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RNA Nanotechnology and Extracellular Vesicles (EVs) for Gene Therapy
Published in Peixuan Guo, Kirill A. Afonin, RNA Nanotechnology and Therapeutics, 2022
Zhefeng Li, Fengmei Pi, Peixuan Guo
Exosomes have great potential as delivery vectors (Zomer et al., 2010; van Dommelen et al., 2012; El-Andaloussi et al., 2013a; Melo et al., 2014) for therapeutic RNA that can remain fully functional after delivery into cell. They can enter cells through multiple routes including membrane fusion, tetraspanin and integrin receptor-mediated endocytosis, lipid raft-mediated endocytosis, or micropinocytosis. However, there is limited specificity regarding the recipient cells (Marcus & Leonard, 2013; van Dongen et al., 2016). Lack of specific cell targeting by exosomes has led to low therapeutic efficacy and potential toxicity (van Dommelen et al., 2012; El-Andaloussi et al., 2013a; El-Andaloussi et al., 2013b). There are several strategies to manipulate the targeting manner of exosomes have been developed over the decades. One example is to express certain cell-type-specific protein-based targeting ligands on their surface via genetic fusion. Neuron acetylcholine receptor-specific peptide RVG has been fused to EV membrane protein Lamp2b to be overexpressed on dendritic cells (varez-Erviti et al., 2011c). GE11 peptide, which is a ligand to EGFR (Epidermal Growth Factor Receptor), was fused to the transmembrane domain of the platelet-derived growth factor receptor to be overexpressed on EV donor HEK293T cells (Ohno et al., 2013). RGD peptide was fused to EV protein Lamp2b; thus, the EVs can deliver the chemical drug doxorubicin specifically to tumor cells (Tian et al., 2014). One problem in using fusion peptide for targeted exosome delivery is that the displayed peptide can be degraded during EV biogenesis (Hung & Leonard, 2015) (ex. LAMP2) (varez-Erviti et al., 2011c; Ohno et al., 2013; Tian et al., 2014; Hung & Leonard, 2015).
Latest advances in extracellular vesicles: from bench to bedside
Published in Science and Technology of Advanced Materials, 2019
Tomofumi Yamamoto, Nobuyoshi Kosaka, Takahiro Ochiya
Several articles have described the effectiveness of inhibiting EV production, which inhibits cancer progression in vitro and in vivo. Kosaka et al. revealed that knockdown of nSMase2, which is required for the synthesis of ceramide, reduced EV secretion and miR-210 transfer, resulting in suppression of angiogenesis and metastasis in a xenograft mouse model [106]. The lysosome-associated membrane protein-2 (LAMP-2) is associated with endocytosis [107], knockdown of LAMP-2 improved the therapeutic effect of sunitinib in pancreatic neuroendocrine tumors [108]. In addition, it has been shown that other molecules, such as RAB27A/B, TSG101, TSAP6, which are related to EV secretion, are involved in the EV secretion from cancer cells. Although therapeutic strategies for targeting EVs derived from cancer cells are effective, there are several issues to apply before clinical use. These genes have key roles in multiple cell biological phenomena, thus, their downregulation in normal cells would have deleterious effects on normal cell functions. Therefore, identification of the genes related to cancer-specific EV secretion mechanisms is needed before using EV-targeting therapy. It has also been suggested that EV-targeting therapy may affect normal cells [103]. To identify ‘cancer-specific molecules’ is indispensable for the future development of EV-targeting anticancer therapeutics. EV biogenesis is still unclear, and some challenging issues remain; however, the EV research field is developing rapidly. Thus, we hope that EV-targeting therapy will become a standard therapy for cancer patients.
Exenatide promotes the autophagic function in the diabetic hippocampus: a review
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Eman Mohammed Elsaeed, Ahmed Gamal Abdelghafour Hamad, Omnia S. Erfan, Mona A. El-Shahat, Fathy Abd Elghany Ebrahim
Lysosomes are the main organelles regulating all the steps following autophagosome formation. They are capable of breaking down any biological material, as they contain acid hydrolases. Their integrity is primarily influenced by two factors: the soluble acid hydrolases and the lysosomal membrane proteins. A vacuolar ATPase maintains an acidic (pH ≤5) milieu by pumping protons into the lysosomal lumen, making the acid hydrolases able to work. The lysosomal membrane proteins such as lysosome-associated membrane protein (LAMP-1 & LAMP-2) act to protect the cytoplasm from the action of the acid hydrolases and regulate the fusion of the lysosomes with other organelles, including the autophagosomes [15].