Near-Infrared-II Photothermal Agents Targeting Lipid Droplets to Ameliorate Obesity Through Induction of Adipose...

Obesity has emerged as one of the most critical global health challenges. However, current anti-obesity pharmacotherapies are limited by suboptimal efficacy and significant side effects. White adipose tissue (WAT) browning may contribute to ameliorating obesity. In this study, a water-soluble lipophilic second near-infrared region (NIR-II) photothermal agent, CPDT-BBT-N (BTN), which specifically targets lipid droplets (LDs) and accumulates in adipocytes, was developed. Upon NIR irradiation, BTN induced a strong photothermal effect, enabling localized mild hyperthermia that specifically triggers white adipocyte browning with high efficiency and minimal off-target effects. WAT browning markedly accelerated the burning of the excessive fat accumulated in adipocytes. Notably, this intervention also showed systemic metabolic benefits. In high-fat diet (HFD)-induced obese mice, the BTN + NIR treatment attenuated weight gain by 20%, reduced subcutaneous WAT mass by 43%, and decreased visceral fat mass by 35%. Furthermore, it significantly reduced serum cholesterol (38%), triglycerides (30%), insulin (30%), and glucose levels (35%) while improving insulin sensitivity. Mechanistically, mild thermal stimulation promoted calcium influx in adipocytes, upregulating the expression of the thermogenic protein UCP1, enhancing mitochondrial oxidative respiration, and facilitating lipid catabolism. Together, these findings provide a novel and feasible strategy for effectively and safely managing obesity.