Abstract

Nanomaterials have high potential as powerful tools for nanomedicine in a wide range of most promising applications as highly specific devices for diagnosis and therapy. Yet, despite enormous research activities in the design and synthesis of nanomaterials for biomedicine, only a small number of those have made their way to clinical use. The unavoidable formation of a biomolecular adsorption layer, the ‘protein corona’ or ‘biomolecular corona’ around nanoparticles (NPs) has been recognized as a major roadblock on the way toward the efficient design of nanomedicines. It masks the generic NP properties and creates a new ‘biological identity’ that largely controls the interactions with the biological environment. Therefore, for successful design of nanomedical devices, researchers must anticipate formation of this protein adlayer and its ensuing effects. In this review, we summarize our current knowledge in the field and focus on three topics that appear to be important for furthering progress in our ability to predict in-vivo responses to NP incorporation from in-vitro studies. First, we address fundamental physicochemical issues of protein corona formation as revealed by recent in-vitro studies, with a focus on the underlying mechanistic details. Second, we illustrate with recent examples how our present, still incomplete understanding can already be exploited to control protein corona formation in the organism, including important processes involving the immune system. Third, recent advances in the transition from in-vitro to in-vivo studies of protein adsorption will be summarized, which is obviously a key step in NP development for nanomedicine. We conclude this review with an outlook on possible future developments in the field.

Highlights

  • Studies of interactions of artificial bulk materials with biomolecules have a long-standing history due to their importance for the development of biocompatible medical devices, e.g. catheters, joint replacements, or stents [1]

  • If these proteins are preadsorbed under suitable conditions, they will form a shell of folded proteins that may even be recognized as “self” by the immune system

  • Only a few types of NPs have been approved by the US Food and Drug Administration (FDA), mostly for cancer therapy, and a few more are in the approval pipeline [204]

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Summary

Introduction

Studies of interactions of artificial bulk materials with biomolecules have a long-standing history due to their importance for the development of biocompatible medical devices, e.g. catheters, joint replacements, or stents [1]. ‘protein corona’ [11] and, subsequently, ‘biomolecular corona’ [12] (to acknowledge the presence of other biomolecules, e.g. lipids and carbohydrates) have been coined to describe this adsorption layer It conceals the ‘physicochemical identity’ of the pristine NPs and confers a ‘biological identity’ to the NPs because cells within an organism interact with this adlayer rather than the NP surface, mainly via receptor proteins resident in the plasma membrane [12]. The physical nature of the protein corona is largely governed by the (surface) properties of the NPs and by the types and (relative) amounts of biomolecules (and their individual properties) present in the biofluid [13e16] It is affected by external factors such as incubation time, temperature, shear forces due to flow (e.g. in vitro in reactors or in vivo in the bloodstream), and may even reflect the history of the entire trajectory taken by a NP migrating through different compartments of an organism [12,17e20]. We discuss ongoing challenges and give an outlook on research directions that may help enhance the effectiveness of the development of NPs for diagnostics and therapy

Current views of the protein corona
Temporal evolution of the protein corona
Characterization of the protein corona
NP properties
Protein properties
NP-protein interactions
Nanoparticle engineering for control of the protein corona
Opsonization of adsorbed proteins by the complement system
Corona engineering to prevent immunoglobulin adsorption
Corona design by using specific protein binding
Corona design using engineered proteins
In-vivo experiments to study corona formation
In vivo corona formation
Findings
Conclusions and perspectives
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