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      Recent Advances in Understanding the Protein Corona of Nanoparticles and in the Formulation of “Stealthy” Nanomaterials

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          In the last decades, the staggering progress in nanotechnology brought around a wide and heterogeneous range of nanoparticle-based platforms for the diagnosis and treatment of many diseases. Most of these systems are designed to be administered intravenously. This administration route allows the nanoparticles (NPs) to widely distribute in the body and reach deep organs without invasive techniques. When these nanovectors encounter the biological environment of systemic circulation, a dynamic interplay occurs between the circulating proteins and the NPs, themselves. The set of proteins that bind to the NP surface is referred to as the protein corona (PC). PC has a critical role in making the particles easily recognized by the innate immune system, causing their quick clearance by phagocytic cells located in organs such as the lungs, liver, and spleen. For the same reason, PC defines the immunogenicity of NPs by priming the immune response to them and, ultimately, their immunological toxicity. Furthermore, the protein corona can cause the physical destabilization and agglomeration of particles. These problems induced to consider the PC only as a biological barrier to overcome in order to achieve efficient NP-based targeting. This review will discuss the latest advances in the characterization of PC, development of stealthy NP formulations, as well as the manipulation and employment of PC as an alternative resource for prolonging NP half-life, as well as its use in diagnostic applications.

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          Most cited references 78

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          Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers

          The current gold standard to reduce non-specific cellular uptake of drug delivery vehicles is by covalent attachment of poly(ethylene glycol) (PEG). It is thought that PEG can reduce protein adsorption and thereby confer a stealth effect. Here, we show that polystyrene nanocarriers that have been modified with PEG or poly(ethyl ethylene phosphate) (PEEP) and exposed to plasma proteins exhibit a low cellular uptake, whereas those not exposed to plasma proteins show high non-specific uptake. Mass spectrometric analysis revealed that exposed nanocarriers formed a protein corona that contains an abundance of clusterin proteins (also known as apolipoprotein J). When the polymer-modified nanocarriers were incubated with clusterin, non-specific cellular uptake could be reduced. Our results show that in addition to reducing protein adsorption, PEG, and now PEEPs, can affect the composition of the protein corona that forms around nanocarriers, and the presence of distinct proteins is necessary to prevent non-specific cellular uptake.
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            Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination.

            30-99% of administered nanoparticles will accumulate and sequester in the liver after administration into the body. This results in reduced delivery to the targeted diseased tissue and potentially leads to increased toxicity at the hepatic cellular level. This review article focuses on the inter- and intra-cellular interaction between nanoparticles and hepatic cells, the elimination mechanism of nanoparticles through the hepatobiliary system, and current strategies to manipulate liver sequestration. The ability to solve the "nanoparticle-liver" interaction is critical to the clinical translation of nanotechnology for diagnosing and treating cancer, diabetes, cardiovascular disorders, and other diseases.
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              The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery.

               Claudia Corbo (corresponding) ,  Roberto Molinaro,  Alessandro Parodi (2016)
              In a perfect sequence of events, nanoparticles (NPs) are injected into the bloodstream where they circulate until they reach the target tissue. The ligand on the NP surface recognizes its specific receptor expressed on the target tissue and the drug is released in a controlled manner. However, once injected in a physiological environment, NPs interact with biological components and are surrounded by a protein corona (PC). This can trigger an immune response and affect NP toxicity and targeting capabilities. In this review, we provide a survey of recent findings on the NP-PC interactions and discuss how the PC can be used to modulate both cytotoxicity and the immune response as well as to improve the efficacy of targeted delivery of nanocarriers.

                Author and article information

                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                03 April 2020
                : 8
                1First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua , Padua, Italy
                2Nano-Inspired Biomedicine Laboratory, Institute of Paediatric Research—Città della Speranza , Padua, Italy
                3Department of Pharmaceutical and Pharmacological Sciences, University of Padua , Padua, Italy
                Author notes

                Edited by: Roberto Molinaro, University of Urbino Carlo Bo, Italy

                Reviewed by: Leopoldo Sitia, University of Milan, Italy; Pradipta Ranjan Rauta, University of Texas MD Anderson Cancer Center, United States

                *Correspondence: Marco Agostini m.agostini@ 123456unipd.it

                This article was submitted to Nanobiotechnology, a section of the journal Frontiers in Bioengineering and Biotechnology

                Copyright © 2020 Rampado, Crotti, Caliceti, Pucciarelli and Agostini.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 89, Pages: 19, Words: 16063
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Funded by: Fondazione Cassa di Risparmio di Padova e Rovigo 10.13039/100007479
                Bioengineering and Biotechnology


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