Following this principle, the design of NPs has focused on the development of new strategies to reduce or slow PC formation. This is because PC is often the prime reason for loss of NP stability, quick clearance, and potentially harmful immunologic reactions ( Westmeier et al., 2016). PC has been often considered a “fluid biological barrier,” something to be avoided for the nanoparticles to successfully achieve tumor targeting. SPC is much more dynamic than HPC due to quick exchange in proteins occurring with the biological environment, making it much more elusive to isolate and characterize. PC architecture is normally distinguished in a “hard” PC (HPC) in close contact and strongly interacting with the NP surface, and a more external layer of loosely and indirectly bound proteins defined as the “soft” PC (SPC). The assembly of this protein coating bestows NPs with a new biological identity that determines their colloidal stability, biodistribution, interactions, toxicity, and clearance ( Figure 1). The composition of PC is highly variable and depends on many factors including size, material, and surface charge of NPs. The array of proteins that become attached to nanovectors is collectively referred to as the protein corona (PC), and its assembly is considered the very first interaction between NPs and their biological milieu. In the sixties, Vroman discovered that when a synthetic material, including NPs, comes in contact with any biological fluid, it becomes quickly covered by resident proteins ( Vroman and Lukosevicius, 1964 Vroman et al., 1980). In order to solve these issues, it is paramount to achieve a better understanding of the interaction between NPs and the biological environment they are exposed to. In fact, most of the particles are unable to reach the target and accumulate mostly in off-target organs like the liver, spleen, and lungs, due to mononuclear phagocytic system (MPC) clearance ( Zhang et al., 2016). This high attrition rate can be explained by the sub-optimal biodistribution and safety profile of NPs after administration. However, despite the development of countless nanovector iterations, only a very small fraction of these platforms successfully reached the clinic ( Ventola, 2017). These efforts have brought to the development of a wide swath of nanovectors, with highly heterogeneous compositions and applications. The concept of using nanomaterials to improve the delivery of drugs and enhance the diagnosis of pathologies has driven biomedical research for decades. Nanotechnology for years held the promise of radically improving detection and treatment of many different diseases. 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. These problems induced to consider the PC only as a biological barrier to overcome in order to achieve efficient NP-based targeting. Furthermore, the protein corona can cause the physical destabilization and agglomeration of particles. For the same reason, PC defines the immunogenicity of NPs by priming the immune response to them and, ultimately, their immunological toxicity. 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. The set of proteins that bind to the NP surface is referred to as the protein corona (PC). When these nanovectors encounter the biological environment of systemic circulation, a dynamic interplay occurs between the circulating proteins and the NPs, themselves. This administration route allows the nanoparticles (NPs) to widely distribute in the body and reach deep organs without invasive techniques. Most of these systems are designed to be administered intravenously. 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. 3Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.2Nano-Inspired Biomedicine Laboratory, Institute of Paediatric Research-Città della Speranza, Padua, Italy. 1First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy.Riccardo Rampado 1,2, Sara Crotti 2, Paolo Caliceti 3, Salvatore Pucciarelli 1 and Marco Agostini 1,2 *
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