Flexible Zwitterionic Hydrogel Ultrasonic Patch Enables Spatiotemporally Controlled Delivery of Mangiferin-Loaded Micelles for Accelerating Diabetic Wound Healing

Abstract Diabetic wounds are characterized by persistent inflammation, oxidative stress, impaired angiogenesis, and delayed tissue remodeling, often resulting in chronic nonhealing ulcers. Low-intensity pulsed ultrasound (LIPUS) offers a promising noninvasive therapeutic strategy; however, its clinical efficacy remains constrained by unstable acoustic coupling interfaces and the lack of integrated biological activity. Here, we report an ultrasound-responsive zwitterionic hydrogel patch by incorporating mangiferin-loaded micelles into a topologically entangled PCBOH hydrogel (MF@PCBOH). The mechanically robust hydrogel forms a stable and conformal acoustic interface that efficiently transmits ultrasound under dynamic conditions, whereas the incorporated micelles improve the aqueous dispersibility of mangiferin and enable ultrasound-enhanced release. Under LIPUS stimulation, released mangiferin reduces intracellular ROS, shifts macrophages toward a reparative phenotype, promotes endothelial angiogenesis, and enhances cell migration. As a result, MF@PCBOH accelerates diabetic wound healing in rats, accompanied by reduced inflammation, improved collagen remodeling, and enhanced vascular maturation. Similar therapeutic benefits are observed in a full-thickness porcine wound model, supporting the effectiveness of the hydrogel patch in a large-animal setting. This study demonstrates that integrating a durable acoustic interface with ultrasound-responsive drug delivery offers an effective strategy for diabetic wound repair.