Abstract
RNA Interference (RNAi) has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made to establish catalytic RNA as a new class of biologics for cancer management, a lot of extracellular and intracellular barriers still pose a long-lasting challenge on the way to clinical approval. A series of chemically suitable, safe and effective viral and non-viral carriers have emerged to overcome physiological barriers and ensure targeted delivery of RNAi. The newly invented carriers, delivery techniques and gene editing technology made current treatment protocols stronger to fight cancer. This review has provided a platform about the chronicle of siRNA development and challenges of RNAi therapeutics for laboratory to bedside translation focusing on recent advancement in siRNA delivery vehicles with their limitations. Furthermore, an overview of several animal model studies of siRNA- or shRNA-based cancer gene therapy over the past 15 years has been presented, highlighting the roles of genes in multiple cancers, pharmacokinetic parameters and critical evaluation. The review concludes with a future direction for the development of catalytic RNA vehicles and design strategies to make RNAi-based cancer gene therapy more promising to surmount cancer gene delivery challenges.
Highlights
Gene therapy is the delivery of functional genes into the cell to modulate gene expression and the extent of their expression
EGFR-1 and EGFR-2 were electrostatically complexed with pH-sensitive carbonate apatite (CA)
Concurrent delivery of EGFR-1 and EGFR-2 siRNAs with carbonate apatite exerted significant tumor volume reduction (61%) in contrast to control groups. These results suggested that combined delivery of multiple siRNAs with pH-sensitive CA is a very promising strategy in treating cancer, highlighting a huge potential of pH-responsive drug delivery to the tumor microenvironment [143]
Summary
Gene therapy is the delivery of functional genes into the cell to modulate gene expression and the extent of their expression. The long dsRNA is able to silence gene expression in both nematodes and mammalian cells, but its non-specificity, sequence-independent pathways and activation of innate immune response make it incompatible in gene silencing technology [4,5]. At the beginning of the twentieth century, vigorous research on minimizing the shortcomings of dsRNA concluded that long dsRNAs can be processed into less than 30 base pair sequences, inducing the sequence-specific silencing of targeted genes in mammals [6].
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