Lipid nanoparticles (LNPs) are state-of-the-art siRNA carriers but are limited by modest RNA loading, inefficient endosomal escape, and short-lived silencing due to burst release at escape. To overcome these constraints, we developed lipid-layered core RNA-assembled nanomodules (L-CRAMs) that couple a self-assembled RNA core with fusogenic lipids to enable sustained, high-capacity siRNA delivery. L-CRAMs release siRNA gradually, exhibit fusion-mediated intracellular delivery with limited endo-lysosomal sequestration, and produce robust silencing across single and multiplexed targets in vitro. Compared with MC3-LNPs, L-CRAMs prolonged intracellular gene silencing. Following systemic administration in mice, L-CRAMs induced potent, durable suppression of the clinically relevant liver gene APOC3, accompanied by reductions in serum triglycerides (TG) and triglyceride-rich lipoproteins (TRL). By integrating ultra-high RNA payloads, fusogenic uptake, and programmable multi-gene targeting, L-CRAMs provide a versatile, long-acting RNA interference platform that addresses key limitations of existing LNP systems and advances therapeutic RNA delivery.