A multiscale approach to lipid nanoparticle engineering from molecular structure to in vivo performance

The 2023 Nobel Prize in Physiology or Medicine recognized the discovery of base modifications that enabled effective mRNA vaccine development. Highlighting this, the former president of the Controlled Release Society, Twan Lammers, at the society's 2024 annual meeting, noted that it may soon be time for this recognition to extend to breakthroughs in drug delivery systems. Indeed, it was modern delivery technologies that unlocked the potential of RNA-based medicines, with lipid nanoparticles (LNPs) enabling their clinical translation less than a decade ago. While LNPs have proven essential for many nucleic acid delivery applications, their rational design remains challenged by complex lipid-RNA interactions, biological barriers, and the dynamic nano-bio interface. In this review, we highlight state-of-the-art strategies in LNP development, including computationally guided design, high-throughput screening, and insights into how protein corona formation shapes in vivo performance.