Nitric Oxide-Loaded Nanobubbles for the Treatment of Acute Pulmonary Embolism and Mitigation of Lung Ischemia–Reperfusion Injury

Acute pulmonary embolism (APE) is a life-threatening complication that is primarily caused by the migration of deep vein thrombosis to the lungs. However, current drug treatments have limited efficacy and can lead to lung ischemia–reperfusion injury (LIRI) after thrombolysis. Inhaled nitric oxide has shown potential for APE therapy, but its clinical feasibility is still uncertain. In this study, nitric oxide (NO) was directly encapsulated by nanobubbles to form NO-loaded nanobubbles (NanoNO) as a potential treatment for APE and subsequent LIRI. NanoNO, with a size of 219.27 ± 2.42 nm and a polydispersity index of 0.17, could encapsulate up to 1.1 mM NO. In the LIRI cell model, NanoNO increased NO concentration and superoxide dismutase (SOD) enzyme activities while reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels (2.80-fold), leading to decreased cell apoptosis. In a rabbit model of APE, NanoNO was compared to sodium nitroprusside (SNP, a positive control) for thrombolysis efficacy by using blood gas analysis, pulmonary angiography, echocardiography, and hematoxylin–eosin staining. The results demonstrated that NanoNO was more effective than SNP in thrombolysis, as evidenced by its better ability to remove blood clots, normalize pulmonary arteries, and relieve right ventricular (RV) dilatation. In the LIRI rabbit model, NanoNO decreased serum MDA, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) while increasing serum SOD. Collectively, these findings highlight the potential of NanoNO as a promising therapeutic approach for the treatment of APE and the mitigation of LIRI.