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Abstract

Upon incubation of nanoparticles in biological uids, a new layer called as protein corona is formed on their surface affecting the interactions between nanoparticles and targeted cell during the endocytosis process. In the present study, a mathematical model based on the diffusion of membrane mobile receptors is proposed. Opposing the endocytosis proceeding, membrane bending and tension energies are named as resistant energy. Also, binding energy and free-energy associated with the congurational entropy are called as promoter energy. Utilizing this model, endocytosis of gold nanoparticle (GNP) is simulated to explore the biological media effect. The results reveal that there exists a nanoparticle size of 60nm at which, the endocytosis time is minimum. It has been illustrated that, although for sufficiently small particles of diameter 30nm, membrane tension has a negligible contribution (< 10%) in the resistant energy, it noticeably increases the endocytosis processing time for large particles. Therefore, we report several parametric studies to provide a better insight into the effects of biological media on the ingestion of nanoparticles. Through a detailed analysis of the engulfment of the nanoparticles, it is shown that the nanoparticle radius corresponding to the quickest possible ingestion time is affected in the presence of corona. Moreover, it is found that the formation of this layer can not only affect the endocytosis time but also can lead to incomplete engulfment by decreasing the ligand density on the nanoparticle surface. Use of the proposed model can play a signicant role in advancing the design of nanoparticles in the targeted drug delivery applications.

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... Differences in the structure of proteins constituting the PC causes differential cellular binding, even for NPs with identical PC. PC also impacts interactions between NPs and targeted cells during the endocytosis process [89]. Even subtle changes in the protein composition affect the level of NP uptake [90]. ...
... It is generally clear that NP internalization by cells happens predominantly by active transport rather than by low-yielding passive transport, such as pinocytic clathrin-mediated pathways that mediate cellular uptake of NPs, which end up in lysosomes and endosomes [92]. Also, receptor-mediated endocytosis (RME), another kind of active transport, is an effective route through which NPs are ingested into the cell [89]. This mechanism offers specificity, associated with the receptor-ligand interaction between NPs and the cell membrane. ...
... The efficiency of endocytosis is dependent on various factors including NP size [93,94], surface properties [95], and shape [96][97][98]. Moreover, alongside these primary factors, the biological media, under forming PC on the NP, can significantly impact the efficiency of the endocytosis process [89]. ...
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Proteins are known to play important roles in the biosynthesis of metallic nanoparticles (NPs), which are biological substitutes for conventionally used chemical capping and stabilizing agents. When a pristine nanoparticle comes in contact with a biological media or system, a bimolecular layer is formed on the surface of the nanoparticle and is primarily composed of proteins. The role of proteins in the biosynthesis and further uptake, translocation, and bio-recognition of nanoparticles is documented in the literature. But, a complete understanding has not been achieved concerning the mechanism for protein-mediated nanoparticle biosynthesis and the role proteins play in the interaction and recognition of nanoparticles, aiding its uptake and assimilation into the biological system. This review critically evaluates the knowledge and gaps in the protein-mediated biosynthesis of nanoparticles. In particular, we review the role of proteins in multiple facets of metallic nanoparticle biosynthesis, the interaction of proteins with metallic nanoparticles for recognition and interaction with cells, and the toxic potential of protein-nanoparticle complexes when presented to the cell.
... The intracellular milieu contains compounds for cell growth, proliferation, differentiation and death that are distributed throughout the cytoplasm, nucleus, mitochondria, endoplasmic reticulum and Golgi complex [4]. Endocytosis opens a window of opportunity for communication of materials, energy and information between the inside and outside of cells; such a process provides the essential link for life and physiological activities [5,6]. ...
... Formation of a protein corona increased the time required for endocytosis. In addition, the presence of a protein corona significantly reduced ligand density on the Au nanostructure surface, resulting in defective engulfment [4]. Surface alteration is not always a negative factor for cellular uptake of nanoparticles. ...
... In addition to the microenvironment, another parameter that should be taken into account when performing in vivo investigations is protein adsorption on the surface of the nanoparticles within the circulation. The adsorbed serum proteins in this protein corona may adversely influence how nanoparticles enter cells, such as the time required for internalization [4,283]. ...
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Humans are exposed to nanoscopical nanobiovectors (e.g. coronavirus SARS-CoV-2) as well as abiotic metal/carbon-based nanomaterials that enter cells serendipitously or intentionally. Understanding the interactions of cell membranes with these abiotic and biotic nanostructures will facilitate scientists to design better functional nanomaterials for biomedical applications. Such knowledge will also provide important clues for the control of viral infections and the treatment of virus-induced infectious diseases. In the present review, the mechanisms of endocytosis are reviewed in the context of how nanomaterials are uptaken into cells. This is followed by a detailed discussion of the attributes of man-made nanomaterials (e.g. size, shape, surface functional groups and elasticity) that affect endocytosis, as well as the different human cell types that participate in the endocytosis of nanomaterials. Readers are then introduced to the concept of viruses as nature-derived nanoparticles. The mechanisms in which different classes of viruses interact with various cell types to gain entry into the human body are reviewed with examples published over the last five years. These basic tenets will enable the avid reader to design advanced drug delivery and gene transfer nanoplatforms that harness the knowledge acquired from endocytosis to improve their biomedical efficacy. The review winds up with a discussion on the hurdles to be addressed in mimicking the natural mechanisms of endocytosis in nanomaterials design.
