A methacrylated carboxymethyl chitosan hydrogel loaded with α-mangostin nano-micelle promotes infected diabetic wound healing involving PPAR-γ modulation

CMCSMA/F127/TPGS@α-MG hydrogel promotes infected diabetic wound healing. • F127/TPGS micelles improve the aqueous solubility and sustained release of α-MG. • The composite hydrogel disrupts biofilms and achieves 99.6% wound closure. • α-MG modulates PPAR-γ, attenuating inflammation and promoting angiogenesis. Diabetic wounds pose a major clinical challenge owing to their complex microenvironment and persistent inflammation. To address this issue, we engineered a multifunctional, in situ photocrosslinkable composite hydrogel (CMCSMA/F127/TPGS@α-MG) to promote wound healing. To overcome the hydrophobicity of the antimicrobial agent α-mangostin (α-MG), it was first encapsulated in F127/TPGS nanomicelles. These micelles were then integrated into a methacrylated carboxymethyl chitosan (CMCSMA) matrix, enabling rapid conformal gelation upon 405 nm light irradiation. The resulting hydrogel exhibited a biphasic sustained-release profile, excellent biocompatibility, and potent contact-killing and anti-biofilm activities against Staphylococcus aureus ( S. aureus ). In an S. aureus -infected diabetic wound model, the hydrogel significantly accelerated wound closure, achieving 99.6% closure by day 14, and facilitated high-quality tissue regeneration characterized by complete re-epithelialization and orderly collagen deposition. Furthermore, an integrated approach combining network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation revealed that the therapeutic efficacy of sustained local α-MG delivery involves the modulation of the PPAR-γ pathway. This regulatory process suppresses the NF-κB/COX-2 inflammatory axis and upregulates pro-angiogenic markers, including VEGF, CD31, and α-SMA. Collectively, this dual-action platform, which synergizes physical barrier protection with targeted molecular modulation, represents a promising translational strategy for refractory diabetic wounds. Schematic illustration of the preparation process and functional attributes of the in situ forming CMCSMA/F127/TPGS@α-MG hydrogel. Download: Download high-res image (67KB) Download: Download full-size image