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    • Increasing trans epithelial transport efficiency is another

    2021-09-06

    Increasing trans-epithelial transport efficiency is another area where different strategies are being developed for overcoming transcytosis. Enhancing the affinity for the basal membrane and weakening apical exocytosis through the optimisation of surface hydrophobicity have been demonstrated [79]. Surface modification of nanoparticles for enhancing their aggregation, has been reported to facilitate improved cellular retention in 4 T1 cells, both in vitro and in vivo through decreasing their exocytosis and minimizing the backflow to the bloodstream [90]. Control of histamine release from mast Q-VD Oph mg has also been observed by tweaking the exocytosis profile of PLGA nanoparticles added to these cells [78].
    Conclusion and future directions This review highlights the potential role of exocytosis in influencing nanoparticle and nanocomplex based gene delivery. Non-viral gene delivery utilizes inorganic nanoparticles as well as lipids, polymers and peptides which can form complex with nucleic acids and mediate its delivery. Of the many factors that are likely to control the gene delivery efficiency, cellular retention and exocytosis is the least understood. We have tried to summarize the possible intracellular fate of nanocomplexes carrying transgene(Fig. 3), while highlighting the desired trafficking and release pathways for effective transgene delivery to nucleus (Fig. 3C). Many articles have reported the exocytosis of internalized nanoparticles from cells after their uptake. Nanoparticles and nanocomplexes once internalized can leave the cells through multiple pathways, depending on variable factors. However, lysosome and multi vesicular body (MVB) mediated cellular egress could be the major pathways. Nanoparticle exocytosis patterns are very variable and influenced by multiple factors including physiological changes. The significance of these studies and how the different intrinsic and extrinsic factors controlling exocytosis can be manipulated for better cellular retention is likely to help in developing improved strategies for gene delivery. Several areas need to be explored better in order to quantitate and understand exocytosis and cellular retention. For example studying exocytosis of organic nanocomplexes has been hindered by the possibility of their dissociation in the cytoplasm and stability issues. One of the ways to tackle this is to use differential and density-gradient subcellular fractionation methods. Both the carrier and the cargo can be separately assayed in this way. However, the analytical precision of such studies need to be improved. Cellular retention also needs to be analysed along with intracellular localization studies for better prediction of outcomes in gene delivery. Strong exocytosis versus high cellular retention in undesirable cellular compartments can both be detrimental to gene delivery efficiency. Predicting rates of exocytosis in relation to that of endocytosis could provide important insights into the process as well and provide better frameworks for time-window of opeation. Such studies have been carried out in case of polymeric nanoparticles where a mathematical model based on mass action law predicts nanoparticle exocytosis to be 7 times slower than the process of endocytosis [91]. Experimental studies analysing exocytosis rates can also add to better understanding of the area. For example by calculating mean square displacement values, the rate constants for exocytosis of different inorganic and organic nanoparticles like SWNT, AuNP and poly (D,l-lactide-co-glycolide) was found to be in range of 10−4 to 10−3 [38]. Moreover, highly variable cellular retention and egress behaviour of nanoparticles depending upon a plethora of factors makes it difficult to make significant associations and predictions. Broader classifications like understanding cellular retention behaviour in cancerous versus non-cancerous cells and comparing exocytosis profile depending on chemical nature of the nanoparticle might shed some predictive light to this area.