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.

Nat Commun 17, 2187 (2026). https://doi.org/10.1038/s41467-026-69017-8