Bioadhesive Polydopamine-Vitamin A Derivative Hydrogels Reprogram the Wound Microenvironment for Scarless Wound Healing and Hair Follicle Regeneration

Abstract

Achieving scarless healing combine with skin appendage regeneration remains an extremely challenging task in the treatment of skin wounds. Vitamin A derivatives have shown great potential for follicle neogenesis and scarless repair but suffer from poor solubility, instability, photosensitivity, and toxicity in wound healing process. Here, we present a multifunctional bioadhesive hydrogel system that integrates polydopamine (PDA) nanoparticles with Vitamin A derivatives to promote functional skin regeneration. The PDA nanoparticles stabilized and enabled pH-responsive release of Vitamin A derivatives, while simultaneously providing reactive oxygen species (ROS) scavenging and antioxidant protection. Embedded within an imine-crosslinked adhesive hydrogel network, this platform achieved strong tissue adhesion, sustained drug delivery, and favorable immune microenvironment modulation. In vivo, using both rats burn wounds and rabbit hypertrophic scar models, the optimized formulation accelerated wound closure, rebalanced collagen deposition, suppressed myofibroblast activation, and markedly prevented pathological fibrosis. Strikingly, it also induced robust de novo hair follicle formation, indicating true functional tissue restoration. Transcriptomic and immunofluorescence analyses further revealed downregulation of pro-fibrotic and inflammatory pathways alongside activation of regenerative signaling, including M2 macrophage polarization and suppression of M1 phenotype in treated wounds. This work introduces an early Vitamin A-based nanocomposite hydrogel with dual anti-scarring and regenerative functions, offering a promising strategy for advanced wound care.