Understanding the protein corona - implications for nanomedicine and environmental health

(Nanowerk Spotlight) Nanoparticles are increasingly prevalent in our society, and as their use continues to expand, understanding their interaction with their local environments becomes vital. One critical aspect of these interactions is the formation of a biomolecular corona, which consists of proteins, lipids, sugar moieties, nucleic acids, and metabolites that spontaneously adsorb onto the surface of nanoparticles when they are introduced into biological fluids.
The protein corona is a complex and dynamic biological phenomenon that significantly influences the physiochemical properties and, thus, the behavior and fate of synthetic nanoparticles in biological systems. However, it is an often-overlooked factor in the application of nanoparticle-based solutions in medicine and environmental contexts.
We have covered this intriguing topic extensively over the years: on how personalized protein coronas determine fate and cytotoxicity of nanoparticles or can result in different therapeutic or toxic impacts of identical nanoparticles; but also how research in this field could lead to early cancer detection with sensory protein corona 'fingerprints'. Understanding the role of this protein corona appears to be a critical factor for successful clinical translation of medical nanotechnologies.
Protein coronas can be made up of a variety of proteins, including some that are present in very small amounts. These low-abundance proteins can have an important role in how nanoparticles interact with biosystems, but they have not been studied as extensively as the more abundant proteins.
Despite the challenges in reproducibility, experimental standardization, and the need for a deeper understanding of low-abundance components, protein corona research has made significant strides over the past few decades. The application of artificial intelligence (AI) and machine learning in protein corona studies has shown promise in deciphering complex patterns and predicting disease outcomes, which can lead to advancements in personalized nanomedicine.
History of protein corona research
History of protein corona research. AI, artificial intelligence; ML, machine learning; NP, nanoparticle; SA, sensor array. The superscript numbers refer to papers referenced in the article. (Image: Prof. Morteza Mahmoudi, Michigan State University) (click on image to enlarge)
The protein corona has been a subject of study for decades, with a significant milestone in 2007 when the term was coined by Kenneth A. Dawson and his team in an article in PNAS. What makes this topic so fascinating and relevant is that the protein corona can unpredictably alter nanoparticle outcomes, such as their function, uptake, biodistribution, immunological responses, and toxicity. This poses a challenge for therapeutic nanomedicine, as the protein corona can mask the intended reactivity of nanoparticle surfaces, block cell membrane receptors, and even enhance cytotoxicity.
Despite these challenges, the protein corona also offers new opportunities for diagnostic and personalized nanomedicine. For instance, the protein corona can be used for disease diagnosis, optimization of cell internalization, and improving the in vivo biodistribution of nanomedicines. The enrichment of plasma proteins onto nanoparticles can create a protein corona "fingerprint" that can be employed for personalized detection of biomarkers and assist in risk stratification, prognosis, and disease recognition. Additionally, selectively coating nanoparticles with purposely designed protein coronas can regulate cell-dependent uptake, promote blood circulation, and enhance therapeutic efficacy.
A timely review in Nature Reviews Materials ("The protein corona from nanomedicine to environmental science") covers the current state of protein corona research in nanomedicine, highlights challenges in research methodology and characterization, and discusses the role of artificial intelligence in advancing the field. Additionally, the review explores the opportunities offered by the protein corona for addressing healthcare and environmental issues and emphasizes how understanding its formation can improve the safety and efficacy of nanobiotechnology products.
While initial studies primarily focused on biomedical applications and human toxicity, the environmental aspect, known as the eco-corona, has been emerging more recently and has been discussed in detail in a review article in Nature Nanotechnology.
The eco-corona consists of proteins and other biomolecules such as metabolites and natural organic matter, which form as nanomaterials, enter the environment. Proteins play a central role in eco-corona studies due to their structural characterization, receptor engagement, and signaling. The eco-corona influences nanomaterial uptake, distribution, and environmental impact. It also imparts a biological identity, making nanomaterials recognizable by cells or organisms. This research is particularly important in the context of biological and ecological impacts of protein-corona-coated nanoplastics.
Despite remaining challenges, there are opportunities for method development and impactful systems for future eco-corona studies. Understanding the environmental dimensions of the protein corona can help create more sustainable and environmentally safe nanomaterials while enhancing the efficacy of nanomaterials used in remediation and the agri-food sector.
Artificial intelligence
Artificial intelligence (AI) and machine learning algorithms have been harnessed for data-driven discoveries of nanoparticle-biological interactions and complexities. They can identify important variables that affect protein corona formation on specific types of nanoparticles and have predicted diseases in patients using personalized protein corona fingerprints.
A better understanding of the composition, pattern, and decoration of biomolecules at the surface of nanoparticles, supplemented by AI, can facilitate the development of safer and more effective nanomedicine technologies with desired biological fates. However, several challenges remain in the field of protein corona research. These include nanoparticle heterogeneity, interpretation of protein patterns, and induced perturbations of immunological and toxicological responses.
Achieving reproducible data sets across research groups involved in protein corona research is a major challenge. This is largely due to the variability of biological systems from which the protein corona has been studied, the lack of unifying standards for nano-bio characterization protocols, and inconsistencies in experimental reporting strategies.
The development of new methodologies to probe the conformation of proteins in the biomolecular corona layer is also needed, as this information can help understand and predict the recognition of nanoparticles by immune systems and their responses to nanomedicine technologies.
Low-abundance proteins
Another issue in protein corona research is the lack of attention given to the role of low-abundance proteins and biomolecules compared to the bulk corona compositions. Studying these components can lead to a deeper understanding of biosystem responses, enabling the development of safer and more efficient therapeutic approaches.
Additionally, the role of disease-specific lipids and metabolomes, which can substantially alter the interaction of plasma proteins with nanoparticles, should be considered in protein corona research. Furthermore, a thorough investigation of the interactions between nanoparticles and biological membranes is essential, as it plays a crucial role in determining the uptake, trafficking, and ultimate fate of nanoparticles within cells. Understanding these interactions can help improve targeted drug delivery and the development of nanocarriers for various therapeutic applications.
The future of protein corona research will involve the development of more standardized protocols, greater understanding of the role of low-abundance proteins, and more comprehensive studies of nanoparticle-biological membrane interactions. Furthermore, integrating information on the eco-corona and considering the role of disease-specific lipids and metabolomes in protein corona research can contribute to a more holistic understanding of nanoparticle-biological interactions.
As the knowledge of the protein corona expands, there is potential for significant advancements in nanomedicine, including improved drug delivery, disease diagnosis, and personalized therapies. Ultimately, the integration of protein corona research with other relevant fields, such as nanotoxicology and ecological studies, can lead to the development of safer and more effective nanotechnologies that benefit both human health and the environment.
Michael Berger By – Michael is author of three books by the Royal Society of Chemistry:
Nano-Society: Pushing the Boundaries of Technology,
Nanotechnology: The Future is Tiny, and
Nanoengineering: The Skills and Tools Making Technology Invisible
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