Keratin nanoparticle-loaded hydrogel microneedles for programmed repair of radiation-induced skin injury.

Radiation-induced skin injury (RISI) poses a significant clinical challenge, with its core pathology involving epidermal barrier disruption caused by excessive reactive oxygen species (ROS) accumulation, oxidative stress, and cell apoptosis. However, effective local treatment options for RISI remain highly limited. Therefore, we developed a phase-transition hydrogel microneedle system loaded with keratin nanoparticles (KNPs@M/G MNs) for the multi-target combinatorial therapy of RISI based on a physical phase-transition mechanism. Specifically, these microneedles penetrate the stratum corneum to precisely deliver therapeutic agents to the epidermis. They rapidly undergo gelation in the skin and release the drugs in a programmed manner: mangiferin is initially released to scavenge radiation-induced ROS, thereby preventing oxidative DNA damage. Subsequently, KNPs are released in a sustained manner to inhibit the inflammatory response via modulation of the nuclear factor kappa B (NF-κB) pathway, maintain cell viability through anti-apoptotic effects, and upregulate cytokeratins (K) 14 and 17, thereby promoting barrier reconstruction and hair follicle regeneration. Collectively, the KNPs@M/G microneedle system exerts therapeutic effects through early-stage antioxidative protection followed by later-stage anti-inflammatory, anti-apoptotic, and pro-regenerative activities, presenting an innovative strategy for the treatment of RISI.