least one collagen mRNA.

[0062] In some embodiments of the present invention, the collagen includes at least one of COL11A1, COL1A1, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL6A6, COL12A1, COL17A1, COL18A1, COL28A1, or COLGALT1.

[0063] In some embodiments of the present invention, the collagen mRNA-LNP is as described above.

[0064] In some embodiments of the present invention, the product includes at least one of a drug, a pharmaceutical composition, a cosmetic, or a biological material.

[0065] In some embodiments of the present invention, the drug, pharmaceutical composition, or cosmetic further includes pharmaceutically or cosmetically acceptable excipients.

[0066] In some embodiments of the present invention, the categories of cosmetics include serums, lotions, creams, and masks.

[0067] In some embodiments of the present invention, the cosmetic ingredients further include at least one of glycerin, hyaluronic acid, propylene glycol, or butylene glycol.

[0068] In some embodiments of the present invention, the cosmetic is prepared by adding pharmaceutically or cosmetically acceptable excipients or auxiliary ingredients to the above-mentioned COL11A1 composition as the active ingredient.

[0069] In some embodiments of the present invention, the cosmetics include aqueous solutions, emulsions, creams, powders, gels, jelly, serums, or masks.

[0070] In some embodiments of the present invention, the acceptable excipients include at least one of diluents, binders, wetting agents, humectants, thickeners, solvents, emulsifiers, cosolvents, preservatives, pH adjusters, osmotic pressure adjusters, surfactants, and buffers.

[0071] In some embodiments of the present invention, the auxiliary ingredients include at least one of whitening agents, emollients, anti-acne agents, ultraviolet absorbers, and skin conditioning agents.

[0072] In some embodiments of the present invention, the auxiliary ingredients further include at least one of collagen, vitamins, tea polyphenols, and coenzyme Q10.

[0073] In some embodiments of the invention, the application also includes the development of biomaterials.

[0074] The collagen mRNA-LNP of this invention holds great promise for the development of biomaterials. For example, it can be formulated into various topical dosage forms and combined with other therapeutic methods (such as biomaterial scaffolds) as a novel treatment for skin injuries. Furthermore, it may possess excellent tissue engineering properties and can be used as a 3D-printed scaffold material to promote tissue regeneration and repair.

[0075] In some embodiments of the present invention, the application further includes building a drug screening platform.

[0076] This invention discovers a novel therapeutic target for skin damage repair: COL11A1, a member of the collagen family, is a newly discovered key regulatory factor, providing a novel molecular target and therapeutic approach for developing new drugs targeting wound healing disorders. It can be used as a high-throughput screening platform for novel drugs, helping to rapidly discover and validate new drug targets with clinical value.

[0077] The aforementioned applications provide a solid foundation for technological advancements in multiple fields and demonstrate broad market value and social benefits.

[0078] A third aspect of the present invention provides the use of a COL11A1 composition in the preparation of a skin damage repair drug, the COL11A1 composition comprising a COL11A1 active ingredient and a delivery carrier;

[0079] The active ingredient of COL11A1 includes at least one of the following (b1) to (b8):

[0080] (b1) COL11A1 polypeptide or its biologically active fragment;

[0081] (b2) Nucleic acid molecules encoding the COL11A1 polypeptide or its active fragment;

[0082] (b3) When (b2) is included, the nucleic acid molecule includes mRNA;

[0083] (b4) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more chemical modifications;

[0084] (b5) When (b4) is included, the chemical modification includes: replacing uridine with N1-methylpseudouridine;

[0085] (b6) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more structural elements;

[0086] (b7) When including (b6), the structural element includes: a 5' end capped structure, optimized 5' and 3' untranslated regions, or a 3' end Poly(A) tail;

[0087] (b8) When (b3) is included, the delivery carrier includes an LNP.

[0088] The COL11A1 composition provided by this invention comprises a therapeutically effective amount of COL11A1 active ingredient, wherein the COL11A1 active ingredient is selected from at least one of the following:

[0089] a) Type XI collagen α1 chain (COL11A1) polypeptide or its biologically active fragment;

[0090] b) A nucleic acid molecule encoding the COL11A1 polypeptide or its active fragment.

