Preclinical efficacy of engineered CircRNA-GDF15@LNP for sustained weight loss and metabolic regulation in diet-induced obese mice.

Obesity as a global epidemic demands effective therapies, with three core management goals: appetite suppression, metabolic acceleration, and weight rebound prevention. Unfortunately, current obesity treatments often fail to simultaneously achieve these goals, and some may cause adverse effects or poor long-term efficacy, thereby complicating the clinical management process. Herein, a novel long-acting circular RNA (CircRNA) based formulation (CircGDF15@LNP) is designed for precise obesity control and metabolic improvement. This delivery system was optimized from established lipid nanoparticle (LNP) formulations, and combines structurally optimized CircRNA encoding mutant growth differentiation factor 15 (GDF15), taking advantage of the high stability and long-lasting expression of CircRNA for efficient GDF15 protein replacement therapy. After biweekly intravenous injection into diet-induced obesity (DIO) mice for 4 weeks, CircGDF15@LNP exhibits prolonged GDF15 overexpression and stable RNA persistence in vitro and in vivo, subsequently activating PPARα/γ signaling and UCP1 expression in liver and adipose tissue to regulate lipid metabolism and adaptive thermogenesis. This study presents a versatile CircRNA-based GDF15 protein replacement therapy for metabolic disorder therapy and provides an innovative approach for addressing obesity and related metabolic complications.