Abstract
Despite decades of research, the successful clinical translation of intravenously administered nanomedicines is underwhelming. One significant barrier to progress is the opsonization and rapid clearance from the bloodstream due to protein corona formation as an innate immune response. Biocompatible nanoparticle coatings that act as a barrier between the nanomaterial and the physiological environment are being continuously explored to elevate delivery success. However, the formation and composition of protein coronae, especially across species, are still poorly understood, which hinders the progress of translation from preclinical animal models to human applications. Here, we use quantitative protein assays, LC-MS proteomics, and machine learning to catalog the protein coronae from human and mouse serum formed on poly(lactic-co-glygolic) acid (PLGA) nanoparticles and explore the impact of a large library of coatings comprised of cholinium fatty acid-based ionic liquids (ILs) from 4- to 10-carbon chains with varying degrees of unsaturation. We discover that the species matters, with vast changes in the coronae being observed, depending on the source of the serum sample. Additionally, even very small changes in the ionic liquid anion structure result in the formation of diverse hard coronae. We identify several ILs that show enriched dysopsonins and depleted opsonins relative to serum that are promising candidates for future development as therapeutics or in biosensing.