ROS-responsive microneedle patch delivering NMN@Cu/CeO₂ nanozyme for restoring immune microenvironment and mitochondrial homeostasis to potentiate diabetic wound healing

Chronic oxidative stress, mitochondrial dysfunction, impaired Nicotinamide adenine dinucleotide (NAD⁺) biosynthesis, and angiogenesis inhibition are key factors contributing to delayed diabetic wound healing. Restoring mitochondrial homeostasis through NAD⁺ replenishment and reactive oxygen species (ROS) elimination shows therapeutic potential, yet its effective translation requires multifunctional dressings that combine NAD⁺ supplementation, ROS-responsive antibacterial activity, and localized therapeutic agent delivery to advance diabetic wound healing. Herein, we developed a nanozyme-integrated ROS-responsive microneedle patch (NMN@Cu/CeO₂-MN) for co-delivering nicotinamide mononucleotide (NMN) and Cerium oxide copper nanozymes (Cu/CeO₂). NMN was electrostatically loaded into PEI-functionalized nanozymes to enhance NAD⁺ biosynthesis. The patch was constructed with a methacryloylated gelatin (GelMA)-based needle tip embedded with composite nanozymes and a polyvinyl alcohol/phenylboronic acid-modified poly-L-lysine (PVA/EPL-PBA) antibacterial needle base. This design enables sustained and localized delivery while providing robust antibacterial and pro-regenerative properties. NMN@Cu/CeO₂-MN promoted endothelial cell proliferation, migration, tube formation, and mitochondrial homeostasis by scavenging intracellular ROS and restoring NAD⁺ metabolism. In diabetic mice, the patch significantly enhanced M2 macrophage polarization, alleviated inflammation, and accelerated wound healing through activation of the SIRT1/Nrf2/HO-1 signaling pathway, accompanied by enhanced angiogenesis and collagen deposition. These findings suggest that NMN@Cu/CeO₂-MN represents a potent therapeutic strategy targeting mitochondrial dysfunction and metabolic imbalance in diabetic wound repair.