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

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.