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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE284483 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:Aging is characterized by a gradual decline in function, partly due to molecular damage that accumulates over time. Human skin is highly susceptible to both chronological aging and environmental damage in the form of UV photoaging. This results in detrimental structural and physiological changes with age. In this study we sought to comprehensively address both chronological and photoaging at the single-cell level, and to explore genetic and environmental factors, revealing their influences on the aging process. We included samples from young, middle-aged, and old individuals, and with these samples, we compared chronological aging and photoaging. Utilizing single-cell RNA sequencing, we created a comprehensive human skin cell atlas, that offers insights into the cellular composition and functions. We investigated the renewal ability of epidermis stem cells as they age and extended the study to fibroblasts, hair follicles, and endothelial cells. Examining the genetic landscape of aging in keratinocytes, we identified two distinct "gene modules" with altered gene expression during aging. Furthermore, we uncovered that skin aging involves interactions between epidermal keratinocytes and dermal fibroblasts, as well as extensive communication of keratinocytes with various other skin cell types as revealed through ligand-receptor pairs. Interactions, such as COL17A1-A1b1complex, highlighted a direct link between keratinocytes and fibroblast stimulation for collagen production. Most importantly, A key gene, MYO1, associated with skin aging was identified, leading to the development of an innovative mRNA treatment aimed at promoting skin rejuvenation by targeting this gene. Experimental results demonstrated that the mRNA treatment reduces basal stem cell senescence, increases basal stem cell proliferation, and enhances collagen production in fibroblasts via keratinocyte-fibroblast communication. The MYO1-targeted treatment is validated as an effective strategy for reversing skin aging by targeting cellular mechanisms.

Project description:UVA1 makes up ~75% terrestrial ultraviolet radiation (UVR) is increasingly being used for the treatment for inflammatory skin disorders. It is also the major UVR spectral source in tanning lamps, however we lack human data to understand its effects on gene expression and further consequences. Using erythemally equivalent doses of UVA1 (50J/cm2) and UVB (30mJ/cm2) ~1MED (minimal erythema dose), this study examines time dependent whole genome expression, mRNA and protein changes in 12 skin types I/II individuals. The top upregulated pathway at 6h is inflammation through IL17 signaling for UVA1 (p=1.16e-6) and UVB (p=2.1e-4). At 24h the top upregulated pathway is extracellular matrix remodeling for UVA1 (p=5.5e-7) and UVB (p=2.9e-22). We show key spectral differences with matrix metalloproteinases (MMP): UVB upregulates MMP1 mRNA (p=0.0062), MMP3 mRNA (p=0.0016), MMP10 mRNA (p=0.028) at 24h compared to UVA1, MMP12 mRNA is upregulated by UVA1 at 6h and not by UVB (p=0.02). In a further 3 skin type I/II we show that MMP12 protein is formed by UVA1 (p=0.04) at 24h and that DQM-bM-^DM-" collagen type IV(likely MMP12 activity) hydrolysis occurs by UVA1 (p=0.027) at 10h. DQM-bM-^DM-" collagen type I hydrolysis occurs predominantly by UVB at 24h (p=0.031). Both UVA1 and UVB upregulate MMP1 at 10h and 24h. There is more MMP1 and MMP12 protein and activity in the epidermis than in dermis in all volunteers. We conclude that the biological processes that occur after 24h in human skin in vivo in response to erythemally equivalent doses of UVA1 and UVB are similar however there are key spectral differences: UVB plays a larger role in upregulating key MMPs in the epidermis. MMP12 is a UVA1 specific biomarker found predominantly in the epidermis and maybe useful as a marker of UVA1 exposure. We hypothesise that its formation by UVA1 could be related to the ability of UVA1 to produce significantly more oxidatively generated DNA than UVB (8oxodG). 47 samples were processed. The RNA was isolated from human skin samples of individual donors pre- or post irradiation with UVA or UVB. Skin biopsies were taken either before, 6h post, or 24h post exposure. Different doses of UVA were applied. Each condition was available from five or nine individuals, as indicated in the samples description below.

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

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