[0091] Preferably, the nucleic acid molecule is messenger RNA (mRNA); when the active ingredient is a nucleic acid molecule (especially mRNA), the COL11A1 composition further comprises a delivery carrier for delivering the nucleic acid molecule to skin target cells; the delivery carrier is preferably a lipid nanoparticle (LNP).

[0092] In some embodiments of the present invention, the above-described COL11A1 composition is provided for the following applications: preparing products that promote skin wound healing; and / or preparing products that promote ECM remodeling of skin cells; and / or preparing products that promote collagen tissue regeneration of skin cells; and / or preparing products that repair skin scars or scar tissue; and / or constructing skin damage repair models.

[0093] In some embodiments of the present invention, the product includes at least one of a drug, a pharmaceutical composition, a cosmetic, or a biological material.

[0094] In some embodiments of the present invention, the drug, pharmaceutical composition, or cosmetic further includes pharmaceutically or cosmetically acceptable excipients.

[0095] In some embodiments of the present invention, the categories of cosmetics include serums, lotions, creams, and masks.

[0096] In some embodiments of the present invention, the cosmetic ingredients further include at least one of glycerin, hyaluronic acid, propylene glycol, or butylene glycol.

[0097] In some embodiments of the present invention, the cosmetic is prepared by adding pharmaceutically or cosmetically acceptable excipients or auxiliary ingredients to the above-mentioned COL11A1 composition as the active ingredient.

[0098] In some embodiments of the present invention, the cosmetics include aqueous solutions, emulsions, creams, powders, gels, jelly, serums, or masks.

[0099] In some embodiments of the present invention, the acceptable excipients include at least one of diluents, binders, wetting agents, humectants, thickeners, solvents, emulsifiers, cosolvents, preservatives, pH adjusters, osmotic pressure adjusters, surfactants, and buffers.

[0100] In some embodiments of the present invention, the auxiliary ingredients include at least one of whitening agents, emollients, anti-acne agents, ultraviolet absorbers, and skin conditioning agents.

[0101] In some embodiments of the present invention, the auxiliary ingredients further include at least one of collagen, vitamins, tea polyphenols, and coenzyme Q10.

[0102] A fourth aspect of the present invention provides a skin damage repair medicament comprising a COL11A1 composition, said COL11A1 composition comprising a COL11A1 active ingredient and a delivery carrier;

[0103] The active ingredient of COL11A1 includes at least one of the following (b1) to (b8):

[0104] (b1) COL11A1 polypeptide or its biologically active fragment;

[0105] (b2) Nucleic acid molecules encoding the COL11A1 polypeptide or its active fragment;

[0106] (b3) When (b2) is included, the nucleic acid molecule includes mRNA;

[0107] (b4) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more chemical modifications;

[0108] (b5) When (b4) is included, the chemical modification includes: replacing uridine with N1-methylpseudouridine;

[0109] (b6) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more structural elements;

[0110] (b7) When including (b6), the structural element includes: a 5' end capped structure, optimized 5' and 3' untranslated regions, or a 3' end Poly(A) tail;

[0111] (b8) When (b3) is included, the delivery carrier includes an LNP.

[0112] In some embodiments of the present invention, the skin injury includes chronic healing injury or acute healing injury.

[0113] In some embodiments of the present invention, the chronically healing injury includes at least one of diabetic foot ulcers, pressure ulcers, or venous ulcers, but is not limited thereto.

[0114] In some embodiments of the present invention, the acute healing injury includes at least one of burns, surgical incisions, lacerations, abrasions, or trauma, but is not limited thereto.

[0115] In some embodiments of the present invention, the skin scar or scar tissue includes hypertrophic scars or keloids.

[0116] In some embodiments of the present invention, the skin damage repair agent includes, but is not limited to, at least one of topical preparations, injections, skin dressings, or biomaterial complexes.

