Abstract
Extracellular protein coronas (exPCs), which have been identified in various biofluids, are recognized for their pivotal role in mediating the interaction between nanoparticles and the cytomembrane. However, it is still unclear whether various exPCs can induce different levels of intracellular proteostasis, which is of utmost importance in preserving cellular function, and eliciting distinct intracellular biological behaviors. To investigate this, two types of exPC-coated iron oxide nanoparticles (IONPs) are prepared and used to investigate the influence of exPCs on extracellular and intracellular biological outcomes. The results demonstrate that the formation of exPCs promotes the colloidal stability of IONPs, and the discrepancies in the components of the two exPCs, including opsonin, dysopsonin, and lipoprotein, are responsible for the disparities in cellular uptake and endocytic pathways. Moreover, the differential evolution of the two exPCs during cellular internalization leads to distinct autophagy and glycolysis activities, which can be attributed to the altered depletion of angiopoietin 1 during the formation of intracellular protein coronas, which ultimately impacts the PI3K/AKT-mTOR signaling. These findings offer valuable insights into the dynamic characteristics of exPCs during cellular internalization, and their consequential implications for cellular internalization and intracellular metabolism activity, which may facilitate the comprehension of PCs on biological effects of NPs and expedite the design and application of biomedical nanoparticles.