RNA Drug Delivery Using Biogenic Nanovehicles for Cancer Therapy

Abstract

RNA-based therapies have been promising method for treating all kinds of diseases, and four siRNA-based drugs and two mRNA-based drugs have been approved and are on the market now. However, none of them is applied for cancer treatment. This is not only because of the complexity of the tumor microenvironment, but also due to the intrinsic obstacles of RNAs. Until now, all kinds of strategies have been developed to improve the performance of RNAs for cancer therapy, especially the nanoparticle-based ones using biogenic materials. They are much more compatible with less toxicity compared to the ones using synthetic polymers, and the most widely studied biogenic materials are oligonucleotides, exosomes, and cell membranes. Particular characteristics make them show different capacities in internalization and endosomal escape as well as specific targeting. In this paper, we systematically summarize the RNA-based nano-delivery systems using biogenic materials for cancer therapy, and we believe this review will provide a valuable reference for researchers involved in the field of biogenic delivery and RNA-based therapies for cancer treatment.

Keywords: RNA delivery; biogenic materials; cancer; cell membranes; exosomes; oligonucleotide.

FIGURE 1

Schematic illustration of delivery barriers in (A) extracellular and (B) intracellular regions (Kim HJ. et al., 2016).

FIGURE 2

The biogenic materials used for RNAs delivery including oligonucleotides assemblies with different shapes, exosomes loading RNAs using various manners, and membranes derived from different cell types with specific characteristics.

FIGURE 3

Preparation and application of chemically modify DNA strands for RNAs delivery. (A) Schematic illustration of copper-free azide-alkyne click reaction between azide and DBCO. (B) The DNA structures formed by click reaction with controlled architectures, such as dimer, trimer, cross-shape, and 1D polymer DNA frame (Lin et al., 2019). (C) Synthesis route of PDA-coated nucleic acid nanogel. (D) Schematic illustration of endosomal escape and PTT induced by PDA (Ding L. et al., 2020).

FIGURE 4

Schematic illustration of construction and Dicer-triggered disassembly of the SF-loaded porous RNA nanospheres (PRS@SF) (Chen HY. et al., 2020).

FIGURE 5

Schematic illustration of PEI-modified nucleic acid nanoparticles (NANPs) and its capacity in endosomal escape (Juneja et al., 2020).

FIGURE 6

Illustration of RNA nanostructure formed by pRNA. (A) Struture of 3WJ domain composed of three RNA oligomers (Shu et al., 2011). (B) Scheme of EGFR-modified 3WJ-pRNA for siRNA targeted delivery (Zhang et al., 2021). (C) Structure of RNA micelles formed by cholesterol-decorated 3WJ-pRNA for miRNA delivery (Yin et al., 2019). (D) Newly developed 6WJ-pRNA for drugs and miRNA targeted delivery (Wang H. et al., 2021).

FIGURE 7

Mechanism of exosomes in immune escape. (A) CD47 protects exosomes from being cleared by monocytes and macrophages: flow cytometry analysis of AF647-tagged siRNA in exosomes with normal/knockout (KO)/high-expression CD47 in the circulation (Kamerkar et al., 2017). (B) Cltc blocking inhibits the macrophages endocytosis and decreases the accumulation of DiR-loaded exosomes in liver and spleen (C) (Wan et al., 2020).

FIGURE 8

Preparation of exosome-mimics nanovesicles via serial extrusion and loaded with siRNA using electroporation method (Yang et al., 2016).

FIGURE 9

The SN-38 and siRNA delivery system decorated with CCM and ROS-sensitive NBC exhibit high capacity in tumor targeting and endosomal escape (Fei et al., 2020).

FIGURE 10

Schematic illustration of Angiopep 2 peptide-decorated charge-conversional biomimetic nanocomplexes with efficient endosomal escape for glioblastoma treatment (Liu et al., 2020).

FIGURE 11

Intracellular trafficking pathways of siRNA-loaded NPs (Qiu et al., 2019). (A) The targeting ability of EhCv/siRNA NPs via endosome-Golgi-ER pathway and avoid the lysosome. (B) The intracellular trafficking pathways of different NPs.