Novel Swelling‐Lytic Cell Death Triggered by Cargo‐Free Ionizable Lipid Nanoparticles

Abstract Lipid nanoparticles (LNPs) are recognized as robust and versatile drug delivery platforms holding significant promise for personalized and precision medicine applications. However, their intrinsic biological effects, including dose‐limiting toxicity and acute inflammation, limit their widespread application. Elucidating the underlying mechanisms paradoxically enables dual‐path optimization: targeted mitigation strategies for adverse effects and deliberate amplification of adverse effects for repurposing (“waste‐to‐resource”). Here, cargo‐free lipid nanoparticles containing the ionizable phospholipid IP9 (ipLNP) are found to induce broad swelling (bubble) morphology and lytic cell death across multiple cell types. ipLNP‐induced cell death involves reactive oxygen species (ROS) increase, lipid peroxidation, and GSDME cleavage, but is only inhibited by vitamin E among the tested inhibitors. By exploring the effects of vitamin E, lysosome‐associated lytic cell death is found to be triggered by ipLNP and mediated by lysosome membrane destabilization. Moreover, ipLNP exhibits remarkable potential as novel Th1/Th17‐directing vaccine adjuvants and emerging cancer therapeutic agents, not merely as drug carriers.