Anti-bacterial layer coated Zn-doped mesoporous silica drug-carry platform for infected wound healing by inhibiting ferroptosis via the AMPK/Nrf2 axis.

Abstract

Impaired infected wound healing is closely associated with mitochondrial dysfunction, and ferroptosis has emerged as a key mechanism connecting oxidative stress to mitochondrial damage. Baicalein holds potential for modulating this process, yet its application is constrained by poor bioavailability. Herein, a multifunctional nano-delivery system (Ba@Zn-MSN@CH) was rationally designed for infected wound treatment. Zinc-doped mesoporous silica nanoparticles (Zn-MSN) were synthesized to serve as a baicalein carrier. Carboxymethyl chitosan (CMCS) and dihydrocaffeic acid were covalently grafted onto the surface of the nanoparticles via silanization and amidation reactions, leading to the formation of a stable core-shell structure. The introduction of macromolecular coating was found to not only prolong drug release but also enhance antioxidant and antibacterial efficacy. What's more, Ba@Zn-MSN@CH effectively alleviated mitochondrial damage by inhibiting ferroptosis, thereby restoring cell proliferation, migration, and angiogenesis, and ultimately accelerating infected wound healing. Mechanistically, Ba@Zn-MSN@CH inhibited ferroptosis by inducing AMP-activated Protein Kinase α (AMPKα) phosphorylation in fibroblasts. AMPKα sustained the abundance of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently suppressed lipid peroxidation and inhibited ferroptotic cell death through upregulation of downstream antioxidant factors. Collectively, these findings demonstrated that Ba@Zn-MSN@CH accelerated infected wound healing by inhibiting ferroptosis through activation of the AMPK/Nrf2 signaling pathway, highlighting the potential of baicalein-based nanotherapeutics as a promising strategy for infected wound management.