Lipid nanoparticles (LNPs) have emerged as modular and potent vehicles for nucleic acid delivery, offering a potentially promising new strategy for cancer therapy. This study investigates how LNP elasticity, modulated through variations in sterol lipid structure and sterol lipid molar ratio, affects LNP endocytosis and mRNA transfection in liver (HepG2), ovarian (OVCAR8), and lung (H1299) cancer cell lines. All LNP formulations were characterized for size, polydispersity index, and mRNA encapsulation efficiency and subsequently assessed for mRNA transfection in HepG2, OVCAR8, and H1299 cancer cells. In vitro screening showed that LNP elasticity influences mRNA transfection across all three cell types. Specifically, LNPs of intermediate stiffness enhanced mRNA transfection in HepG2 and OVCAR8 cells whereas LNPs with low stiffness improved mRNA transfection in H1299 cells. Mechanistic endocytosis studies showed that clathrin-mediated and lipid raft-mediated endocytosis pathways contribute to LNP uptake in all three cell lines. These findings highlight the promise of tuning LNP elasticity to enhance mRNA delivery to cancer cells and potentially improve the therapeutic efficacy of LNPs for cancer therapy applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s44258-026-00082-w.
Shuler et al. (Thu,) studied this question.