Influence of protein aggregates, extracellular vesicles, and lipoprotein fusion on ionizable lipid nanoparticles protein corona analysis

Since 2018, ionizable lipid nanoparticles (LNPs) have revolutionized nucleic acid therapeutics. However, achieving potent extrahepatic delivery remains a formidable challenge, primarily due to rapid hepatic uptake driven by apolipoprotein adsorption. While analyzing the LNP protein corona is essential for engineering organ-specific tropism, these soft materials present unique analytical hurdles. Co-isolation of blood-borne contaminants, such as extracellular vesicles and lipoproteins, often masks the true corona composition. This perspective examines the critical need for refined proteomic strategies to distinguish genuine corona proteins from impurities. We propose tailored investigative approaches, suggesting the LNP protein corona significantly differs from the rigid shells observed on inorganic nanoparticles. Engineering organ-specific LNPs requires a deep understanding of the protein corona, yet its fluid nature makes analysis difficult. This perspective identifies how blood contaminants mask true corona composition and advocates for refined strategies to study these unique lipid-protein interfaces.