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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
SiRNAs are currently in different clinical trial stages for the treatment of many human diseases. Predominantly, siRNA therapies are used for the treatment of metabolic and biochemical disorders, chronic viral infections, and for oncological diseases. Stable siRNA-liposome complexes have been well explored compounds for clinical siRNA therapies. Table 13.1 shows some of the siRNAs currently in clinical trials for different diseases.
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Post-transcriptional processing can also be modulated by small RNA species, typically ~21–26 nucleotides long, known as small interfering RNA (siRNA) and miRNA (63). miRNAs and siRNAs are produced in different ways but have similar functions on selective mRNA degradation. After their synthesis, miRNA and siRNA form part of the RNA-inducing silencer complex (RISC). The miRNA and siRNA confer specificity to the RISC complex by binding complementary sequences in their target mRNA, which results in either the degradation of the target mRNA or inhibition of mRNA translation, which ultimately results in changes in protein abundance. More than 2,000 miRNA transcripts have been so far identified; it is estimated that up to 30% of human gene transcripts may be affected by this type of regulation. miRNA-induced alterations in protein abundance are subtle (often less than 10% change in abundance), but a single miRNA can alter the abundance of tens to hundreds of diverse proteins, meaning that changes in miRNA in response to stimuli such as exercise can have important implications when it comes to adaptive changes. To add further complexity, while one miRNA can have many targets, simultaneously one transcript may be targeted by several miRNAs. Changes in miRNA abundance occur in response to both aerobic (64) and resistance (65) exercises, and so miRNA may be involved in modulating the adaptive response to exercise training (51) (alterations in miRNA with endurance and resistance exercise are discussed in detail in Chapter 6).
siRNA Delivery for Therapeutic Applications Using Nanoparticles
Published in Yashwant Pathak, Gene Delivery, 2022
Conjugation of small molecules, such as peptides or polymers, with the sense strands of siRNA produces the smallest siRNA nanoparticles at 10 nm size [11]. Modification of sense strands of siRNA maintain the degradation effect on mRNA because the recognition of mRNA involves the antisense strand. Studies show that siRNA conjugation with CPPs and PEG has increased gene transfer in vivo. siRNA conjugated to cholesterol in sense strand are able to slice multiple genes in mice, including endogenous apolipoprotein B gene expression in the liver and jejunum and p38 mitogen-activated protein (MAP) kinase in the lungs [12]. In vivo gene silencing to hepatocytes was observed by siRNA modified with Long chain fatty acids (> C18) and bile-salt derivatives. A similar effect was also produced by siRNA based dynamic polyconjugate, consisting of acid responsive polymers that contain PEG and a NAG targeting ligand. When these nanoparticles interact with the endosome, PEG is released due to acid responsive polymer targeting the ligand, making a hydrophilic to hydrophobic transition, and resulting in endosomal disruption [13, 14, 15].
Clinical pharmacology of siRNA therapeutics: current status and future prospects
Published in Expert Review of Clinical Pharmacology, 2022
Ahmed Khaled Abosalha, Jacqueline Boyajian, Waqar Ahmad, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
Simply, siRNAs are designed to block the expression of targeted genes at the post-transcriptional stage by degrading the mRNA that governs the regulation of these genes. Therefore, siRNAs are designated as small double-stranded RNA duplexes with a 21–23 nucleotide length. One strand of this duplex is complementary to the mRNA of the gene of interest and known as the ‘guiding’ or ‘antisense’ strand. This guiding strand can easily and specifically recognize the mRNA of the targeted gene and degrade it, a process known as ‘gene silencing.’ Gene silencing begins when a long double-stranded RNA (dsRNA) is cleaved by a specific dicer enzyme, a member of the RNAase family, into short siRNAs. Then, these siRNAs are incorporated into a multi-protein complex termed, ‘ (RISC).’ Subsequently, siRNA binds to argonaute-2 receptors, a crucial component of RISC, with a consequent cleavage of siRNA duplex into two strands: the passenger (sense) strand and the guiding strand. The sense strand is degraded while the guiding strand recognizes the complementary mRNA of the gene of interest and destroys it into numerous nonfunctional units. This process downregulates the expression of targeted genes and proteins as demonstrated in Figure 1 [29–32].
Genotoxicity evaluation of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG), a novel siRNA nanoparticle for the treatment of fibrotic disease
Published in Drug and Chemical Toxicology, 2022
Hyeon-Young Kim, Tae Rim Kim, Sung-Hwan Kim, In-Hyeon Kim, Youngho Ko, Sungil Yun, In-Chul Lee, Han-Oh Park, Jong-Choon Kim
RNA interference (RNAi), a conserved mechanism for gene silencing, is attractive therapeutic tool for treating various diseases, including cancer, viral infections, and genetic disorders (Bumcrot et al. 2006, DiFiglia et al. 2007, Tseng et al. 2009, Steinbach et al. 2012). However, clinical application of small interfering RNA (siRNA) for RNAi is still limited by poor stability and inefficient cellular uptake of siRNA (Lee et al. 2014). Moreover, it has been reported that siRNA cause undesirable side effects owing to the toxicities associated with the off-target effects by silencing unintended genes or nonspecific immune stimulatory effects (Robbins et al. 2009). Recently, researchers have attempted to overcome the issues associated with toxicities and inefficient cellular uptake and target-gene silencing of siRNA by incorporating structural or chemical modifications in these molecules (Jeong et al. 2009, Kanasty et al. 2013, Falsini et al. 2014).
Study on lipid nanomicelles targeting placenta for the treatment of preeclampsia
Published in Journal of Drug Targeting, 2022
Yang Liu, Qimeng Zhang, Xingli Gao, Tong Wang
Therefore, the main barrier to siRNA therapy is the delivery of siRNA to target cells. Currently, siRNA delivery vectors include viral, non-viral, aptamer and peptide macromolecules to enhance the uptake and silencing of target cells. After injection, the delivery system should avoid renal filtration, phagocyte uptake, serum protein aggregation, and endogenous nuclease degradation in blood circulation to reach the target cells. After passing through the blood vessels, it passes through the extracellular matrix and fibrin, which are dense networks of polysaccharides. This process may cause large molecules to be held up, slowed down or interrupted during transport. After reaching the target cells, it needs to be ingested by endocytosis while remaining intact and active. The poor safety of viral vectors limits their clinical applicability [27]. As for the research on non-viral carriers, nanoparticles, cationic lipids and polymers have been used to encapsulate and successfully improve the efficacy and safety of siRNA therapeutics [28].