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

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.