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

ABSTRACT 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.