[0117] Specifically, the topical preparation includes, but is not limited to, gels or sprays.

[0118] Specifically, the skin dressing includes, but is not limited to, foam dressings, alginate dressings, or other commonly used dressings.

[0119] In some embodiments of the present invention, the skin damage repair drug is administered topically.

[0120] In some embodiments of the present invention, the administration method of the skin damage repair drug includes at least one of intradermal injection, injection around the skin damage wound, or direct contact with the skin damage wound.

[0121] Specifically, direct contact with the skin injury includes applying directly to the skin injury, directly covering the skin injury, or other reasonable methods of administration.

[0122] In some embodiments of the present invention, the administration regimen of the skin damage repair drug includes single or multiple administrations, and the administration frequency can be adjusted according to the type and severity of the skin damage, for example, once every 3 to 7 days.

[0123] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention may be realized and obtained by means of the structures particularly pointed out in the description, claims, and drawings. Attached Figure Description

[0124] Figure 1 The structural diagram of plasmid COL11A1-pU57-KAN provided in the embodiments of the present invention;

[0125] Figure 2 This is a schematic diagram of the verification results (agarose gel electrophoresis) of the plasmid prepared in Example 1 of the present invention;

[0126] Figure 3 The images show the distribution of Flu-eGFP mRNA 6 hours after injection of 1 μg (left image) and 10 μg (right image) Flu-eGFP mRNA-LNP in Example 2 of this invention.

[0127] Figure 4 The images show the distribution of Flu-eGFP mRNA 24 hours after injection of 1 μg (left image) and 10 μg (right image) Flu-eGFP mRNA-LNP in Example 2 of this invention.

[0128] Figure 5 The images show the distribution of Flu-eGFP mRNA 48 hours after injection of 1 μg (left image) and 10 μg (right image) Flu-eGFP mRNA-LNP in Example 2 of this invention.

[0129] Figure 6 The images show the distribution of Flu-eGFP mRNA 72 hours after injection of 1 μg (left image) and 10 μg (right image) Flu-eGFP mRNA-LNP in Example 2 of this invention.

[0130] Figure 7 The graphs show the mRNA decay curves at 6h, 24h, 48h, 72h, and 96h after injection of 1μg and 10μg Fluc-eGFP mRNA-LNP in Example 2 of this invention.

[0131] Figure 8 This is a schematic diagram of the HE staining results of the slides used in the modeling test in Embodiment 3 of the present invention;

[0132] Figure 9 This is a schematic diagram showing the effect of Fluc-eGFP mRNA-LNP on promoting healing in a mouse skin burn model in Example 3 of the present invention;

[0133] Figure 10 This is a schematic diagram showing the results of the healing-promoting effect of COL11A1 mRNA-LNP in a mouse skin burn model in Example 3 of the present invention;

[0134] Figure 11 This is a schematic diagram of the HE staining results of mouse skin sections in the COL11A1 mRNA-LNP administration group in Example 3 of the present invention - 1;

[0135] Figure 12 This is a schematic diagram of the HE staining results of mouse skin sections in the COL11A1 mRNA-LNP administration group in Example 3 of the present invention - 2;

[0136] Figure 13 This is a schematic diagram of the HE staining results of mouse skin sections in the Fluc-eGFP mRNA-LNP administration group in Example 3 of the present invention - 1;

[0137] Figure 14 This is a schematic diagram of the HE staining results of mouse skin sections in the Fluc-eGFP mRNA-LNP administration group in Example 3 of the present invention. Detailed Implementation

[0138] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0139] In the description of this invention, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0140] In the description of this invention, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, where a and b are both real numbers. Unless otherwise stated, the various reaction or operation steps may be performed sequentially or not. Preferably, the reaction methods in this invention are performed sequentially.

[0141] Experimental methods in the following examples, unless otherwise specified, are generally performed under standard conditions or as recommended by the manufacturer. Unless otherwise specified, the materials and reagents used in these examples are commercially available.

