Spatiotemporal ultrasound-driven piezoelectric electro-NO therapy restores neuro-vascular-immune homeostasis for radiation ulcer repair

Radiation ulcers (RUs) represent a devastating and intractable complication arising from radiotherapy, driven by a self-perpetuating pathological cascade featuring persistent oxidative stress, unresolved chronic inflammation, progressive neurovascular destruction, and recurrent bacterial infection, which cannot be sufficiently mitigated by conventional single-target therapeutic interventions. Both electrical stimulation (ES) and nitric oxide (NO) therapy exhibit promising regenerative potential for tissue repair; nevertheless, traditional ES relies on invasive implanted electrodes with unsatisfactory spatial controllability, whereas exogenous NO delivery suffers from insufficient spatiotemporal precision and potential off-target cytotoxicity. Herein, we developed an injectable collagen hydrogel (CKPB) integrating with potassium sodium niobate nanoparticles loaded with an ultrasound-sensitive NO donor. Upon non-invasive ultrasound triggering, this integrated platform achieves wireless generation of localized electric fields as well as spatiotemporally tunable NO release. In a murine RUs model, CKPB/US treatment efficiently facilitated nerve regeneration, M2 macrophage polarization, angiogenesis, antioxidant defense and antibacterial properties. Such multi-faceted therapeutic effects contribute to the recovery of near-physiological epidermal architecture, improved functional blood perfusion, and strengthened overall tissue integrity. Collectively, this work establishes a noninvasive, dual-modality strategy to reconstruct neuro-vascular-immune homeostasis, offering a rational framework for coordinating multimodal signals to target complex pathological microenvironments.