... Efficient delivery of drugs by MNP-coated nanocomposites requires a thorough knowledge of the proteic behavior of the drug molecule [247][248][249]. Pharmacokinetic behavior is of utmost importance since it can lead to better drug administration and by this, to more efficient disease treatment and management [250,251]. ...
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Magnetic nanoparticles (MNPs) have evolved tremendously during recent years, in part due to the rapid expansion of nanotechnology and to their active magnetic core with a high surface-to-volume ratio, while their surface functionalization opened the door to a plethora of drug, gene and bioactive molecule immobilization. Taming the high reactivity of the magnetic core was achieved by various functionalization techniques, producing MNPs tailored for the diagnosis and treatment of cardiovascular or neurological disease, tumors and cancer. Superparamagnetic iron oxide nanoparticles (SPIONs) are established at the core of drug-delivery systems and could act as efficient agents for MFH (magnetic fluid hyperthermia). Depending on the functionalization molecule and intrinsic morphological features, MNPs now cover a broad scope which the current review aims to overview. Considering the exponential expansion of the field, the current review will be limited to roughly the past three years.
... Once nanoparticles are injected into the systemic circulation, nanoparticles encounter serum components, such as proteins, resulting in the formation of a protein corona on the surface. The formation of a protein corona is critical for the design of efficient and safe nanoparticles for tissue-targeting, nanomedicines, and other applications, so research related to the protein corona is a subject of great interest [136][137][138][139][140][141][142][143][144][145][146]. Although protein corona formation on a nanoparticle surface may adversely affect targeting [147], controlling them can also be applied to achieve more effective targeting [51,54,55,[148][149][150][151][152][153][154]. ...
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The era of the aging society has arrived, and this is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such neurological disorders are serious costly diseases that have a significant impact on society, both globally and socially. Gene therapy has great promise for the treatment of neurological disorders, but only a few gene therapy drugs are currently available. Delivery to the brain is the biggest hurdle in developing new drugs for the central nervous system (CNS) diseases and this is especially true in the case of gene delivery. Nanotechnologies such as viral and non-viral vectors allow efficient brain-targeted gene delivery systems to be created. The purpose of this review is to provide a comprehensive review of the current status of the development of successful drug delivery to the CNS for the treatment of CNS-related disorders especially by gene therapy. We mainly address three aspects of this situation: (1) blood-brain barrier (BBB) functions; (2) adeno-associated viral (AAV) vectors, currently the most advanced gene delivery vector; (3) non-viral brain targeting by non-invasive methods.
... Shadmani and workers at cellular level disclosed the how impact of corona formation leads to receptor mediated endocytosis of gold nanoparticles. The optimal value based on mathematical model for corona particle (bare diameter 40 nm vs. 60 nm corona particle) and ligand density ~1500 μm − 2 over 100 nm of gold nanoparticle are accounted to reduce endocytosis time via balance approach of membrane-tension energy and ligand receptor interaction density indicating the pivotal role in silico modeling of NC design [94]. ...
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Background In past few decades, the research on engineered nanocarriers (NCs) has gained significant attention in cancer therapy due to selective delivery of drug molecules on the diseased cells thereby preventing unwanted uptake into healthy cells to cause toxicity. Scope of review The applicability of enhanced permeability and retention (EPR) effect for the delivery of nanomedicines in cancer therapy has gained limited success due to poor accessibility of the drugs to the target cells where non-specific payload delivery to the off target region lack substantial reward over the conventional therapeutic systems. Major conclusions In spite of the fact, nanomedicines fabricated from the biocompatible nanocarriers have reduced targeting potential for meaningful clinical benefits. However, over expression of receptors on the tumor cells provides opportunity to design functional nanomedicine to bind substantially and deliver therapeutics to the cells or tissues of interest by alleviating the bio-toxicity and unwanted effects. This critique will give insight into the over expressed receptor in various tumor and targeting potential of functional nanomedicine as new therapeutic avenues for effective treatment. General significance This review shortly shed light on EPR-based drug targeting using nanomedicinal strategies, their limitation, and advances in therapeutic targeting to the tumor cells.
... Shadmani and workers at cellular level disclosed the how impact of corona formation leads to receptor mediated endocytosis of gold nanoparticles. The optimal value based on mathematical model for corona particle (bare diameter 40 nm vs. 60 nm corona particle) and ligand density ~1500 μm − 2 over 100 nm of gold nanoparticle are accounted to reduce endocytosis time via balance approach of membrane-tension energy and ligand receptor interaction density indicating the pivotal role in silico modeling of NC design [94]. ...