[0142] Example 1: Construction of COL11A1 mRNA-LNP

[0143] 1. Construction of COL11A1 mRNA template

[0144] First, the CDS sequence of COL11A1 was determined (refer to the NCBI sequence library for details). The CDS sequence was then optimized using rat codons to ensure it did not contain the BspQI site. Next, it was chemically modified to replace uridine with N1-methylpseudouridine. Then, corresponding structural elements were added to enhance its function, including: a 5' cap structure (Cap1), optimized 5' and 3' untranslated regions (UTR), and a 3' poly(A) tail.

[0145] Finally, a linear DNA template containing the T7 promoter, 5' untranslated region (UTR), open reading frame (ORF) encoding the COL11A1 protein, 3' UTR, and Poly(A) tail sequence was constructed.

[0146] Based on the above mRNA synthesis requirements, the corresponding sequence was designed and synthesized, and then ligated into the pU57-KAN vector to obtain the complete plasmid COL11A1-pU57-KAN (referred to as COL11A1 plasmid). The structural map of this plasmid is shown below. Figure 1 As shown, the complete plasmid sequence is as shown in SEQ ID NO: 1. Simultaneously, a fluorescent reporter mRNA plasmid was constructed: the COL11A1 gene sequence was replaced with the genes encoding enhanced green fluorescent protein (eGFP) and firefly luciferase (FLuc), and cloned into the same in vitro transcription vector pU57-KAN with a T7 promoter, optimized 5'-UTR, 3'-UTR, and Poly(A) tail. The constructed plasmid is Fluc-eGFP-pU57-KAN (abbreviated as GFP plasmid), and its sequence is as shown in SEQ ID NO: 2.

[0147] The synthesized plasmids were identified using first-generation sequencing to ensure their structural and sequence accuracy, which would be essential for the large-scale synthesis of mRNA templates. This part of the work was completed on the BGI synthesis platform.

[0148] 2. COL11A1 mRNA template synthesis

[0149] The correctly identified COL11A1 plasmid and GFP plasmid were expanded to obtain sufficient plasmids for in vitro mRNA transcription and LNP preparation.

[0150] (1) Transform the constructed COL11A1 plasmid and GFP plasmid template into competent cells: Thaw the Stbl3 supercompetent cells (Beyotime D1081M) (100μL) completely on ice, add 10μl of the constructed plasmid COL11A1-pU57-KAN or plasmid Flu-eGFP-pU57-KAN (100ng), mix gently, incubate on ice for 30min, and then quickly place in a 42℃ water bath for 90s; add 800ul LB liquid medium (without kanamycin), and culture at 37℃ with shaking for 1h (150r / min).

[0151] The formula for LB medium is as follows:

[0152] 10g of tryptone;

[0153] 5g of yeast extract;

[0154] 10g of sodium chloride (NaCl);

[0155] Agar powder (LB solid medium only) 15-20g;

[0156] Add double-distilled water to 1000mL, adjust the pH to 7.2 with 5mol / L NaOH (about 0.2ml), and autoclave.

[0157] (2) Spreading: Take 50 μl of revived bacterial culture and spread it on selective LB solid medium containing kanamycin (Sangon A414917) resistance. Place the culture dish in a 37℃ constant temperature incubator and incubate for 30 min.

[0158] (3) Cultivation: After the bacterial solution is completely absorbed by the culture medium, invert the plate (to prevent condensation from dripping and affecting colony growth) and incubate overnight (about 13 hours) in a constant temperature incubator at 37°C until colonies appear.

[0159] (4) Picking single colonies: Using a sterile pipette tip or inoculation loop, pick 5 single colonies from the plate and add them to 5 bottles of 200ml LB liquid complete medium. Place them in a 37℃ constant temperature shaker and shake at 200-250rpm overnight (about 13h).

[0160] (5) Collecting bacteria: Centrifuge the turbid bacterial solution at high speed, discard the supernatant, and obtain bacterial precipitate.

[0161] (6) Plasmid extraction: Plasmids were extracted using the Tiangen endotoxin-free plasmid extraction kit (Tiangen, DP117) to obtain a high-purity plasmid DNA solution.

