Engineered polypeptide cascade-release platform restores macrophage plasticity for accelerated diabetic wound healing

Persistent inflammatory episodes driven by immune cell dysregulation pose a formidable clinical challenge in diabetic wound healing. Sustained and coordinated regulation of the immune niche within diabetic wounds is critical for tissue regeneration. Here, we develop a programmed therapeutic strategy based on arginine-lysine-methionine third-generation dendrimeric polypeptides whose dopamine-coated surfaces contain ferrous ions (G3D-Pmet₂₅@PDA) to reprogram the immune niche. G3D-Pmet₂₅@PDA exhibits a core-shell structure: ferrous ions on the surface are rapidly released under near-infrared (NIR) laser irradiation, while methionine chains encapsulated within the dopamine shell undergo a reactive oxygen species (ROS) triggered hydrophilic transition that liberates arginine for cascade release. Under NIR laser irradiation, G3D-Pmet₂₅@PDA initiates a clearance program targeting dysregulated immune cells and concurrently reprograms the energy metabolism of newly recruited immune cells, thereby reshaping the immune niche to alleviate inflammation and activate tissue-regenerative programs for accelerated healing. Moreover, sustained low-dose nitric oxide release caused by arginine accelerates angiogenesis, which is beneficial for tissue regeneration. These findings expand the perspective on the intricate coordination of the immune system in diabetic wound repair and reveal new strategies for novel immunomodulatory biomaterials.