Chitosan-shielded stem cell exosomes as a tight-junction-modulating bio-shuttle for enhanced transdermal delivery and skin rejuvenation.

Mesenchymal stem cell-derived exosomes (Exo) have emerged as potent therapeutic agents for skin regeneration; however, their clinical translation is often impeded by poor colloidal stability and the formidable barrier of the stratum corneum. In this study, we developed a novel "bio-shuttle" system by engineering chitosan-shielded exosomes (cExo) via precise electrostatic surface assembly. The optimized cExo exhibited a uniform hydrodynamic diameter of 216 nm and a robust positive surface charge of +30.7 mV, ensuring superior structural integrity. To evaluate their transdermal potential, we employed a Caco-2 cell monolayer model and Franz diffusion cell analysis using porcine skin. Notably, cExo significantly increased the paracellular flux of Lucifer Yellow (LY) across the Caco-2 barrier compared to bare Exo, suggesting that the cationic chitosan shell effectively modulates tight junctions to facilitate transport. This mechanism was further supported by ex vivo porcine skin penetration assays, where cExo achieved a two-fold higher fluorescence intensity in the dermis layer than bare Exo after 12 h. Furthermore, in vitro functional assays confirmed that cExo markedly accelerated fibroblast wound healing, reducing the scratch gap from 810 μm to 336 μm while maintaining enhanced antioxidant and anti-inflammatory properties. These findings demonstrate that cExo serve as an innovative, high-permeability skin-booster platform, offering a strategic advancement in non-invasive aesthetic medicine and regenerative skincare.