Understanding the biological identity of metal-organic framework through profiling proteomic fingerprinting of protein corona

Metal-organic frameworks (MOFs) have garnered substantial interest in the biomedical field due to their unique physicochemical properties, such as high porosity and favorable biocompatibility. Upon exposure to biological environments, biomaterials interact with various proteins that adsorb spontaneously onto their surfaces, leading to the formation and evolution of a protein layer known as the protein corona (PC). However, the composition of the PC on MOFs and its influence on their biological identity remain poorly understood. In this study, we systematically examine protein corona formation on three types of MOF materials (ZIF-8, MIL-53(Fe), and UiO66) in serum, alongside their associated biological effects. Proteomics analysis revealed significant differences in protein corona composition across the three MOFs, particularly in the abundance and types of predominant proteins. Subsequent biological assessments indicated that PC formation mitigated the cytotoxicity, oxidative stress, and immune response of macrophages toward MOFs. Regarding cellular uptake, protein corona formation markedly inhibited the uptake of ZIF-8 and MIL-53(Fe) by macrophages, while enhancing the internalization of UiO66 via clathrin-mediated endocytosis, microtubule-dependent transport, and phagocytosis. Additionally, the PC of these MOFs were enriched with opsonins and dysopsonins that influence phagocytosis. This study is the first to reveal the proteomic composition of PC on these three representative MOFs and to elucidate the role of PC in modulating the biological identities of MOFs in macrophage interactions. These findings offer valuable insights for advancing MOFs-based drug delivery systems in clinical applications and provide new perspectives for exploring the complex physiological behaviors of protein coronas on biomaterials.