Engineered internal architecture of core-shell lipid nanoparticles promotes efficient mRNA endosomal release

Abstract

Messenger RNA (mRNA) therapeutics rely on lipid nanoparticles (LNPs) for delivery, yet inefficient endosomal escape remains a major bottleneck, with only a small fraction of internalized cargo reaching the cytoplasm. Conventional LNPs encapsulate mRNA in amorphous lipid cores, where partial charge neutralization and lack of structural order limit protonation-driven membrane disruption. Here, we present an architectural strategy that engineers LNP internal structure using ionizable lipid-coated gold nanoparticles (IC-AuNPs) as rigid, pH-responsive cores. The Au cores template the formation of radially ordered core-shell architectures that stabilize particles at physiological pH while amplifying charge segregation and curvature stress under acidic endosomal conditions. As a result, Au-LNPs achieve a twofold increase in endosomal escape and ~100-fold greater cytoplasmic mRNA diffusion compared to conventional LNPs. Functionally, Au-LNPs enhance mRNA expression in vitro, increases in vivo protein production up to sevenfold, boost antibody responses to SARS-CoV-2 vaccines, and improve therapeutic efficacy in a triple-negative breast cancer model.