Adipose-targeted nanohybrid as a browning inducer for synergistic hyperthermia–pharmacotherapy of obesity

Abstract

Inducing adipose browning to increase energy expenditure has recently emerged as a promising approach for antiobesity treatment. However, its therapeutic efficacy is often limited by poor adipose-targeted drug delivery and suboptimal browning efficiency. To address these challenges, an adipose-targeting aptamer (Apt8) and browning agent resveratrol (Res) were used to construct an Apt-modified and Res-loaded degradable mesoporous silica–coated Au nanorods nanocarriers (NC), termed Res@NC@Apt8, achieving adipose-targeted hyperthermia–pharmacotherapy. Upon internalization by adipocytes, laser irradiation induces mild local hyperthermia (LHT) via Res@NC@Apt8, triggering calcium ion (Ca²⁺) influx. Simultaneously, the interaction of the nanohybrid with local glutathione (GSH) releases Res. The dual mechanisms activate the adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway, reduce the lipid droplet content, enhance mitochondrial biogenesis, and accelerate metabolism, thereby synergistically promoting adipose browning. Intravenous Res@NC@Apt8 administration in obese mice significantly drives adipose reduction and further achieves excellent antiobesity therapeutic efficacy. This synergistic treatment achieves a superior weight reduction of 17.2% compared with 6.9% and 10.6% achieved using LHT and pharmacotherapy alone, respectively. This study introduces a novel strategy for achieving activatable LHT and drug release for synergetic obesity treatment.