Triphasic sequential gas delivery via a photo-instructive hydrogel for enhanced diabetic skin wound healing

Near infrared light-triggered three-dimensional adaptive release in depth, time and dose for the treatment of diabetic foot ulcers. • A triphasic sequential NO release hydrogel achieves antibacterial, angiogenic and remodeling effects. • Triphasic sequential strategy for adapting NO dosage enhances the NO metabolic microenvironment at the wound condition, ultimately expediting wound healing. Diabetic foot ulcer (DFU) requires spatiotemporal coordinated modulation of the inflammatory response and tissue regeneration process, which is still the bottleneck. Here, a triphasic-sequential hydrogel was explored to tackle the infection treatment and tissue regeneration in DFU. The PDA@B6/L-Arg hydrogel was loaded with near infrared-responsive polydopamine nanoparticles, carrying the nitric oxide (NO) donors for different healing stages. Upon exposure to laser irradiation, 1) the PDA@B6/L-Arg hydrogel rapidly released a substantial amount of nitric oxide (NO) (μM) from N , N ′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine (BNN6), thereby synergistically achieving effective anti-bactericidal and anti-inflammatory effects; 2) L-Arg, as the substrate for nitric oxide synthases NOS, provided the support for deep angiogenesis; 3) the hydrogel degraded, allowing the released L-Arg to penetrate the wound and promote additional extracellular matrix remodeling. Compared to non-sequential NO therapy, PDA@B6/L-Arg hydrogel exhibited spatiotemporal modulation, enhancing the biofilm inhibition and angiogenesis. Furthermore, PDA@B6/L-Arg hydrogel, as a reactive oxygen species-scavenging agent, simultaneously attenuating inflammatory to improve the healing efficiency of chronic wounds, achieving 97.9% closure of infected wounds. It offers a promising therapeutic option for managing diabetic foot ulcers.