Ultrasound-Driven Nitric Oxide Generation for Enhanced Sonodynamic–Photothermal Therapy

Recently, green gas therapy based on nitric oxide (NO) has gained considerable attention in cancer treatment. The supplementation of exogenous NO and its controlled release represent promising strategies for adjuvant tumor therapy. In this study, we developed a novel ultrasound (US)-triggered NO generation and release nanoplatform that integrates NO therapy, sonodynamic therapy, and photothermal therapy (PTT) into a collaborative therapeutic modality. An environmentally friendly biomacromolecule, polydopamine, was employed to coload chlorin e6 (Ce6) and NO donor (BNN6), resulting in the nanocomposite PDA-Ce6/BNN6 (PCB). A single US stimulus simultaneously activated Ce6 to produce reactive oxygen species (ROS) and promoted BNN6 to release NO. The dual effects of ultrasonic mechanical action and physiological modulation by NO substantially improved local vascular function and enhanced tumor cell permeability, thereby increasing the targeted accumulation of PCB within tumors. Reactive nitrogen species (RNS) derived from NO and ROS further exacerbated oxidative damage and enhanced the sensitivity of tumor cells to hyperthermia. Both in vitro and in vivo experiments demonstrated that ultrasonic stimulation of NO/ROS/RNS combined with PTT effectively inhibited tumor cell growth and proliferation. The findings suggest that NO gas therapy based on extracorporeal US can significantly amplify the efficacy of PTT and offer new insights for developing other combined strategies aimed at physically regulating deep tumors.