Dual-layer microneedles for immunomodulation and infection-responsive therapy in diabetic foot ulcers

Diabetic foot ulcers (DFU) are a refractory form of chronic wound characterized by persistent infection and impaired healing. Distinct from other hard-to-treat infections, DFU are aggravated by neuropathy, vasculopathy, and immune dysfunction, which hinder microbial clearance and tissue repair. Their management is further challenged by antibiotic overuse, rising resistance, and the limited efficacy of current therapies. To address these issues, we developed the dual-layer microneedles (IGR MNs) platform that integrated a nitroreductase (NTR)-responsive fluorescent probe for real-time infection monitoring with near-infrared (NIR)-triggered photothermal therapy. The microneedle tips were loaded with liposome-encapsulated antibacterial and immunomodulatory agents for controlled, on-demand release, while the base layer incorporated the infection-responsive probe for spatially precise detection. The IGR MNs overcame the limitations of conventional single-layer microneedles by simultaneously enabling diagnosis and therapy. In vivo evaluations in diabetic wound models demonstrated efficient infection detection, reduced local inflammation, enhanced collagen deposition and neovascularization, and significantly accelerated wound closure. This antibiotic-free strategy enables targeted biofilm disruption and immunomodulation, providing a clinically translatable approach for managing refractory, infected diabetic wounds. We designed a double-layered bullet-shaped microneedle system. The NTR-responsive probe integrated into the microneedle tips enables real-time monitoring of bacterial infection at the wound site, allowing for on-demand drug delivery based on the infection status. This system achieves the goals of eradicating bacteria, alleviating inflammation, and promoting angiogenesis and tissue regeneration.