Abstract
RNA interference (RNAi) uses small interfering RNAs (siRNAs) to mediate gene-silencing in cells and represents an emerging strategy for cancer therapy. Successful RNAi-mediated gene silencing requires overcoming multiple physiological barriers to achieve efficient delivery of siRNAs into cells in vivo, including into tumor and/or host cells in the tumor micro-environment (TME). Consequently, lipid and polymer-based nanoparticle siRNA delivery systems have been developed to surmount these physiological barriers. In this article, we review the strategies that have been developed to facilitate siRNA survival in the circulatory system, siRNA movement from the blood into tissues and the TME, targeted siRNA delivery to the tumor or specific cell types, cellular uptake, and escape from endosomal degradation. We also discuss the use of various types of lipid and polymer-based carriers for cancer therapy, including a section on anti-tumor nanovaccines enhanced by siRNAs. Finally, we review current and recent clinical trials using NPs loaded with siRNAs for cancer therapy. The siRNA cancer therapeutics field is rapidly evolving, and it is conceivable that precision cancer therapy could, in the relatively near future, benefit from the combined use of cancer therapies, for example immune checkpoint blockade together with gene-targeting siRNAs, personalized for enhancing and fine-tuning a patient’s therapeutic response.
Highlights
The discovery of RNA interference (RNAi) in 1998 by Fire et al [1], laid the foundations for the development of new gene-targeting methodologies based on RNA oligonucleotides
RNAi approaches represent a promising avenue for further investigation in cancer therapy, as they are considered less toxic than classical chemotherapy, and less invasive than surgery
The potent gene silencing capacity of small interferingRNAs (siRNAs) is a feature that bodes for their use as ideal novel cancer therapeutics
Summary
The discovery of RNA interference (RNAi) in 1998 by Fire et al [1], laid the foundations for the development of new gene-targeting methodologies based on RNA oligonucleotides. MiRNAs are natural dsRNA molecules produced by all cells, which impact the function of many genes by blocking target mRNA translation [4]. DsRNA molecules produced by all cells, which impact the function of many genes by blocking target mRNA translation [4] These RNA duplexes are produced from a stem-loop structure called the precursorare miRNA and from are processed intostructure short dsRNAs by Dicer. In overcome physiological andcells cellular barriers, hindering access to the cytoplasm of target addition, due to the ubiquitous presence of RNAses, siRNAs need to avoid enzymatic cells (Figure 2), where they are able to fulfill their regulatory function. Active targeting: Inclusion of a targeting ligand on the surface of the NPs
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