Mechanical movements generated by movable lipids break endosomal barriers for enhanced mRNA therapeutics

Lipid nanoparticles (LNPs), composed of ionizable lipids, phospholipids, cholesterol, and PEGylated lipids, have been successfully used in messenger RNA (mRNA) vaccine development. Despite substantial progress, endosomal entrapment after cellular internalization is still a critical bottleneck limiting the vaccine efficacy. While the efforts to optimize lipid pK_a, spatial conformation, and LNP composition have been made, further fine-tuning of these parameters shows diminishing returns in improving effectiveness. Here, we propose a previously unreported parameter, programmable mechanical movement. LNPs are expected to destabilize endosomal membranes through conducting mechanical movements under specific inputs, achieving robust endosomal escape. Specifically, we demonstrate a light-emitting diode (LED)-driven movable lipid (i.e., phenylazothiazole lipid) capable of performing mechanical movements. We integrate the movable lipids into the BNT162b2 formulation from Pfizer-BioNTech. Upon LED irradiation, the movable lipids within LNPs function as molecular rotors, thereby facilitating endosomal membrane destabilization. This strategy has achieved exciting preclinical results in enhancing mRNA-LNP cancer vaccine efficacy.