A Core–Shell Microneedle Platform for the Spatiotemporal Codelivery of Dual-Agent Therapeutics Precisely Orchestrates Diabetic Wound Healing

Abstract Chronic non-healing of diabetic wound (DW) remains a critical clinical challenge worldwide. Sustained oxidative stress and prolonged inflammatory responses disrupt the wound microenvironment, while bacterial colonization and biofilm formation on the wound bed compromise drug penetration, consequently leading to suboptimal outcomes with conventional approaches. Here, we developed a core-shell structured microneedle (MN) patch system, designated as MN@Ple/ExoQ10, to precisely regulate the DW microenvironment through sequential drug release. The MN@Ple/ExoQ10 features a biphasic agent release profile, comprising a natural antimicrobial peptide (Pleurocidin) in the outer shell layer, that exerts anti-infective effects during the initial phase of wound healing, while engineered exosomes (ExosQ10) in the core layer alleviate oxidative stress and modulate immune responses subsequently. This study details that the sustained release of ExosQ10 effectively inhibits high glucose (HG)-induced ferroptosis in vitro, demonstrating potent antioxidant activity and anti-inflammatory capacity. Furthermore, in a S. aureus-infected diabetic mouse wound model, MN@Ple/ExoQ10 demonstrates potent antibacterial activity while mitigating oxidative stress, suppressing inflammation and promoting angiogenesis, thereby accelerating wound healing. Collectively, the developed spatiotemporally controlled MN system overcomes bacterial barriers and stabilizes exosomal delivery, enabling comprehensive regulation of the microenvironment in DWs. This breakthrough approach presents a novel and translational strategy for DW therapy.