Endosomal Escape of Lipid Nanoparticles: A Perspective on the Literature Data

Endosomal escape remains a critical bottleneck for the intracellular delivery of nucleic acids by lipid nanoparticles (LNPs), largely due to its low efficiency and poorly understood mechanism. While various models, including proton sponge effect/osmotic lysis and membrane destabilization/fusion, have been proposed, none are fully validated or sufficient for guiding rational LNP design. Herein, I reevaluate existing data, presenting strong evidence that LNPs escape the endosomal compartment through the recently discovered vesicle budding-and-collapse (VBC) mechanism. A critical subsequent finding is that endosomal escape triggers the formation of an insoluble lipid/nucleic acid aggregate within the cytoplasm. The slow dissolution of this aggregate emerges as an additional, potentially rate-limiting, bottleneck to functional nucleic acid delivery. By reconciling previously puzzling experimental observations, the VBC mechanism provides a powerful theoretical framework for the rational design of LNPs with enhanced endosomal escape and overall functional delivery efficiencies.