[0162] (7) Plasmid identification: The extracted plasmids are identified by first-generation sequencing to ensure their structure and sequence accuracy for the preparation of mRNA LNPs.

[0163] Each plasmid tube was digested with BspQ1 enzyme, and the reaction was carried out at 50°C for 1 hour; then at 80°C for 20 minutes to inactivate the BspQ1 enzyme. The reaction system is as follows:

[0164]

[0165] The extracted COL11A1 plasmid, GFP plasmid, and COL11A1 plasmid and GFP plasmid after single enzyme digestion were subjected to agarose gel electrophoresis to verify the correctness of the bands. The results are as follows: Figure 2 It can be seen that the plasmid bands extracted from Stbl3 competent cells after transformation by shaking were clear, and only a single band was observed after enzyme digestion. The bands were correct, and this template is suitable for the preparation of mRNA transcribed in vitro.

[0166] 3. Preparation of COL11A1 mRNA-LNP

[0167] (1) Plasmid linearization: Using a specific restriction endonuclease, a single cut is made at the end of the gene sequence encoding the plasmid to cut the circular plasmid into a linear DNA template. The correctness of the linear DNA template band is verified by agarose gel electrophoresis.

[0168] (2) In vitro transcription: Using linearized DNA as a template, a large number of mRNA molecules were synthesized, and the correct mRNA molecule bands were verified by agarose gel electrophoresis.

[0169] (3) Purification and quality control: Impurities (such as unreacted nucleotides, enzymes, DNA templates, etc.) in the reaction system are removed to obtain high-purity mRNA. The integrity and size of the mRNA are detected by gel electrophoresis, and its concentration and purity are determined by ultraviolet spectrophotometer.

[0170] (4) LNP preparation and quality control:

[0171] Lipid material formulations: ALC0315 (medkoo, 556006), ALC0159 (medkoo, 556014), DSPC (Avanti, 850365), Cholesterol (Echelon Biosciences, L-6012).

[0172] A lipid-ethanol solution was prepared according to the molar ratio of ALC0315:DSPC:Chol:ALC0159 (DMG-PEG2000) of 50:10:38.5:1.5. After determining the concentration of mRNA, it was diluted to the desired concentration using sodium citrate solution at pH 4 based on the lipid concentration. An LNP preparation device was constructed using a syringe pump, syringe, microfluidic chip, and connecting tubing. The ethanol solution of lipid molecules and the aqueous solution of mRNA were mixed in a specific ratio to obtain LNP-mRNA. The collected solution was diluted 50 times with PBS, purified by ultrafiltration, and the particle size, uniformity, and zeta potential of the LNP-mRNA were measured using a dynamic light scattering instrument. The nucleic acid content before and after demulsification with Triton X-100 solution was detected using the Quant-iTRiboGreen RNA reagent. The drug loading and encapsulation efficiency were calculated based on the difference in nucleic acid content.

[0173] The preparation results of COL11A1 mRNA-LNP and Fluc-eGFP mRNA-LNP are shown in Table 1 below:

[0174] Table 1

[0175] plasmid Total RNA (mg) Total LNP / mg Fluc-eGFP mRNA-LNP 1.5 0.7 COL11A1 mRNA-LNP 16 8

[0176] The prepared COL11A1 mRNA-LNP and Fluc-eGFP mRNA-LNP were characterized, including particle size, polydispersity index, encapsulation efficiency, and drug loading. The results are shown in Table 2 below.

[0177] Table 2

[0178]

[0179] The above results demonstrate that COL11A1 mRNA-LNP and Flux-eGFP mRNA-LNP were successfully prepared, and their characterization results are satisfactory, allowing for subsequent use.

[0180] Example 2: In vivo fluorescent transfection experiment of mRNA-LNP in mice

[0181] In vivo imaging experiments were performed in mice using high-purity Fluc-eGFP mRNA-LNP prepared in Example 1.

