Surface Charge‐Determined Protein Coronas of Nanoparticles Control Endothelial Cells Uptake Under Low Magnitude Shear Stress

Nanoparticles (NPs) are promising for atherosclerosis (AS) drug delivery, which involves exposure to low magnitude shear stress, including low shear stress and oscillatory shear stress. While NPs surface charge affects biodistribution and cellular uptake, its role in AS-targeted accumulation remains unclear. In this study, positively charged NPs (pNPs), near-electrically neutrally charged NPs (eNPs), and negatively charged NPs (nNPs) were employed to investigate their distribution and uptake in mice and endothelial cells (ECs). Here, we found that nNPs exhibited significantly greater accumulation and uptake by ECs at both atherosclerotic sites and regions subjected to low magnitude shear stress compared to pNPs and eNPs. Proteomic analysis revealed that the surface charge of the NPs profoundly influenced the composition of the protein corona. Specifically, nNPs adsorbed several orders of magnitude more apolipoprotein H (APOH) from serum than pNPs. Furthermore, low magnitude shear stress increased the levels of surface phospholipids, which are specific receptors for APOH, on ECs, thereby promoting the uptake of nNPs by ECs. In conclusion, our study uncovers a mechanism by which nNPs preferentially accumulate within atherosclerotic areas and uptake by ECs exposure to low magnitude shear stress, and provides insights for designing charge-optimized NPs for cardiovascular drug delivery.