Ultrasound Responsive Nanotherapeutics for Multimodal Reprogramming of Obese Fat

Obesity remains a major global health challenge due to the lack of therapeutic strategies that directly address the complex multifactorial pathology of obese adipose tissue. Here, we present a translatable nanotherapeutic strategy that enables targeted and holistic remodeling of obese white adipose tissue (WAT) through a triple-modality approach combining sonothermal, nitric oxide (NO), and nanocatalytic therapy based on gold nanoparticles functionalized with S-nitrosothiols (SNO@AuNP). Serving as an antenna to harvest ultrasound energy and a mimic to antioxidant enzymes, SNO@AuNP produces localized mild-hyperthermia, releases a therapeutic level of NO, and scavenges reactive oxygen species (ROS), whereby inducing browning and breaking the vicious couplings between oxidative stress, hypoxia, and inflammation in obese WAT. In a high-fat-diet-induced obese mouse model, this synergistic therapy significantly reduced the targeted subcutaneous WAT (60.1%) and the remote visceral WAT (62.2%) within 18 days, essentially relieved obesity-associated type 2 diabetes, and significantly attenuated hyperlipidemia, systemic oxidative stress, and inflammation. The interconnected intracellular, paracrine, and endocrine signaling pathways underlying the treatment were elucidated, offering mechanistic insights for developing effective approaches for obesity and its metabolic complications.