The protein corona spontaneously develops and evolves on the surface of nanoscale materials when they are exposed to biological environments, altering their physiochemical properties and affecting their subsequent interactions with biosystems. In this Review, we provide an overview of the current state of protein corona research in nanomedicine. We next discuss remaining challenges in the research methodology and characterization of the protein corona that slow the development of nanoparticle therapeutics and diagnostics, and we address how artificial intelligence can advance protein corona research as a complement to experimental research efforts. We then review emerging opportunities provided by the protein corona to address major issues in healthcare and environmental sciences. This Review details how mechanistic insights into nanoparticle protein corona formation can broadly address unmet clinical and environmental needs, as well as enhance the safety and efficacy of nanobiotechnology products. 

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The protein corona from nanomedicine to environmental science

With the progression of nanotechnology, a growing number of nanomaterials have been created and incorporated into organisms and ecosystems, which raises significant concern about potential hazards of these materials on human health, wildlife, and the environment. Two-dimensional (2D) nanomaterials are one type of nanomaterials with thicknesses ranging from that of a single atom or of several atoms and have been proposed for a variety of biomedical applications such as drug delivery and gene therapy, but the toxicity thereof on subcellular organelles remains to be studied. In this work, we studied the impact of two typical 2D nanomaterials, MoS2 and BN nanosheets, on mitochondria, which are a type of membranous subcellular organelle that provides energy to cells. While 2D nanomaterials at a low dose exhibited a negligible cell mortality rate, significant mitochondrial fragmentation and partially reduced mitochondrial functions occurred; cells initiate mitophagy in response to mitochondrial damages, which cleans damaged mitochondria to avoid damage accumulation. Moreover, the molecular dynamics simulation results revealed that both MoS2 and BN nanosheets can spontaneously penetrate the mitochondrial lipid membrane through the hydrophobic interaction. The membrane penetration induced heterogeneous lipid packing resulting in damages. Our results demonstrate that even at a low dose 2D nanomaterials can physically damage mitochondria by penetrating the membrane, which draws attention to carefully evaluating the cytotoxicity of 2D nanomaterials for the potential biomedical application.

2D MoS2 and BN Nanosheets Damage Mitochondria through Membrane Penetration.

Two-dimensional (2D) materials have attracted tremendous interest ever since the isolation of atomically thin sheets of graphene in 2004 due to the specific and versatile properties of these materials. However, the increasing production and use of 2D materials necessitate a thorough evaluation of the potential impact on human health and the environment. Furthermore, harmonized test protocols are needed with which to assess the safety of 2D materials. The Graphene Flagship project (2013-2023), funded by the European Commission, addressed the identification of the possible hazard of graphene-based materials as well as emerging 2D materials including transition metal dichalcogenides, hexagonal boron nitride, and others. Additionally, so-called green chemistry approaches were explored to achieve the goal of a safe and sustainable production and use of this fascinating family of nanomaterials. The present review provides a compact survey of the findings and the lessons learned in the Graphene Flagship.

Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective.

Graphene-based nanoparticles are widely applied in many technology and science sectors, raising concerns about potential health risks. Emerging evidence suggests that graphene-based nanomaterials may interact with microorganisms, both pathogens and...

The gut microbiome meets nanomaterials: exposure and interplay with graphene nanoparticles

Graphene oxide, a typical two-dimensional carbon-based nanomaterial, has been broadly applied in different industries because of its unique mechanical, electric and thermal properties. These extensive applications will unavoidably release graphene...

DNA damage caused by light-driven graphene oxide: A new mechanism

Applications of reduced graphene oxide (rGO) in many different areas have been gradually increasing owing to its unique physicochemical characteristics, demanding more understanding of their biological impacts. Herein, we assessed the toxicological effects of rGO in mammary epithelial cells. Because the as-synthesized rGO was dissolved in sodium cholate to maintain a stable aqueous dispersion, we hypothesize that changing the cholate concentration in the dispersion may alter the surface property of rGO and subsequently affect its cellular toxicity. Thus, four types of rGO were prepared and compared: rGO dispersed in 4 and 2 mg/mL sodium cholate, labeled as rGO and concentrated-rGO (c-rGO), respectively, and rGO and c-rGO coated with a protein corona through 1 h incubation in culture media, correspondingly named pro-rGO and pro-c-rGO. Notably, c-rGO and pro-c-rGO exhibited higher toxicity than rGO and pro-rGO and also caused higher reactive oxygen species production, more lipid membrane peroxidation, and more significant disruption of mitochondrial-based ATP synthesis. In all toxicological assessments, pro-c-rGO induced more severe adverse impacts than c-rGO. Further examination of the material surface, protein adsorption, and cellular uptake showed that the surface of c-rGO was coated with a lower content of surfactant and adsorbed more proteins, which may result in the higher cellular uptake observed with pro-c-rGO than pro-rGO. Several proteins involved in cellular redox mediation were also more enriched in pro-c-rGO. These results support the strong correlation between dispersant coating and corona formation and their subsequent cellular impacts. Future studies in this direction could reveal a deeper understanding of the correlation and the specific cellular pathways involved and help gain knowledge on how the toxicity of rGO could be modulated through surface modification, guiding the sustainable applications of rGO.

Biological Impacts of Reduced Graphene Oxide Affected by Protein Corona Formation.

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Biological Impacts of Reduced Graphene Oxide Affected by Protein Corona Formation.