Osmotic Pressure–Driven Lipid Nanoparticles Enable Potent Cytosolic Delivery of Nucleic Acids

ABSTRACT Lipid nanoparticles (LNPs) underpin the success of mRNA vaccines and other nucleic acid therapeutics, yet inefficient endosomal escape—typically less than 5%—remains a fundamental barrier limiting their potency and clinical translation. Here, we introduce salt‐loaded lipid nanoparticles (SLNPs), a simple and broadly applicable platform that leverages osmotic pressure to achieve efficient cytosolic delivery of nucleic acids. By encapsulating sodium chloride within the nanoparticle core, SLNPs establish an ionic gradient upon endocytosis that drives water influx, endosomal swelling, and membrane rupture, thereby enabling effective release of cargo into the cytosol. This osmotic mechanism markedly enhances mRNA expression across diverse cell types and achieves superior delivery efficiency compared to benchmark clinical LNPs, both in vitro and in vivo. Mechanistic analyses reveal that Na ⁺ ‐induced osmotic stress directly mediates endosomal destabilization, providing a distinct physical route to overcome a long‐standing biological barrier. SLNPs exhibit low systemic toxicity, robust immune responses, and compatibility with multiple LNP formulations and nucleic acid cargos. This conceptually new yet practical approach addresses a central limitation in nucleic acid delivery, offering a scalable and translationally relevant strategy for next‐generation RNA and gene‐based medicines.