A multifunctional DECM/PLMA hydrogel incorporated with engineered PRP-derived exosomes enabling PHD2 silencing for skin wound repair.

Skin defect repair remains a formidable clinical challenge, characterized by persistent infection risk, compromised angiogenesis, and dysregulated inflammatory responses. Existing hydrogel-based wound dressings fail to simultaneously address structural integrity, antimicrobial efficacy, and spatiotemporal coordination of tissue regeneration. Here, we report the development of a multifunctional bioactive hydrogel system fabricated by integrating decellularized tendon extracellular matrix (DECM) with Poly-L-lysine Methacryloyl (PLMA), and further functionalized with engineered platelet-rich plasma exosomes (PRP-Exos) loaded with siRNA targeting prolyl hydroxylase domain protein 2 (PHD2) via electroporation. The inherent cationic nature of PLMA confers robust, broad-spectrum antibacterial activity, while the sustained release of siRNA-PHD2-laden PRP-Exos achieves efficient PHD2 silencing, thereby stabilizing hypoxia-inducible factor-1α (HIF-1α) and potentiating downstream pro-angiogenic signaling. Concurrently, bioactive cues released from the DECM-based matrix promote fibroblast-to-myofibroblast differentiation and type I collagen biosynthesis, fostering a regeneration-permissive microenvironment. In both normal and diabetic murine full-thickness skin defect models, DEPL@E-SI significantly accelerated wound closure by promoting angiogenesis, inflammation resolution, and extracellular matrix remodeling. These findings establish DEPL@E-SI as a promising therapeutic platform with translational potential for skin tissue engineering and clinical wound management.