Amphiphilic Hyaluronic Acids Enhance Sanshool’s Efficacy against Skin Photodamage via Stability Improvement and Cell Cycle Regulation

Sanshool is a promising skin photoprotective agent with strong UV absorption and great antioxidative activity. However, it faces challenges including poor stability, skin penetration-associated systemic toxicity, and efficacy loss upon chemical modification. To address these issues, amphiphilic hyaluronic acids (HHA) were synthesized and self-assembled to integrate with sanshool via hydrophobic interactions, significantly boosting its photostability by 24% and enhancing its antioxidative activity. In HaCaT cells, HHA-sanshool nanoparticles (NPs) reduced UVB-induced reactive oxygen species, decreased cell apoptosis, and lowered G2/M phase arrest from 42% to approximately 31% (close to the normal level), while also inhibiting excessive autophagy. Moreover, in a mouse model, HHA-sanshool NPs alleviated UVB-induced skin damage, reducing skin thickening by up to 50% and mitigating erythema, protected collagen/elastic fibers, and suppressed proinflammatory factor, with no dermal penetration in vivo . This strategy provides a simple, efficient and safe platform for natural active molecular clinical translation in skin photoprotection. The alternative text for this image may have been generated using AI.