Ultrasound Controlled-Release Hydrogel Promotes Diabetic Wound Healing via Neuroimmune Modulation and Synergistic ROS Scavenging

Diabetic wound (DW) is a diabetes complication characterized by high morbidity and disability rates. Previous therapeutic systems focused on macrophages while neglecting the upstream regulatory factor of neuropeptide-mediated neuroimmune communication. In addition, precise delivery is directly important for the treatment of DW. This study constructed an amphiphilic prodrug molecule MC by covalently conjugating calcitonin gene-related peptide (CGRP) with manganese porphyrin (MnP). MC was then co-assembled with DSPE-PEG-folic acid to form targeted nanoparticles MCF. Subsequently, MCF was loaded into an ultrasound-responsive hydrogel to obtain the MCF@CA system, integrating neuroimmune modulation and reactive oxygen species (ROS) scavenging functions. Upon local administration, ultrasound triggering enables the on-demand release of the nanodrug MCF from MCF@CA. Subsequently, FA targets M1 macrophages, prolonging wound retention time. MnP scavenges ROS, improving fibroblast function and promoting macrophage polarization towards an anti-inflammatory phenotype. This study presents an ultrasound-responsive hydrogel MCF@CA delivering targeted nanoparticles where CGRP regulates the regenerative transition of the immune microenvironment. Animal experiments confirmed that MCF@CA combined with ultrasound significantly promotes DW healing by enhancing collagen deposition, immune modulation, and improving blood supply. Therefore, this study provides an on-demand controlled delivery platform with clear translational potential for diabetic wound therapy.