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Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Ramasamy Paulmurugan, Uday Kumar Sukumar, Tarik F. Massoud
Since the discovery of silencing RNAs for modulating gene expression in plants [15], and later for its application in animal cells [16] and clinical translation for various therapies in humans [17], the development of clinically compatible delivery systems have become the prime focus of many research groups. Others have embarked on identifying new targets for RNA interference (RNAi) therapies. While lipoplexes are effective for complexing negatively charged nucleic acids and delivering them across cell membranes, the toxicity associated with lipoplexes, and challenges in identifying the optimal formulation needed to achieve a balanced charge ratio needed for in vivo delivery without toxicity, have both proven to be particular obstacles. In addition, the stability of these complexes in the systemic circulation and protecting the loaded nucleic acids from nucleases are other important challenges. Currently, SNALPs of various physicochemical properties have been used for siRNA and miRNA deliveries into cells and in vivo in living animals. Small RNAs are effective for the treatment of a range of human diseases, including cancer, but delivering intact forms of RNA to cells of target tissues in vivo after systemic administration remains a challenging task. In addition, it is crucial to deliver intact RNAs to the cytoplasm of cells without removal by kidney mediated filtration, RES-mediated cellular uptake and degradation, or aggregation with plasma proteins and blood cells. The existence of these constraints has led researchers to search for alternative delivery systems, as discussed later.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
RNA Interference (RNAi) is a natural process that occurs in all cells and is thought to have evolved as a protection mechanism against RNA viruses. It may also play a role in RNAi-related pathways such as shaping the chromatin structure of a genome. The cell responds to the introduction of extraneous dsRNA by destroying all intracellular mRNA of the same sequence. The phenomenon was first observed in the Caenorhabditis elegans worm and later in drosophila, trypanosomes, and planaria. The post-transcriptional gene silencing (PTGS) observed in plants is thought to operate through a similar RNAi mechanism.
Gene Delivery for Intervertebral Disc
Published in Raquel M. Gonçalves, Mário Adolfo Barbosa, Gene and Cell Delivery for Intervertebral Disc Degeneration, 2018
Gianluca Vadalà, Luca Ambrosio, Vincenzo Denaro
RNA interference (RNAi) is a recently developed strategy to silence the expression of specific genes using small interfering RNA (siRNA) sequences. siRNAs are able to inhibit gene expression by binding in a site- and sequence-specific manner to a targeted mRNA, which undergoes degradation or is simply not translated into the corresponding protein.
Long non-coding RNA-targeting therapeutics: discovery and development update
Published in Expert Opinion on Drug Discovery, 2023
Olga Khorkova, Jack Stahl, Aswathy Joji, Claude-Henry Volmar, Zane Zeier, Claes Wahlestedt
One of the commonly used NBT modalities is short (20–30 nucleotides) single-stranded DNA antisense oligonucleotides (ssDNA ASO) that anneal to target RNA, triggering its degradation by RNAseH (Table 3). Small interfering RNA (siRNA) are double-stranded RNA (dsRNA) molecules that guide their target RNA for degradation in the RNA interference (RNAi) pathway [5,6]. Therapeutic mRNAs are optimized full-length or minimal RNAs that can transiently express a particular protein from a plasmid or viral vector [8]. Therapeutic mRNA technology can potentially be utilized to express full-length lncRNA or lncRNA-based minimal constructs that regulate disease-relevant biological processes. In gene therapy, cDNA encoding the desired protein is incorporated into the host genome using a viral vector or is expressed from a non-integrating plasmid or viral vector. Transposon-based vectors can deliver much larger DNA payloads than viral vectors [9]. Furthermore, technologies developed for mRNA and gene therapy delivery are widely utilized for optimization of other NBT types. Besides delivering mRNAs or cDNAs, these vectors can be used to express ASOs, siRNAs or multifactor DNA/RNA editing constructs, such as CRISPR-CAS9, CRISPR-Cas13, ADARs, TALENs, or specific RNA-degrading CRISPR-Csm complexes (Table 3) [10,11].
Small interfering RNA-based nanotherapeutics for treating skin-related diseases
Published in Expert Opinion on Drug Delivery, 2023
Yen-Tzu Chang, Tse-Hung Huang, Ahmed Alalaiwe, Erica Hwang, Jia-You Fang
siRNA is a double-stranded RNA (dsRNA) consisting of 20‒30 nucleotides in length. The investigation of siRNA originated with the exploration of RNA interference (RNAi). It is a novel class of RNA inhibitors acting by the RNA-induced silencing complex (RISC) to specifically degrade target RNAs [26]. RNAi mediated by dsRNA was first determined by Fire et al. in 1998 [27]. siRNA-mediated gene silencing is then demonstrated to be act as the posttranscriptional sequence-specific procedure [28]. The functional RISC has four subunits: helicase, endonuclease exonuclease, and homology-searching domains. As siRNA binds to RISC, the duplex siRNA can be unwound by helicase, leading to the formation of two single strands. This effect produces the binding of the antisense strand to the target RNA molecules [29]. The endonuclease can hydrolyze mRNA homologous at the area that the antisense strand is bound. RNAi shows an antisense mechanism as a single-stranded RNA binds to the target RNA by Watson – Crick base pairing and recruits a ribonuclease degrading the target RNA (Figure 2). Basically, siRNA can target any gene of interest as long as the coding sequence for the target gene is known. This results in a shorter duration for research and development.
Hyaluronic acid-modified redox-sensitive hybrid nanocomplex loading with siRNA for non-small-cell lung carcinoma therapy
Published in Drug Delivery, 2022
Daoyuan Chen, Peng Zhang, Minghui Li, Congcong Li, Xiaoyan Lu, Yiying Sun, Kaoxiang Sun
Recently, RNA interference (RNAi) technology has become a promising strategy for the treatment of major diseases, such as cancer, cardiovascular diseases, neurodegenerative diseases, etc. (Napoli et al., 1990; Guo et al., 2010; Kapoor et al., 2012; Kim et al., 2016; Lee et al., 2016). However, due to the existence of abundant RNase and the stability problem of RNA, including degradation during transport and transfection, RNAi-based agents are easily inactivated during systemic circulation; on the other side, the safe and effective delivery of RNAi agents, such as siRNA to target cells and efficient release into cytoplasm, still remains major hurdle for the clinical application of therapeutic RNAs, including siRNAs (Verma & Somia, 1997). Therefore, it is critical to design and develop effective RNA delivery vehicles for the clinical trials of RNAi therapeutics.