De Novo Design Strategies of Nanomedicines for Diabetic Wound Microenvironment Remodeling

Diabetic wounds are arrested by a hostile microenvironment of hyperglycemia, inflammation, infection, and hypoxia. Nanomaterials offer solutions, yet existing reviews lack a systematic framework linking their actions to the interconnected pathological network. Here, we present a pathology network-guided analysis. We delineate how engineered nanosystems from metal-based antimicrobials to glucose-responsive nanoreactors and extracellular vesicles can intercept multiple drivers, including advanced glycation end-products, oxidative stress, biofilms, and immune dysregulation. Critically, we propose a temporally phased roadmap that prioritizes neutralization of upstream drivers (hyperglycemia and biofilms) before downstream interventions (reactive oxygen species scavenging, immunomodulation, and angiogenesis), avoiding premature single-target therapy. Beyond efficacy, we critically address design trade-offs: we examine the evidence for metal nanomaterial selectivity toward bacteria versus stressed host cells, confront bacterial adaptive resistance (efflux pumps and biofilm reinforcement), and scrutinize the trade-off, manufacturing scalability, long-term biosafety, and regulatory ambiguities. By integrating mechanistic insights with clinical scalability and regulatory feasibility, we provide a conceptual framework to guide the rational design of next-generation nanomedicines that prioritize genuine synergy over redundant integration, and outline a roadmap for translation.