Protein Coronation-Induced Cancer Staging-Dependent Multilevel Cytotoxicity: An All-Humanized Study in Blood Vessel Organoids

The protein corona effect refers to the phenomenon wherein nanomaterials in the bloodstream are coated by serum proteins, yet how protein coronated nanomaterials interact with blood vessels and its toxicity implications remain poorly understood. In this study, we investigated protein corona-related vessel toxicity by using an all-humanized assay integrating blood vessel organoids and patient-derived serum. Initially, we screened various nanomaterials to discern how parameters including size, morphology, hydrophobicity, surface charge, and chirality-dependent protein corona difference influence their uptake by vessel organoids. For nanomaterials showing substantial differences in vessel uptake, their protein corona was analyzed by using label-free mass spectra. Our findings revealed the involvement of cancer staging-related cytoskeleton components in mediating preferential uptake by cells, including endothelial and mural cells. Additionally, a transcriptome study was conducted to elucidate the influence of nanomaterials. We confirmed that protein coronated nanomaterials provoke remodeling at both transcriptional and translational levels, impacting pathways such as PI3K-Akt/Hippo/Wnt, and membraneless organelle integrity, respectively. Our study further demonstrated that the remodeling potential of patient-derived protein coronated nanomaterials can be harnessed to synergize with antiangiogenesis therapeutics to improve the outcomes. We anticipate that this study will provide guidance for the safe use of nanomedicine in the future.