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BP: Fachverband Biologische Physik
BP 4: Computational Biophysics II
BP 4.2: Talk
Monday, March 9, 2026, 15:30–15:45, BAR/SCHÖ
Transient interactions between cationic ionizable lipids and anionic lipids foster lamellar to hexagonal phase transition — •David Noel Zimmer1,2, Friederike Schmid1, and Giovanni Settanni1,2 — 1Physics Department Johannes-Gutenberg University Mainz — 2Faculty of Physics and Astronomy Ruhr University Bochum
RNA-based therapeutics have demonstrated remarkable efficacy and hold great promise for future applications. The most common delivery systems for these drugs are lipid-based nanoparticles (LNPs), which incorporate ionizable cationic lipids (ICLs) as key components. ICLs are believed to facilitate endosomal escape of the cargo by interacting with anionic lipids in the endosomal membrane, although the underlying molecular mechanism remains unclear. One proposed model suggests that the membrane is destabilized by cone-shaped complexes formed between ICLs and endosomal anionic lipids; clear evidence of stable complexes is still missing. Here[1], we re-examine the problem through equilibrium and nonequilibrium simulations of model membrane systems containing DODMA (ICL), DOPS (anionic lipid) and DOPE (helper lipid). Our results confirm absence of co-localization at equilibrium, but reveal a transient formation of cone-shaped complexes during lamellar-to-inverted-hexagonal phase transitions, which considerably accelerates the transition process. These findings may open new ways for controlling endosomal escape through the rational design of ICLs optimized to interact with cell- or stage-specific endosomal anionic lipids. [1] Zimmer DN, Schmid F, Settanni G. ChemRxiv. 2025; doi:10.26434/chemrxiv-2025-rwb18
Keywords: Lipid-based nanoparticles; anionic/cationic lipids; lamellar-to-hexagonal phase transition; endosomal escape