Spatiotemporally Controlled Double Self‐Emulsifying Microneedles for Co‐Delivery of Eugenol and Puerarin to Promote Healing and Tissue Regeneration of Infected Diabetic Wounds

ABSTRACT

Chronic infected diabetic foot ulcers (DFUs) pose a persistent challenge due to biofilm‐shielded infections, excessive inflammation, and impaired tissue repair. Here, we present a first‐in‐class microneedle system that redefines eugenol (EUG), a natural compound, as a multifunctional self‐assembling material. Beyond its intrinsic therapeutic activity, EUG autonomously forms nanoscale assemblies that penetrate biofilms, suppress inflammation, and act as a natural penetration enhancer. Leveraging these properties, we designed a spatiotemporally controlled microneedle platform integrating dual‐phase EUG self‐assembly with puerarin (PUE) co‐delivery. At the wound surface, EUG assemblies disrupt biofilms and alleviate early inflammation; in deep tissues, their progressive self‐assembly sustains antibacterial and anti‐inflammatory activity. Meanwhile, EUG facilitates PUE diffusion, while its interaction with the chitosan‐based porous matrix ensures gradual release to promote angiogenesis, collagen remodeling, and structured tissue regeneration. Importantly, biodegradable tips detach within 1 h, minimizing secondary trauma. In an infected diabetic rat model, this system halved bacterial burden, reduced interleukin‐6 by 60%, accelerated wound closure by 35%, doubled cluster of differentiation 31 expression, and achieved 96.6% ± 4.3% collagen deposition within 14 days, significantly outperforming a commercial silver dressing. This multifunctional, surfactant‐free biomaterial platform offers a safe and translational strategy to overcome the “infection‐inflammation‐healing barrier” in chronic DFUs.