Navigating the Biomolecular Corona: Biological Interactions and Therapeutic Implications of RNA–Lipid Nanoparticles

Lipid nanoparticles (LNPs) have reshaped RNA therapeutics, underpinning the success of mRNA vaccines and emerging gene therapies. Once introduced into the body, LNPs acquire a dynamic biological identity through the rapid adsorption of biomolecules present in biological fluids, resulting in the formation of a biomolecular corona. Rather than being a passive byproduct, the biomolecular corona substantially alters the physicochemical properties of LNPs and governs key biological processes, including cellular uptake, immune recognition, circulation, and biodistribution, therefore acting as a functional interface that modulates biological interactions and therapeutic outcomes. The corona composition is jointly dictated by intrinsic LNP properties and the surrounding biological milieu. Understanding how the corona regulates the LNP fate and function is essential for translating preclinical insights into predictable clinical outcomes. In this review, we provide a comprehensive overview of how corona formation modulates the in vivo fate of LNPs and shapes therapeutic performance. We discuss strategies to modulate corona composition and downstream biological interactions through lipid design and surface functionalization. Finally, we offer a forward-looking perspective on harnessing the corona as a programmable interface to enable safer, more precise delivery of LNPs, with the aim of broadening the clinical applicability of next-generation RNA therapeutics.