The refractory nature of diabetic foot osteomyelitis (DFO) wounds constitutes a primary cause of disability among diabetic patients. However, currently employed interventions fall short of clinical requirements because of undefined targeting mechanisms, suboptimal wound repair, and significant adverse effects, necessitating innovative therapeutic strategies that transcend traditional paradigms. By utilizing clinical tissue samples, we revealed a critical "triple bottleneck" mechanism wherein intracellular bacterial retention by macrophages drives cellular senescence, thereby impeding both wound healing and bone tissue regeneration in patients with DFO. To address this, we engineered a novel biodegradable microneedle patch (MNs) loaded with Hairyvein Agrimony-derived nanovesicles (HA-NVs)-(HA@MNs), which leverages physical micropuncture to achieve precise, sustained delivery of HA-NVs to DFO wounds, establishing a novel biomaterial platform for the targeted administration of bioactive components from traditional Chinese medicine (TCM). In vitro assays demonstrated that HA@MNs effectively penetrated the stratum corneum barrier, releasing HA-NVs that significantly eradicated intracellular bacteria within macrophages and reversed cellular senescence. Furthermore, bioactive factors within HA-NVs modulate cellular immunity to promote vascular endothelial cell proliferation and neovascularization, thereby ameliorating local microcirculatory dysfunction while accelerating fibroblast migration and collagen deposition; concurrently, they significantly promote bone regeneration by upregulating the osteogenic genes Runx2, OPN, and OCN. In vivo animal models confirmed that this microneedle patch significantly accelerated DFO wound closure and promoted bone regeneration. Overall, this study presents a multifunctional, integrated therapeutic strategy for DFO that combines bioactive components derived from traditional Chinese medicine, an advanced microneedle-based delivery system, and tissue regeneration mechanisms. While still at a preclinical proof-of-concept stage, these findings provide a foundation for DFO treatment.