Article
Abstract Background In past few decades, the research on engineered nanocarriers (NCs) has gained significant attention in cancer therapy due to selective delivery of drug molecules on the diseased cells thereby preventing unwanted uptake into healthy cells to cause toxicity. Scope of review The applicability of enhanced permeability and retention (EPR) effect for the delivery of nanomedicines in cancer therapy has gained limited success due to poor accessibility of the drugs to the target cells where non-specific payload delivery to the off target region lack substantial reward over the conventional therapeutic systems. Major conclusions In spite of the fact, nanomedicines fabricated from the biocompatible nanocarriers have reduced targeting potential for meaningful clinical benefits. However, over expression of receptors on the tumor cells provides opportunity to design functional nanomedicine to bind substantially and deliver therapeutics to the cells or tissues of interest by alleviating the bio-toxicity and unwanted effects. This critique will give insight into the over expressed receptor in various tumor and targeting potential of functional nanomedicine as new therapeutic avenues for effective treatment. General significance This review shortly shed light on EPR-based drug targeting using nanomedicinal strategies, their limitation, and advances in therapeutic targeting to the tumor cells. Keywords Cancer,Tumor metastasis, Nanomedicines, Drug delivery, Receptor targeting,Theranostics.
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0. Abbreviations 106 1. Introduction: overview of forces in biology 108 1.1 Subtleties of biological forces and interactions 108 1.2 Specific and non-specific forces and interactions 113 1.3 van der Waals (VDW) forces 114 1.4 Electrostatic and ’double-layer‘ forces (DLVO theory) 122 1.4.1 Electrostatic and double-layer interactions at very small separation 126 1.5 Hydration and hydrophobic forces (structural forces in water) 131 1.6 Steric, bridging and depletion forces (polymer-mediated and tethering forces) 137 1.7 Thermal fluctuation forces: entropic protrusion and undulation forces 142 1.8 Comparison of the magnitudes of the major non-specific forces 146 1.9 Bio-recognition 146 1.10 Equilibrium and non-equilibrium forces and interactions 150 1.10.1 Multiple bonds in parallel 153 1.10.2 Multiple bonds in series 155 2. Experimental techniques for measuring forces between biological molecules and surfaces 156 2.1 Different force-measuring techniques 156 2.2 Measuring forces between surfaces 161 2.3 Measuring force–distance functions, F(D) 161 2.4 Relating the forces between different geometries: the ‘Derjaguin Approximation’ 162 2.5 Adhesion forces and energies 164 2.5.1 An example of the application of adhesion mechanics of biological adhesion 166 2.6 Measuring forces between macroscopic surfaces: the surface forces apparatus (SFA) 167 2.7 The atomic force microscope (AFM) and microfiber cantilever (MC) techniques 173 2.8 Micropipette aspiration (MPA) and the bioforce probe (BFP) 177 2.9 Osmotic stress (OS) and osmotic pressure (OP) techniques 179 2.10 Optical trapping and the optical tweezers (OT) 181 2.11 Other optical microscopy techniques: TIRM and RICM 184 2.12 Shear flow detachment (SFD) measurements 187 2.13 Cell locomotion on elastically deformable substrates 189 3. Measurements of equilibrium (time-independent) interactions 191 3.1 Long-range VDW and electrostatic forces (the two DVLO forces) between biosurfaces 191 3.2 Repulsive short-range steric–hydration forces 197 3.3 Adhesion forces due to VDW forces and electrostatic complementarity 200 3.4 Attractive forces between surfaces due to hydrophobic interactions: membrane adhesion and fusion 209 3.4.1 Hydrophobic interactions at the nano- and sub-molecular levels 211 3.4.2 Hydrophobic interactions and membrane fusion 212 3.5 Attractive depletion forces 213 3.6 Solvation (hydration) forces in water: forces associated with water structure 215 3.7 Forces between ‘soft-supported’ membranes and proteins 218 3.8 Equilibrium energies between biological surfaces 219 4. Non-equilibrium and time-dependent interactions: sequential events that evolve in space and time 221 4.1 Equilibrium and non-equilibrium time-dependent interactions 221 4.2 Adhesion energy hysteresis 223 4.3 Dynamic forces between biomolecules and biomolecular aggregates 226 4.3.1 Strengths of isolated, noncovalent bonds 227 4.3.2 The strengths of isolated bonds depend on the activation energy for unbinding 229 4.4 Simulations of forced chemical transformations 232 4.5 Forced extensions of biological macromolecules 235 4.6 Force-induced versus thermally induced chemical transformations 239 4.7 The rupture of bonds in series and in parallel 242 4.7.1 Bonds in series 242 4.7.2 Bonds in parallel 244 4.8 Dynamic interactions between membrane surfaces 246 4.8.1 Lateral mobility on membrane surfaces 246 4.8.2 Intersurface forces depend on the rate of approach and separation 249 4.9 Concluding remarks 253 5. Acknowledgements 255 6. References 255 While the intermolecular forces between biological molecules are no different from those that arise between any other types of molecules, a ‘biological interaction’ is usually very different from a simple chemical reaction or physical change of a system. This is due in part to the higher complexity of biological macromolecules and systems that typically exhibit a hierarchy of self-assembling structures ranging in size from proteins to membranes and cells, to tissues and organs, and finally to whole organisms. Moreover, interactions do not occur in a linear, stepwise fashion, but involve competing interactions, branching pathways, feedback loops, and regulatory mechanisms.
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