Engineered Protein Coronas Reveal That Apolipoprotein E Enhances Transport of Particulate Pollutants across the Blood-Brain Barrier

Ultrafine and nanoscale particulate matter (PM) is increasingly implicated in adverse neurological outcomes, yet the molecular mechanisms governing its interaction with blood proteins and transport across the blood–brain barrier (BBB) remain unclear. Here, we establish an engineered protein–corona model to dissect how blood-borne particles acquire BBB-relevant transport properties. Gold nanoparticles were used as a controlled surrogate for PM and functionalized with thiolated DNA aptamers to enable reproducible assembly of defined coronas composed of three physiologically relevant proteins─human serum albumin (HSA), apolipoprotein E (ApoE), and complement component C3b. In a bEnd.3 Transwell BBB model, corona identity dictated enhanced colloidal stability and transcytosis efficiency, with ApoE-enriched coronas nearly doubling apparent permeability and increasing 24 h transport by 1.6-fold relative to bare particles. Mechanistic studies revealed an energy-dependent, predominantly clathrin-mediated uptake pathway. Importantly, ApoE precoronation also enhanced endothelial penetration of polystyrene particles and increased the endothelial cytotoxicity of diverse industrial-source PM samples. This work provides a mechanistic framework linking protein corona composition to BBB penetration, advancing molecular risk assessment of environmentally relevant particulate matter.