<p>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/Exo^Q10, to precisely regulate the DW microenvironment through sequential drug release. The photothermal-responsive microneedle patch MN@Ple/Exo^Q10 features a dual-phase release: the outer shell’s antimicrobial peptide (Pleurocidin) addresses initial infection, while the core’s engineered exosomes (Exos^Q10) mitigate oxidative stress and subsequently regulate immune responses. When combined with near-infrared (NIR)-triggered photothermal therapy, this system effectively promotes the healing of DW. This study details that the sustained release of Exos^Q10 effectively inhibits high glucose (HG)-induced ferroptosis in vitro, demonstrating potent antioxidant activity and anti-inflammatory capacity. Furthermore, in a <i>S. aureus</i>-infected diabetic mouse wound model, MN@Ple/Exo^Q10 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.</p> Graphical abstract <p></p>