[0182] (1) Select two BALB / C mice aged 6-8 weeks and raise them in an SPF-grade environment.

[0183] (2) Hair removal was performed the day before the experiment. Hair was removed from the back of the mice in 2cm×2cm sections using a razor and hair removal cream.

[0184] (3) The Fluc-eGFP mRNA-LNP preparation was injected intradermally into the hairless area on the lower right back of mice.

[0185] (4) Single administration, with the LNP dose set at 1 μg and 10 μg, and the total volume controlled at 100 μL / mouse.

[0186] (5) Mice were intraperitoneally injected with D-luciferin substrate solution (D-Luciferin) (10 μL / g body weight, 200 μL / mouse, dissolved in PBS) at 6 h, 24 h, 48 h, 72 h, 96 h, and 168 h after drug administration. After waiting 5 minutes, mice were then subjected to in vivo imaging using a small animal imaging system. Spectrum CT (PerkinElmer) is used to perform bioluminescence imaging of the injection area in anesthetized mice.

[0187] (6) Data Analysis: Analysis is performed using the Living Image software included with IVIS. Regions of Interest (ROIs) are delineated on the image, such as the entire body or a specific organ. The software automatically calculates the total number of photons (photons / sec) or average radiance (p / sec / cm) within the ROI. 2 / sr).

[0188] In vivo imaging results as follows Figure 3-7 mRNA decay curves were plotted based on in vivo imaging results at different time points.

[0189] As shown in the figure, a strong bioluminescent signal was observed 6 hours after injection, indicating that the mRNA-LNP was successfully delivered and translated into the functional Fluc protein. The bioluminescent signal will be confined to the intradermal injection site, forming a bright spot.

[0190] This embodiment successfully demonstrates that, via intradermal injection, LNP can serve as a highly efficient carrier to deliver the corresponding mRNA to mouse skin and mediate the efficient, sustained, and highly localized expression of the target protein at the injection site.

[0191] Example 3: The healing-promoting effect of COL11A1 mRNA-LNP in a mouse skin burn model

[0192] The high-purity COL11A1 mRNA-LNP and Fluc-eGFP mRNA-LNP prepared in Example 1 were used to conduct a mouse skin burn healing experiment.

[0193] 1. Burn modeling test

[0194] (1) Three 8-week-old male C57BL / 6J mice were selected for scald modeling test to achieve the effect of second-degree burns.

[0195] (2) Shave the fur off the back of the mouse with a razor, apply hair removal cream to the shaved area on the back, cover for 3-4 minutes, wipe off the hair removal cream with a cotton ball, and remove the remaining fur.

[0196] (3) Connect a 1cm diameter ironing head to the metal ironing station (ZSAE936D digital display soldering station), plug in the power, adjust to the Celsius mode, set the temperature to 150℃, preheat for 10 minutes, so that the ironing head temperature reaches 150℃.

[0197] (4) Under anesthesia (isoflurane inhalation), a metal heating plate was used to model the lower right back of the mouse.

[0198] (5) Use a 1cm diameter ironing head, set the temperature to 150℃, and preheat for 10 minutes.

[0199] (6) Before the burn, press the skin around the burn with your hand until the burn is complete to prevent the wound from deteriorating due to skin wrinkling during the burn process. Use a metal burner tip to burn for 12 seconds to create a 1cm diameter wound. Postoperative analgesia should be given.

[0200] (7) Take a sample from the wound site 24 hours later and embed the sample in paraffin.

[0201] (8) Paraffin-embedded tissue sections were stained with hematoxylin and eosin (HE) to observe the degree of skin burns. The results are as follows: Figure 8 As shown in the figure, the entire epidermal structure has disappeared. Cell outlines may still be present, but cell nuclei have disappeared or shrunken. The epidermis has separated from the dermis, forming a clear gap between the epidermal layer and the underlying dermis. The superficial parts of hair follicles, sebaceous glands, and sweat glands are necrotic, but deeper structures (such as hair follicle stem cells) survive, indicating that the modeling was successful.

