Sonosensitized Hemoglobin Nanoparticles for Ultrasound-Triggered NO Gas Therapy of Periodontitis.

Controlled nitric oxide (NO) release within deep periodontal pockets remains a critical unmet need for effective periodontitis therapy, as conventional approaches are plagued by poor targeting, uncontrolled release, and limited deep-tissue penetration. Herein, we engineer sonosensitized hemoglobin nanoparticles (PH-SNO) using heme as an endogenous sonosensitizer and S-nitrosothiol (SNO) as a robust NO donor, enabling ultrasound (US)-mediated synergistic gas-sonodynamic therapy for periodontitis. Upon US irradiation, PH-SNO simultaneously generates reactive oxygen species (ROS) via heme and triggers S-NO bond cleavage for on-demand NO release; ROS and NO further react to form peroxynitrite, exerting potent oxidative-nitrosative stress. This dual effect eradicates major periodontal pathogens, disrupts biofilms, abrogates NF-κB signaling and NLRP3 inflammasome activation, and downregulates pro-inflammatory cytokines. In vivo studies confirm that PH-SNO/US alleviates gingival inflammation, suppresses osteoclast activity, preserves alveolar bone, and promotes tissue repair with excellent biocompatibility, providing a safe, noninvasive, and translatable nonantibiotic therapeutic strategy for periodontitis.