Unlocking the full therapeutic potential of lipid nanoparticles through extrahepatic delivery

Lipid nanoparticles (LNPs) have emerged as versatile and widely utilized delivery systems in both academic research and industrial applications, offering immense potential beyond liver-targeted and infectious disease treatments. Despite their success, a significant limitation of LNPs is their inherent liver tropism following systemic administration. This liver-centric accumulation represents a key bottleneck, restricting the broader therapeutic applications of LNP-based delivery systems. In this review, we explore strategies to overcome this challenge by modulating LNP composition—including ionizable lipids, helper lipids, cholesterol, and other critical components—to achieve extrahepatic targeting. We further discuss recent advancements in surface modification techniques designed to redirect LNPs to organs beyond the liver. Additionally, we highlight recent progress in local delivery approaches, which offer a direct and effective alternative for achieving extrahepatic delivery. By providing a comprehensive overview of current strategies and limitations, we aim to guide future research efforts toward fully realizing the therapeutic potential of LNP-based delivery systems.