Nitric oxide–regulated temporally staged milk exosome hydrogel for the treatment of skin photoaging

Ultraviolet (UV)–induced skin photodamage can lead to sunburn, photoaging, and, in severe cases, precancerous lesions or malignant skin tumors. Cutaneous responses to UV injury exhibit pronounced circadian rhythmicity; however, current strategies focusing solely on physical UV shielding or post-injury repair fail to meet the dynamic physiological demands of photodamaged skin. Herein, we developed a transdermal delivery system based on a tannic acid–hyaluronic acid crosslinked network (mN-Gel) to enable stage-matched delivery of nitric oxide (NO) and milk-derived exosomes (mExos) for dynamic protection and regenerative repair. During the daytime, the hydrogel blocks UV irradiation via the intrinsic light-absorbing properties of tannic acid and rapidly releases NO to enhance mExos penetration, thereby scavenging reactive oxygen species and suppressing early inflammation. At night, sustained release of low levels of NO and mExos modulates the immune microenvironment, promoting cell proliferation, collagen remodeling, and barrier reconstruction. In vitro and in vivo studies demonstrate that this system effectively alleviates UV-induced oxidative stress and inflammation, while restoring tissue architecture and barrier function. Transcriptomic analysis further suggested a stage-associated biological transition from acute injury defense to tissue regenerative repair. Collectively, this work presents a multidimensional and controllable delivery platform integrating physical photoprotection with stage-matched repair for UV-induced skin photodamage and photoaging.