[0202] 2. The healing-promoting effect of mRNA-LNP in a mouse model of skin burns

[0203] (1) Twenty 8-week-old male C57BL / 6J mice were selected and hair was removed in the manner described above 2 days before the burn (D-2).

[0204] (2) After hair removal, the animals were randomly divided into two groups of five each and administered two types of LNPs: Flu-eGFP mRNA-LNP (10 μg) and COL11A1 mRNA-LNP (10 μg), with Flu-eGFP mRNA-LNP serving as a negative control.

[0205] (3) One day before the burn (D-1), a circle with a diameter of 1 cm was marked on the lower right abdomen of the mouse with a skin marker. The corresponding group of LNP was injected intradermally at four points along the edge of the circle: upper left, upper right, lower left, and lower right.

[0206] (4) On the second day after injection (D0), scald models were created in sequence according to the above modeling method to achieve the effect of second-degree burns.

[0207] (5) Observe the wound healing process daily and take photos for record-keeping. Take photos of the wound at a fixed distance and angle (with a ruler placed next to it). Use software such as ImageJ to analyze the wound area and calculate the wound healing rate (%). This is the primary indicator for evaluating the healing effect.

[0208] The photographic results of the Fluc-eGFP mRNA-LNP group and the COL11A1 mRNA-LNP group are as follows: Figure 9 , 10 As shown in the figure, the wound size in the COL11A1 mRNA-LNP treatment group was significantly smaller than that in the control group.

[0209] The above results indicate that the wound healing rate in the COL11A1 mRNA-LNP treatment group was significantly faster than that in the control group. This suggests that by encapsulating COL11A1 mRNA into LNP and injecting LNP locally into the skin layer, the mRNA is efficiently released and expresses a large amount of collagen in mice, thereby significantly accelerating wound closure.

[0210] 3. HE staining analysis of a mouse scald model

[0211] (1) On day 19 after injection, the mice were euthanized in accordance with the protocol approved by the Institutional Animal Ethics Committee (IACUC).

[0212] (2) Fix the mouse in a prone position and gently wipe the area around the wound with an alcohol swab.

[0213] (3) Perform a full-thickness skin excision biopsy using surgical scissors and forceps. The excised sample must be large enough to include: the center of the wound (healed scar tissue), the wound edges (the junction of healing and healing), and adjacent normal skin (as a perfect internal control). Lay the tissue sample flat on a paraffin embedding cassette to prevent curling.

[0214] (4) Label the drug administration group, sampling days and collection date respectively, and immediately place them in fixative to fix for at least 24 hours to prevent tissue autolysis and putrefaction, and to harden the tissue for subsequent processing.

[0215] (5) The fixed tissue was dehydrated by passing it through a series of ethanols, and the xylene was used to make it transparent. The transparent tissue was then immersed in melted paraffin. The immersed tissue was placed in a mold, and after adjusting its orientation, it was embedded in paraffin to form a solid wax block.

[0216] (6) Fix the wax block on the microtome and cut it into continuous thin slices with a thickness of 4-5 micrometers. Float the cut wax slices on a warm water bath to flatten them, then lift them out with a glass slide and bake them in an oven at 60°C to ensure that the tissue slices adhere tightly to the glass slide.

[0217] (7) Pass the glass slide through xylene and gradient ethanol (from high concentration to low concentration) in sequence, and finally into water to remove paraffin and rehydrate the tissue.

[0218] (8) Stain the cell nuclei with hematoxylin solution to make them blue-purple. Remove excess hematoxylin dye with a weak acid (such as acidic alcohol), and then use a weak alkaline water (such as tap water or blueing solution) to make the cell nuclei appear clear blue. Counterstain with eosin solution to make the cytoplasm and extracellular matrix (such as collagen) stain pink in different shades.

[0219] (9) Finally, seal the coverslip with neutral resin to make a permanent slide that can be preserved for a long time.

[0220] HE-stained sections were scanned using a slide scanner, and the results are as follows: Figure 11-14 .

