Intradermal Delivery of Catalase via Extracellular Vesicles for Targeted Photoaging Therapy.

The therapeutic potential of protein-based drugs is often limited by challenges in delivery, including instability, rapid degradation, and poor tissue targeting. Extracellular vesicles (EVs), as naturally derived nanocarriers, offer distinct advantages including biocompatibility, low immunogenicity, and efficient intercellular communication. Here, we engineered a 313 cell line to stably produce catalase (CAT)-loaded EVs (313EVs) that maintained vesicle integrity, exhibited high loading efficiency, and preserved enzymatic activity. Transcriptomic profiling revealed that genetic engineering subtly reshaped EV microRNA cargo, enriching 313EVs in pathways associated with EV uptake, mitochondrial membrane recovery, and DNA repair-supporting their multifaceted roles in mitigating photoaging. Functionally, 313EVs alleviated oxidative stress and restored antioxidant capacity in UVB-damaged fibroblasts. In vivo, intradermal administration resulted in sustained CAT activity, uniform dermal distribution, and marked improvements in wrinkle formation, collagen preservation, and skin elasticity. Notably, depletion of the skin microbiota did not alter therapeutic efficacy, indicating that the therapeutic benefits of 313EVs arise primarily from vesicle-intrinsic mechanisms rather than host-microbe interactions. Collectively, these findings establish 313EVs as a robust and versatile protein-delivery platform and highlight their therapeutic potential for combating oxidative stress-driven skin aging.