Structural Change of ApoE–Lipid Nanoparticles Alters Receptor-Mediated Endocytosis and Induces Endosomal Disruption

-glycero-3-phosphocholine (DSPC) with a porphyrin-lipid conjugate induces highly faceted, irregular LNP membrane morphologies upon ApoE binding. These structural transitions alter receptor-mediated uptake, enhance endosomal disruption, promote cytosolic siRNA release, and ultimately trigger cell apoptosis. Through fluorescence lifetime imaging, we also demonstrate that ApoE promotes LNP intracellular disassembly. Overall, our findings identify lipid-driven structural remodeling of ApoE-LNPs as a critical determinant of their intracellular fate, offering mechanistic insights for the rational design of LNPs and new perspectives on ApoE's role in disease pathogenesis.