A Simplified Three‐Tailed N‐Alkyl Phosphoramidate Lipid Platform Enables Inguinal Adipose‐Accumulated mRNA Delivery for Anti‐Obesity Therapy

ABSTRACT Obesity is a complex metabolic disorder associated with an increased risk of type 2 diabetes, cardiovascular diseases, and metabolic dysfunction‐associated steatotic liver disease. While protein‐based therapies like glucagon‐like peptide‐1 (GLP‐1) receptor agonists (e.g., semaglutide) and fibroblast growth factor 21 (FGF21) analogs show promise, their clinical utility is limited by poor tissue targeting and the need for frequent high‐dose injections. To overcome these challenges, we develop an mRNA‐based therapy encoding a long‐acting GLP‐1/FGF21 fusion protein (mGLP‐1/FGF21), engineered with an IgG4 Fc domain to enhance stability. For adipose tissue‐specific delivery, we design a three‐tailed N‐alkyl phosphoramidate lipid (NPL) formulation with enhanced fluidity in lipid‐rich microenvironments, promoting membrane fusion and endosomal escape to significantly improve adipocyte transfection efficiency. Systematic optimization reveals that removing DOPE (while retaining cholesterol) enhanced delivery efficiency 5‐fold compared to conventional four‐component Lipid Nanoparticle (LNP), without inducing metabolic burden or inflammation upon repeated dosing. The optimized platform effectively delivers mGLP‐1/FGF21, demonstrating potent anti‐obesity effects in mice through synergistic GLP‐1 and FGF21 signaling. Treatment induces significant reductions in body weight and fat mass while preserving lean mass and ameliorating hepatic steatosis. By combining adipose‐accumulated mRNA delivery with dual‐hormone therapy, this study presents a novel and localized strategy for obesity treatment.