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    • Recent studies are beginning to explore

    2022-06-22

    Recent studies are beginning to explore this complex interplay of pathways. For example, intracellular trafficking of poly(lactic-co-glycolic acid)(PLGA) based nanoparticles was studied in detail using 30 different Rab proteins as markers for intracellular transport vesicles (involved in exocytosis, endocytosis and autophagy). Clathrin and caveolae mediated uptake was observed to be prominent in the case of coumarin-6-loaded PLGA nanoparticles. Vesicles recycling PLGA nanoparticles in terminal stages were identified as autophagosomes (LC3 positive), melanosomes (Rab32, Rab38 positive vesicles), classic secretory vesicles (Rab3, Rab27 positive vesicles) and GLUT4 vesicles [33].
    Methods for studying cellular egress of nanoparticles and nanocomplexes
    Studies on exocytosis of nanoparticles from cells
    Strategies to enhance cellular retention of nanoparticles Endocytosis and exocytosis being dynamic processes depend on the concentration of nanocomplexes both inside and outside of the cell. Therefore cellular retention of nanoparticles might also vary with nanoparticle concentration and incubation time. Many studies have shown maximum exocytosis rates when the 873 have internalized nanoparticles to their saturation [31,53]. Time of incubation with nanoparticles before studying the exocytosis also influences the exocytosis profile [21,71]. Therefore, one needs to optimise these conditions to ensure maximum retention. Subcellular distribution of the nanoparticles is a key factor in determining cellular retention and their exocytosis. The fate of nanoparticle depends on uptake pathway and ultimately varies with many factors like shape, size and surface properties. Wang et al. showed that CuO nanoparticle localized in the mitochondria and nucleus could not be excreted [80]. Similarly nanoparticles localized in the lysosomes were reported to be exocytosed more easily than those present in cytoplasm [62]. Size, shape and surface properties have been shown to affect cellular retention and exocytosis of nanoparticles as shown in examples earlier in this text. Thus, one needs to optimise the biophysical factors of the nanoparticles to improve their retention profiles. Based on the available reports on exocytosis of nanoparticles and the associated time frame, we have broadly categorized the recycling as fast, slow and delayed (Fig. 2). Nature of the cell line can be a very important factor. Efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) is far more than that observed in MCF-7 cells [81]. One can therefore choose or design nanoparticles depending upon the intended cell line for use. Tumour cells are reported to exhibit higher exocytosis and thus more recycling of nanoparticles is expected [65]. This can lead to ineffective nanoparticle based gene/drug delivery approaches in many cases unless suitable carrier design or tweaking other extraneous factors is implemented. Exocytosis patterns also differ with external physiological conditions and can depend on a host of exogenous factors like calcium [64], cholesterol [8], serum proteins [71] etc. Of these, modulating the nature of the protein corona on nanoparticle surface appears to be an important strategy for controlling cellular retention. The fact that cells interact with the protein corona on the surface of nanoparticles rather than the native nanoparticle itself [82] makes it important to understand interaction of the nanoparticles with the medium. Limited attempts have been made toward blocking exocytosis for improving the nanoparticle retention. NPC, a thirteen trans-membrane glycoprotein is associated with surface of multivesicular late endosome (or MVB) and its depletion can cause cholesterol accumulation adn lysosomal dysfunction resulting into neural degeneration. Accumulation and enhanced cellular retention of lipid nanoparticle- siRNA complex was reported by Sahay et al. through this process [30]. Lysosomal degradation effected through photothermal effect has also recently been described as a strategy to prevent exocytosis of gate engineered mesoporous silica nanoparticles [83]. Hypoxic preconditioning has also been found to significantly increase nanoparticle retention in human breast cancer cells, which could be a new strategy for improving retention [84]. In situ chemical treatment to induce nanoparticle assembly in amine modified gold nanoparticles to prevent exocytosis with little toxicity has been achieved [66]. Inhibition of Chitosan nanoparticle exocytosis was attempted with the help of vacuoline-1 (prevent lysosomal fusion with plasma membrane) and wortmannin, suggesting prominent role played by multivesicular body and lysosomal pathways [40]. This study also confirmed reuptake of recycled nanoparticles by surrounding cells.