Lipid nanoparticle induced model endosomal membrane disruption
Pramanik, S.; Vasudevan, A.; Liang, Z.; Karole, A.; Berchel, M.; Jaffres, P.-A.; Eygeris, Y.; Sahay, G.
Show abstract
Endosomal escape remains the central bottleneck limiting lipid nanoparticle (LNP)-mediated mRNA delivery. In this study, we use giant unilamellar vesicles (GUVs) mimicking the endosomal membrane to directly visualize the interaction and membrane disruptions caused by two model LNPs constituted by two different ionizable lipids: LP01 and BiP-20 (a Branched ionizable Phospholipid) that are both benchmark ionizable lipids for in vivo gene editing in liver. Despite identical TNS-measured apparent pKa (6.6) for both lipids in our conditions, LP01 LNP showed maximal membrane engagement at pH 5.8, while BiP20 LNP required pH 5.1, demonstrating that bulk pKa alone cannot predict the pH at which functional membrane interaction occurs. Using confocal microscopy, we show that the LNP engagement with the endosomal membrane proceeds through first electrostatic attraction, clustering, membrane disruption by forming highly curved morphologies, and finally leading to the rupture of the whole endosomal mimicking membrane. Notably, the mRNA cargo is released only upon complete lysis of the membrane. This indicates that the membrane destabilization and cargo release are mechanistically distinct steps. These findings establish a cell-free platform for dissecting individual sub-steps of endosomal escape.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Membrane fusion-based drug delivery liposomes transiently modify the material properties of synthetic and biological membranes 95%
- A DNA segregation module for synthetic cells 95%
- Hybrid Protocells based on Coacervate-Templated Fatty Acid Vesicles combine Improved Membrane Stability with Functional Interior Protocytoplasm 94%
Similar papers in this journal
- Lipid packing and cholesterol content regulate membrane wetting and remodeling by biomolecular condensates. 94%
- Prebiotically-relevant low polyion multivalency can improve functionality of membraneless compartments 94%
- Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo 94%
Similar papers in this journal
- Lipid nanoparticle topology regulates endosomal escape and delivery of RNA to the cytoplasm 94%
- Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo 94%
- The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages 92%
"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.