Kaempferol-modified mesenchymal stem cell extracellular vesicle-mimetics promote photoaging repair by suppressing ADAM10.

Abstract

Chronic ultraviolet B (UVB) exposure accelerates skin photoaging by inducing excessive reactive oxygen species (ROS), inflammation, and extensive extracellular matrix (ECM) degradation. Increasing evidence indicates that extracellular vehicles (EVs) derived from mesenchymal stem cells (MSCs) hold promise for mitigating skin photoaging; however, the low yield of naturally secreted EVs poses a significant challenge to their clinical scalability. To overcome this barrier, we generated MSC-derived extracellular vesicle mimetics (MSC-EVMs), which preserved the bioactivity of EVs while enabling high-efficiency production. We further engineered a hybrid nanoplatform-MSC-EVM@Kae-by loading kaempferol (Kae), a natural inhibitor of the ECM-degrading protease ADAM10 with strong antioxidative and anti-inflammatory properties.MSC-EVM@Kae markedly reduced ROS accumulation, DNA damage, and cellular senescence in UVB-irradiated fibroblasts and keratinocytes, while restoring MMP/TIMP homeostasis through ADAM10 suppression. In a UVB-induced photoaging mouse model, microneedle-assisted transdermal delivery of MSC-EVM@Kae significantly improved wrinkle severity, enhanced collagen deposition, and reinforced epidermal barrier integrity.Collectively, our findings demonstrate that kaempferol-loaded MSC-EVM integrate the inherent regenerative potential of MSC-derived vesicles with the pharmacological inhibition of ADAM10, offering a scalable and bioengineered strategy for combating UVB-induced photoaging. This hybrid system provides a promising foundation for next-generation, cell-free therapeutics targeting skin aging and oxidative stress-related disorders.