Platycodon grandiflorum-derived exosome-like nanovesicles drive AMPK-dependent glycolytic beige remodeling to ameliorate obesity

Rationale: Obesity is a global epidemic with limited therapeutic options. Plant-derived exosome-like nanovesicles offer a natural nanoscale therapeutic platform. However, their anti-obesity effects and underlying mechanisms remain largely unexplored. Methods: We isolated exosome-like nanovesicles from the root of Platycodon grandiflorum (P-ELNs) and characterized their physicochemical properties. The therapeutic efficacy of P-ELNs was evaluated in high-fat diet (HFD)-induced and genetic (db/db) mouse models of obesity by assessing changes in body weight, adipose tissue mass, and glucose tolerance. Biodistribution imaging, histological analysis, RNA-sequencing, Western blotting, and Seahorse metabolic analysis were performed to investigate the underlying mechanisms of P-ELNs. Results: P-ELN treatment significantly attenuated body weight gain and reduced WAT mass in obese mice without inducing systemic, hepatic, or renal toxicity. Mechanistically, P-ELNs were found to enhance energy expenditure by inducing non-shivering thermogenesis (NST). This was driven by the AMP-activated protein kinase (AMPK)-dependent remodeling of inguinal WAT into a novel glycolytic beige fat subtype, characterized by the upregulation of myogenic and glycolytic gene programs. Conclusions: Our findings demonstrates that P-ELNs represent a safe and effective nanotherapeutic strategy to combat obesity by driving AMPK-dependent glycolytic beige fat remodeling. This study identifies P-ELNs as a first-in-class pharmacological inducer of this unique beige fat subtype, offering a promising new strategy for the treatment of obesity and related metabolic disorders.