Butterfly-shaped dendrimers with photosensitizer recruitment function for enhanced light-controlled precise cascaded ROS and NO release in multimodal diabetic foot ulcers infections treatment

Diabetic foot ulcers (DFU) infections have been a major setback in wound healing, yet there is no effective therapeutic intervention. Here we report a nano-multidrug co-delivery system based on arginine-terminal butterfly-shaped peptide dendrimers (C&D@Z) that effectively kill bacteria and promote wound healing. Firstly, upon the near-infrared light irradiation, reactive oxygen species (ROS) was generated from the loaded photosensitizers, and then mediated bacteria killing. Next, the excessive ROS reacted with the designed butterfly-shaped dendrimers to generate sustained and abundant nitric oxide (NO), which exerted bactericidal action, as well as produced anti-inflammatory and angiogenesis effects. The co-delivery system, facilitated by the generation of NO, penetrated deeply into the biofilm, thereby effectively eliminating bacteria. The enhanced bactericidal and healing efficiency was investigated through biofilm penetration and wound healing experiments. Collectively, our system leveraged the highly-branched and cavity structures of the butterfly peptide dendrimer to realize the tight contact between the arginine groups and photosensitizer to achieve efficient conversion from ROS to NO, and the C&D@Z exhibited superior NO production, optimal photodynamic therapy utilization and effective penetration performance through cascade reaction between photodynamic therapy and NO therapy, may serve as a promising therapeutic approach for DFU infections.