Ultrasound-induced nitric oxide release from isosorbide dinitrate nanoparticles for on-demand therapy of periodontitis

Nitric oxide (NO) can effectively combat periodontitis by disrupting biofilms and suppressing inflammation; however, its clinical translation has been limited by the lack of a controllable delivery strategy. This study aimed to develop an ultrasound-controlled NO delivery platform based on a clinically approved NO donor for precise periodontitis treatment. A clinically approved NO donor, isosorbide dinitrate (ISDN), was identified that can be efficiently activated by low-intensity ultrasound (2 W/cm 2 ) in the presence of vitamin B 2 tetrabutyrate (TBR) by generating ·OH free radicals, thereby releasing NO in an on-demand and spatiotemporally controlled manner. Thereafter, ISDN-loaded nanoparticles were synthesized, and a miniaturized intraoral ultrasonic transducer for localized NO generation was developed. The reaction between NO and the reactive oxygen species (ROS) produced from TBR formed peroxynitrite, which exerted strong antibacterial and anti-biofilm effects (the bacterial survival rate within the biofilm during the formation stage was less than 10%) and inhibited NLRP3-mediated inflammation. In a rat model of periodontitis, the treatment significantly decreased bacterial load and mitigated inflammation, resulting in a reduction of inflammatory gene expression by approximately 2.4-fold, while maintaining the integrity of alveolar bone structure. Overall, this study presents a highly promising clinical application for ultrasound-controlled NO delivery strategy for precision therapy of periodontitis.