The Therapeutic Potential of mRNA-Mediated Type III Collagen Delivery for Photoaged Skin

Background: Skin aging can be classified into intrinsic and extrinsic types, with photoaging representing a significant form of extrinsic aging. Photoaging is caused by prolonged exposure to ultraviolet (UV) radiation, resulting in cellular damage, collagen degradation, and the development of wrinkles and pigmentation changes; severe cases can even lead to skin cancer. This condition affects individual aesthetics and health and imposes a broader societal burden, including increased healthcare costs and reduced quality of life. Addressing photoaging is critical, as effective treatments can enhance skin health, improve mental well-being, and alleviate the burden on healthcare systems, highlighting the importance of preventive and therapeutic strategies. Objective: This study aimed to develop a novel drug based on human type III collagen mRNA (hCOL3A1 mRNA) and to investigate its role in treating UVB-induced skin photoaging. Methods: We designed and synthesized the complete hCOL3A1 mRNA sequence and encapsulated it in lipid nanoparticles for skin delivery. The expression of the hCOL3A1 mRNA drug in human fibroblasts was examined by in vitro experiments, and its potential therapeutic effects on UVB-induced aging, oxidative stress, and inflammation were evaluated. In addition, we evaluated the efficacy of the hCOL3A1 mRNA drug on UVB-induced skin photoaging by an in vivo model. Results: It was found that the hCOL3A1 mRNA drug was effective in reducing UVB-induced skin photoaging, suggesting that the hCOL3A1 mRNA drug could be used as a therapeutic intervention for UVB-induced photoaging and also providing a novel approach to restore aging skin by increasing endogenous collagen production and reducing oxidative and inflammatory damage Conclusion: hCOL3A1 mRNA-LNP, as a novel protein therapeutic approach, overcomes the limitations of retinoic acid (RA) therapy, provides a simpler and more efficient therapeutic option, and is expected to be a new treatment for skin photoaging. Overall design: RNA-seq profilling of balb/c-nude mice and UVB irradiation on their dorsal skin every other day for 8 weeks and tissue collection at day 28 ,The UV irradiation protocol started at an initial intensity equivalent to the minimal erythemal dose (MED) of 1 MED (60 mJ/cm²) for the first 2 weeks. The intensity was then gradually increased to 2 MED (120 mJ/cm²) in the third week, 3 MED (180 mJ/cm²) in the fourth week, and maintained at 4 MED (240 mJ/cm²) from the fifth to eighth week of the experiment.