Engineering siRNA therapeutics: challenges and strategies

Abstract

Small interfering RNA (siRNA) is a potential method of gene silencing to target specific genes. Although the U.S. Food and Drug Administration (FDA) has approved multiple siRNA-based therapeutics, many biological barriers limit their use for treating diseases. Such limitations include challenges concerning systemic or local administration, short half-life, rapid clearance rates, nonspecific binding, cell membrane penetration inability, ineffective endosomal escape, pH sensitivity, endonuclease degradation, immunological responses, and intracellular trafficking. To overcome these barriers, various strategies have been developed to stabilize siRNA, ensuring their delivery to the target site. Chemical modifications implemented with nucleotides or the phosphate backbone can reduce off-target binding and immune stimulation. Encapsulation or formulation can protect siRNA from endonuclease degradation and enhance cellular uptake while promoting endosomal escape. Additionally, various techniques such as viral vectors, aptamers, cell-penetrating peptides, liposomes, and polymers have been developed for delivering siRNA, greatly improving their bioavailability and therapeutic potential.

The functions and mechanisms of long non-coding RNA in colorectal cancer

“…The current research lacks a comprehensive understanding of the mechanism of action of lncRNA, which limits its potential in clinical applications ( 238 , 239 ). 5.Treatment strategies based on lncRNA, such as siRNA and antisense oligonucleotides (ASO), face issues such as low delivery efficiency, poor specificity, and off target effects, which further limit their therapeutic efficacy ( 240 ).…”

Reprogramming tendon healing: a guide to novel molecular tools

“…Despite the growing interest in the potential tissue-engineering applications for siRNA and RNAi technology in general, practical limitations to their use in the clinic are still to be overcome ( Ali Zaidi et al, 2023 ). siRNAs can be degraded by endosomal nucleases or remain trapped indefinitely in non-functional stress granules or other cytoplasmatic bodies, which would greatly affect their efficacy ( LeCher et al, 2017 ; Wang et al, 2021 ).…”

“…siRNAs can be degraded by endosomal nucleases or remain trapped indefinitely in non-functional stress granules or other cytoplasmatic bodies, which would greatly affect their efficacy ( LeCher et al, 2017 ; Wang et al, 2021 ). Additionally, siRNA entrapment can also occur in the extracellular space, where proteins from the serum could form a non-functional protein-siRNA complex, thus, hindering the siRNA therapeutic effect ( Ali Zaidi et al, 2023 ).…”

The Role of Mesenchymal Stem Cell Exosomes in the Onset and Progression of Alzheimer's Disease

“…Small interfering RNA (Small interfering RNA; siRNA) is a double-stranded RNA [58] of 20 to 24 bp that can mediate RNA interference. SiRNA delivery is necessary and sufficient for cells to undergo RNA interference, so therapies using exogenous siRNA to directly mediate cellular autologous RNA interference are increasingly emerging [59]. Especially with the increasing enrichment of human genome database data and the development and improvement of computer gene editing software, the research related to siRNA has flourishing [60].…”