A Comprehensive Review of Small Interfering RNAs (siRNAs): Mechanism, Therapeutic Targets, and Delivery Strategies for Cancer Therapy

Abstract

Small interfering RNA (siRNA) delivery by nanocarriers has been identified as a promising strategy in the study and treatment of cancer. Short nucleotide sequences are synthesized exogenously to create siRNA, which triggers RNA interference (RNAi) in cells and silences target gene expression in a sequence-specific way. As a nucleic acid-based medicine that has gained popularity recently, siRNA exhibits novel potential for the treatment of cancer. However, there are still many obstacles to overcome before clinical siRNA delivery devices can be developed. In this review, we discuss prospective targets for siRNA drug design, explain siRNA drug properties and benefits, and give an overview of the current clinical siRNA therapeutics for the treatment of cancer. Additionally, we introduce the siRNA chemical modifications and delivery systems that are clinically sophisticated and classify bioresponsive materials for siRNA release in a methodical manner. This review will serve as a reference for researchers in developing more precise and efficient targeted delivery systems, promoting ongoing advances in clinical applications.

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“…, 2013 ). ErbB1-specific interventions in current clinical use and in development include function-blocking anti-ErbB1 antibodies, ErbB1-selective small molecule kinase inhibitors, ErbB1-directed siRNA, and PROTAC strategies that target ErbB1 for degradation ( Zhang, 2023 ; Zhang et al. , 2023 ).…”

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“…Nevertheless, a wide, heterogeneous variety of ncRNAs have complex regulatory and structural functions. Several classes of ncRNAs have been identified, including transfer RNAs (tRNAs) and tRNA-derived small RNAs (tDRs or tRFs) ( 115 ); ribosomal RNAs (rRNAs) ( 116 ), microRNAs (miRNAs) ( 117 ); small interfering RNAs (siRNAs) ( 118 ); small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) ( 119 ), circular RNAs (circRNAs) ( 120 ); long ncRNAs (lncRNAs) and transposable elements ( 121 , 122 ); piwi-interacting RNAs (piRNAs) ( 123 ); Y RNA ( 124 ); and vault particle-associated RNAs (vtRNAs) ( 125 ).…”

“…The utility of ncRNAs for diagnosis and progression and as therapeutic targets and predictive biomarkers has been widely explored owing to their high degree of conservation, specific expression patterns and stability ( 126 - 128 ). miRNAs, circRNAs, lncRNAs, siRNAs and piRNAs have been shown to play crucial roles as regulators of the response to chemotherapy, immunotherapy and molecular-targeted therapy in different types of cancer ( 117 , 118 , 126 , 129 , 130 ).…”

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“…Subsequently, the guide strand binds to the complementary sequence of the target mRNA to activate Argonaute 2 endonuclease (Ago 2) within RISC. Ago 2 cleaves the target mRNA, thus compromising protein expression [69]. The therapeutic potential of siRNAs arises from their high specificity, restriction to the cytoplasm which precludes genome integration, remarkable efficiency, and target versatility [69].…”

“…Ago 2 cleaves the target mRNA, thus compromising protein expression [69]. The therapeutic potential of siRNAs arises from their high specificity, restriction to the cytoplasm which precludes genome integration, remarkable efficiency, and target versatility [69]. However, despite their numerous advantages, substantial obstacles must be surmounted to effectively harness the power of siRNAs.…”