Oral delivery of RNAi for cancer therapy

Abstract

Cancer is a major health concern worldwide and is still in a continuous surge of seeking for effective treatments. Since the discovery of RNAi and their mechanism of action, it has shown promises in targeted therapy for various diseases including cancer. The ability of RNAi to selectively silence the carcinogenic gene makes them ideal as cancer therapeutics. Oral delivery is the ideal route of administration of drug administration because of its patients' compliance and convenience. However, orally administered RNAi, for instance, siRNA, must cross various extracellular and intracellular biological barriers before it reaches the site of action. It is very challenging and important to keep the siRNA stable until they reach to the targeted site. Harsh pH, thick mucus layer, and nuclease enzyme prevent siRNA to diffuse through the intestinal wall and thereby induce a therapeutic effect. After entering the cell, siRNA is subjected to lysosomal degradation. Over the years, various approaches have been taken into consideration to overcome these challenges for oral RNAi delivery. Therefore, understanding the challenges and recent development is crucial to offer a novel and advanced approach for oral RNAi delivery. Herein, we have summarized the delivery strategies for oral delivery RNAi and recent advancement towards the preclinical stages.

Keywords: Bioengineering; Cancer; Oral RNAi; Oral medicines; RNAi therapeutics.

Fig. 1

siRNA-mediated gene silencing mechanism. Naked siRNA or nanoparticle-loaded siRNA enters the cell through endocytosis. After endosomal escaping, two strands of siRNA get separated into the passenger and guide strand. The guide strand along with RISC binds with the targeted mRNA and with the help of Ago2 breaks down the mRNA for selective gene silencing

Fig. 2

Graphical representation shows the number of publications on oral siRNA delivery in each year

Fig. 3

Timeline for evolution of some oral RNAi-mediated therapeutics and their milestone

Fig. 4

Illustration of mucus layer as a barrier for drug delivery. Positively charged, hydrophilic small molecule can diffuse through mucus layer to get absorbed through the epithelium. Large molecule cannot pass the mucus barrier due to steric barrier. Furthermore, a molecule of any size can interact with different components of mucus and get trapped there. Both naked siRNA and siRNA loaded in carrier must pass the mucus barrier to enter the epithelium. The image was adapted from “Drug Diffusion Through Mucus Barriers” BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

Fig. 5

The scheme shows how nuclease enzyme breaks down the naked siRNA. However, nanocarrier or chemical modification can prevent the payload of siRNA from enzymatic degradation

Fig. 6

The mechanism on how siRNA enters the cell by endocytosis and forms endosome. The endosomal content gets degraded by the lysosomal enzyme, and it then goes to the Golgi network for processing. The image was adapted from “Cellular Environment (Background)” BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

Fig. 7

The scheme displayed major carriers that have been used and considered a potential vehicle for RNAi delivery

Fig. 8

Scheme shows the rationale and designing strategies of the siRNA conjugated delivery system. Adapted with permission from [213]. Copyright 2015 Elsevier