[0221] As shown in the figure, by comparing with normal skin areas, the healing quality of the COL11A1 mRNA-LNP treatment group can be clearly assessed, such as scar thickness and collagen arrangement regularity, which are significantly better than those of the control group.

[0222] The above is a detailed description of the preferred embodiments of this application. However, this application is not limited to the above embodiments. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of this application. All such equivalent modifications or substitutions are included within the scope defined by the claims of this application.

Claims

1. Application of a collagen mRNA-LNP in the preparation of skin damage repair drugs.

2. The application according to claim 1, characterized in that, The collagen mRNA-LNP includes an LNP vector loaded with at least one collagen mRNA.

3. The application according to claim 1 or 2, characterized in that, The collagen includes at least one of COL11A1, COL1A1, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL6A6, COL12A1, COL17A1, COL18A1, COL28A1, or COLGALT1.

4. The application according to claim 1, characterized in that, The skin lesions include chronic healing lesions or acute healing lesions.

5. The application according to claim 4, characterized in that, The chronic healing injury includes at least one of diabetic foot ulcer, pressure ulcer, or venous ulcer; And / or, the acute healing injury includes at least one of burns, surgical incisions, or trauma.

6. The application according to claim 1, characterized in that, The types of skin damage repair drugs include at least one of topical preparations, injectable preparations, skin dressings, or biomaterial complexes; And / or, the administration method of the skin damage repair drug includes at least one of intradermal injection, injection around the skin damage wound, or direct contact with the skin damage wound.

7. The application of a collagen mRNA-LNP in at least one of (a1) to (a5): (a1) Develop and / or prepare products that promote the healing of skin wounds; (a2) Develop and / or prepare products that promote ECM remodeling of skin cells; (a3) Develop and / or prepare products that promote the regeneration of collagen tissue in skin cells; (a4) Develop and / or prepare products for repairing skin scars or scar tissue; (a5) Construct a skin damage repair model; The collagen mRNA-LNP includes an LNP vector loaded with at least one collagen mRNA.

8. The application according to claim 7, characterized in that, The product includes at least one of a drug, a pharmaceutical composition, a cosmetic, or a biological material.

9. The application according to claim 8, characterized in that, The drugs, pharmaceutical compositions, and cosmetics also include pharmaceutically or cosmetically acceptable excipients.

10. The use of a COL11A1 composition in the preparation of a skin damage repair medicament, said COL11A1 composition comprising a COL11A1 active ingredient and a delivery carrier; The active ingredient of COL11A1 includes at least one of the following (b1) to (b8): (b1) COL11A1 polypeptide or its biologically active fragment; (b2) Nucleic acid molecules encoding the COL11A1 polypeptide or its active fragment; (b3) When (b2) is included, the nucleic acid molecule includes mRNA; (b4) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more chemical modifications; (b5) When (b4) is included, the chemical modification includes: replacing uridine with N1-methylpseudouridine; (b6) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more structural elements; (b7) When including (b6), the structural element includes: a 5' end capped structure, optimized 5' and 3' untranslated regions, or a 3' end Poly(A) tail; (b8) When (b3) is included, the delivery carrier includes an LNP.

11. A skin damage repair drug, characterized in that, The composition includes a COL11A1 composition comprising an active ingredient of COL11A1 and a delivery carrier; The active ingredient of COL11A1 includes at least one of the following (b1) to (b8): (b1) COL11A1 polypeptide or its biologically active fragment; (b2) Nucleic acid molecules encoding the COL11A1 polypeptide or its active fragment; (b3) When (b2) is included, the nucleic acid molecule includes mRNA; (b4) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more chemical modifications; (b5) When (b4) is included, the chemical modification includes: replacing uridine with N1-methylpseudouridine; (b6) When (b3) is included, the mRNA encoding the COL11A1 polypeptide or its active fragment contains one or more structural elements; (b7) When including (b6), the structural element includes: a 5' end capped structure, optimized 5' and 3' untranslated regions, or a 3' end Poly(A) tail; (b8) When (b3) is included, the delivery carrier includes an LNP.

Images