pH-Sensitive Amino Lipid-Driven Pore Formation Enables Endosomal Escape of Lipid Nanoparticles
Singh, A. P.; Shibata, K.; Miyazaki, Y.; Shinoda, W.
Show abstract
Lipid nanoparticles (LNPs) have transformed nucleic acid delivery for vaccines and gene therapies, yet their efficiency remains limited by incomplete endosomal escape. While experimental studies have revealed endosomal membrane disruption facilitating cytosolic release, the molecular basis of this process remains poorly understood. Here, we employ molecular simulations to elucidate how LNPs fuse with the endosomal membrane and release their payloads. We identify multiple fusion pathways, with a dominant stalk-pore mechanism. Our simulations reproduce and rationalize key experimental observations, including the transfer of ionizable lipids from LNPs to the membrane, which promotes nucleic acid reorientation and facilitates stalk formation and expansion. Furthermore, lipid shape, pH sensitivity, membrane tension, and nucleic acid encapsulation emerge as critical molecular determinants of endosomal escape efficiency. These findings advance our mechanistic understanding of intracellular delivery and provide a framework for the rational design of LNPs with improved performance for gene therapies and RNA vaccines.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Accurate Simulation of Coupling between Protein Secondary Structure and Liquid-Liquid Phase Separation 96%
- How cell penetrating peptides behave differently from pore forming peptides: structure and stability of induced transmembrane pores 96%
- Inositol hexakisphosphate (IP6) accelerates immature HIV-1 Gag protein assembly towards kinetically-trapped morphologies 95%
Similar papers in this journal
- Breakage of Hydrophobic Contacts Limits the Rate of Passive Lipid Exchange Between Membranes 96%
- Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis 96%
- Intrinsically disordered membrane anchors of Rheb, RhoA and DiRas3 small GTPases: Molecular dynamics, membrane organization, and interactions 95%
Similar papers in this journal
- Efficient quantification of lipid packing defect sensing by amphipathic peptides; comparing Martini 2 & 3 with CHARMM36 96%
- Particle deformability enables control of interactions between membrane-anchored nanoparticles 96%
- Simulation of FUS protein condensates with an adapted coarse-grained model 95%
Similar papers in this journal
- SAXS Curves of Detergent Micelles: Effects of Asymmetry, Shape Fluctuations, Disorder, and Atomic Details 96%
- Hijacking of Cellular Functions by Severe Acute Respiratory Syndrome Coronavirus-2. Permeabilization and Polarization of the Host Lipid Membrane by Viroporins. 95%
- Nucleation of Biomolecular Condensates from Finite-Sized Simulations 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.