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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
The application of RNA interference technology, such as siRNA, to knockdown gene expression has been of great interest (Pecot et al., 2011). The nanometer-scale EVs (Valadi et al., 2007; van Dommelen et al., 2012; El-Andaloussi et al., 2013a; El-Andaloussi et al., 2013b) can deliver biomolecules into cells by direct fusion with the cell membrane through tetraspanin domains or back fusion with endosomal compartment membranes for endosome escape. Therapeutic payloads, such as siRNA, can fully function after delivery to cells by EVs (Valadi et al., 2007; van Dommelen et al., 2012; El-Andaloussi et al., 2013a; El-Andaloussi et al., 2013b). However, EVs lack selectivity and can also randomly fuse to healthy cells. To generate specific cell-targeting EVs, approaches by in vivo expression of cell-specific peptide ligands on the surface of EVs have been explored (varez-Erviti et al., 2011c; Ohno et al., 2013). However, in vivo expression of protein ligands is limited to the availability of ligands in their producing cell types (van Dommelen et al., 2012; El-Andaloussi et al., 2013a), (Wiklander et al., 2015). It would be desirable for in vivo cancer cell targeting using in vitro surface display technology to display nucleic acid-based or chemical targeting ligands on EVs.
Targeted Systemic Combinatorial Delivery of siRNA Polyplexes–Functional Quantum Dot-siRNA Nanoplexes
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
RNA interference (RNAi)-based therapy has been extensively investigated over the past decades, which provides an option to combat many severe diseases including cancer [3]. Attractively, siRNA, as one of the RNAi therapeutics, offers a tremendous potential for sequence-specific suppression of gene expression via mRNA degradation pathways [51]. However, successful applications of RNAi-based cancer therapy require sufficient intracellular delivery of siRNA to the target site and effective knockdown of targeted transcripts. Thus, an ideal siRNA delivery system should possess multifunctionalities to conquer multiple barriers all the way to its site of action [52]. Generally, the siRNA carrier needs to incorporate siRNA into nanoparticles of suitable size to protect siRNA from nucleases and renal clearance and also enables passive targeting to tumor by enhanced permeability and retention (EPR) effect [53]. Surface shielding domains are also essential to limit the interaction with serum proteins during its extracellular transportation. Next, the siRNA delivery vehicle needs to mediate efficient and selective cellular uptake, which can be achieved through specific targeting ligands. And finally, sufficient intracellular endosomal escape of siRNA is another critical issue. In recent years, great efforts have been made in the development of various siRNA carriers. Polymeric materials [54–66], liposomes [67,68], inorganic platforms [69], and hybrid systems [16,26,70,71] all showed their potential [11]. However, systemic delivery of siRNA directed to the tumor site remains a major limitation.
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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Gene therapy is the use of genes as medicine that involves the transfer of a therapeutic or working gene (DNA and RNA) copy into specific cells of a patient in order to repair gene defects due to mutations [403–409, 413, 420–426]. This technique has been studied in clinical settings for a variety of cancer types and other disease involving gene defects. Cancer cells possess upregulated or inappropriately expressed genes, which leads to uncontrolled cell growth. Identification of target genes could lead to development of tailored anticancer agents with which the toxic side effect of cancer chemotherapies could be overcome. For example, RNAi-based gene therapies, i.e., sequence-specific post-transcriptional silencing of gene expression mediated by small double-stranded (dsRNA), have the potential to treat a variety of human genomic disorder, especially in combination with conventional therapies such as chemotherapy [419, 424]. Whereas knockdown of a target mRNA is not feasible with sense and antisense RNAs, dsRNA can lead to an effective and a specific mRNA knockdown. After dsRNA is introduced into cells it is cleaved by the enzyme dicer, a member of the RNaseIII family of dsRNA-specific ribonucleases [407, 409, 421, 424]. This enzymatic cleavage degrades the RNA to 19–23 bp duplexes, each with a 2-bp 3′ overhang [703, 408, 422].
The non-viral vectors and main methods of loading siRNA onto the titanium implants and their application
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Liangrui Chen, Mingxuan Bai, Ruiyu Du, Hao Wang, Yi Deng, Anqi Xiao, Xueqi Gan
The structure of siRNA is unstable and easy to be degraded by nuclease, so the transfection efficiency is very low. Besides, due to its large size (∼13 kDa) and high negative charge, naked siRNA is hard to penetrate cellular membranes [19] not to mention achieving gene silencing. Thus vectors are indispensable for successful siRNA delivery [20], which can stabilize siRNA by conjugating or encapsulating siRNA sequences to protect it from degradation [14]. So that they can help keeping physical and biological properties of siRNA as well as enhancing cellular uptake [21, 22]. The ideal siRNA vectors need to fulfill the following functions: (1) protect siRNA from nuclease degradation in circulation; (2) exhibit a proper pharmacokinetic and tissue distribution profile to deliver siRNA to disease-relevant organs; and (3) facilitate efficient uptake of siRNA into target cells and release siRNA into cytoplasm to knockdown the target gene [15]. Vectors are generally divided into two categories, namely, viral and non-viral. Non-viral vectors have become the mainstream of research and development because of their high biosafety [23]. Common non-viral vectors include liposomes, polymers and nanoparticles, which are most widely used at present. In this part, polymeric, nanomaterial-mediated and lipid-based siRNA delivery vectors (Table 1) are introduced in detail.