Nanoparticle Association with Brain Cells Is Augmented by Protein Coronas Formed in Cerebrospinal Fluid

Neuronanomedicine harnesses nanoparticle technology for the treatment of neurological disorders. An unavoidable consequence of nanoparticle delivery to biological systems is the formation of a protein corona on the nanoparticle surface. Despite the well-established influence of the protein corona on nanoparticle behavior and fate, as well as FDA approval of neuro-targeted nanotherapeutics, the effect of a physiologically relevant protein corona on nanoparticle-brain cell interactions is insufficiently explored. Indeed, less than 1% of protein corona studies have investigated protein coronas formed in cerebrospinal fluid (CSF), the fluid surrounding the brain. Herein, we utilize two clinically relevant polymeric nanoparticles (PLGA and PLGA-PEG) to evaluate the formation of serum and CSF protein coronas. LC–MS analysis revealed distinct protein compositions, with selective enrichment/depletion profiles. Enhanced association of CSF precoated particles with brain cells demonstrates the importance of selecting physiologically relevant biological fluids to more accurately study protein corona formation and subsequent nanoparticle-cell interactions, paving the way for improved nanoparticle engineering for in vivo applications.