Multifunctional vesicle-secreting bioadhesive dermatomimetic hydrogel for enhanced extensive wound healing

Extensive skin wounds pose significant clinical challenges due to delayed healing, persistent inflammation and insufficient tissue regeneration. Here, we develop a photocrosslinked dermatomimetic hydrogel (DA-Col/HA) with bioadhesiveness and spatiotemporal controllability, composed of dopamine-conjugated collagen type III (DA-Col) and hyaluronic acid (HA). The DA-Col/HA gel, by mimicking the native extracellular matrix, promotes wound healing through accelerating hemostasis and its antioxidant/anti-inflammatory activities, specifically by scavenging ROS and inducing macrophage M2 polarization. On the other hand, the half-life of retinoic acid (RA), a key regulator of epithelial differentiation, is increased by 1.4 times after being encapsulated in adipose-derived stem cell extracellular vesicles (ADSC-EVs). In an extensive wound rat model, the mixture of RA-loaded ADSC-EVs and DA-Col/HA gel (EVs@RA-gel) significantly accelerates wound closure and facilitates the formation of follicle-like structures through enhanced re-epithelialization, accelerated neovascularization, and collagen deposition. Altogether, this multifunctional vesicle-secreting bioadhesive dermatomimetic hydrogel offers a promising therapeutic strategy for treating extensive skin wounds.