Innovations in Biomaterial Design toward Successful RNA Interference Therapy for Cancer Treatment

Abstract

Gene regulation using RNA interference (RNAi) therapy has been developed as one of the frontiers in cancer treatment. The ability to tailor the expression of genes by delivering synthetic oligonucleotides to tumor cells has transformed the way scientists think about treating cancer. However, its clinical application has been limited due to the need to deliver synthetic RNAi oligonucleotides efficiently and effectively to target cells. Advances in nanotechnology and biomaterials have begun to address the limitations to RNAi therapeutic delivery, increasing the likelihood of RNAi therapeutics for cancer treatment in clinical settings. Herein, innovations in the design of nanocarriers for the delivery of oligonucleotides for successful RNAi therapy are discussed.

Keywords: RNA interference; biomaterials; cancer; liposomal delivery; nanomedicine; polymeric nanocarriers.

Figure 1.

Mechanisms of RNA interference undergone by siRNA and miRNA therapeutics for specific gene silencing. In both siRNA and miRNA-based RNA interference, the oligonucleotides are loaded into nanocarriers before being internalized by target cells. Once internalized, the oligonucleotides are incorporated into the RNA-induced silencing complex (RISC), where it is paired with a target mRNA strand for translational repression or gene silencing.

Figure 2.

Various nanoparticulate delivery systems for RNA interference.

Figure 3.

Construction of an intelligent liposomal delivery system. Reproduced with permission.^[13] Copyright 2020, American Chemical Society.

Figure 4.

Structures of common cationic lipids used in liposomal formulations: (a) DOTAP (b) DOTMA (c) DMAPAP (d) Staramine (e) Stearylamine

Figure 5.

GFP expression following delivery of GFP-specific siRNA with cationic liposomes. H4II-E cells were treated with GFP-specific siRNA alone or cationic liposome/siRNA complexes. (a) Untreated H4II-E cells, (b) treated with siRNA alone, (c) treated with Lipofectamine®/siRNA complex, (d) treated with conventional liposome/siRNA complex, (e) treated with PEGylated liposome/siRNA complex, and (f) treated with PLR-PEGylated liposome/siRNA complex. Reproduced with permission.^[14] Copyright 2020, Elsevier.

Figure 6.

Schematic representation of ternary anionic siRNA lipoplexes prepared with: (a) low anionic lipid/siRNA molar charge ratios; and (b) high anionic lipid/siRNA molar charge ratios Reproduced with permission. ^[60] Copyright 2012, Elsevier.

Figure 7.

Common lipids used in anionic liposomal systems (a) DOPG (b) DSPE (c) CHEMS

Figure 8.

Schematic illustration of SLNs loaded with paclitaxel and quantum dots, and the formation of polyelectrolyte complex of SLNs with siRNA for synergistic paclitaxel-siRNA combination therapy. Reproduced with permission.^[68] Copyright 2013, Wiley.

Figure 9.

Chemical structures of cationic polymers a) polyethylenimine and b) poly (amidoamine)

Figure 10.

Schematic of nanopompon system used to deliver anti-miR21 to breast cancer cells. The delivery system utilized a condensed nanoball of anti-miR21, polyethylenimine and targeting agent dehydroascorbic acid. Reproduced with permission.^[90] Copyright 2019, Elsevier

Figure 11.

Biodegradable, oncosensitive, megamer-based (BOMB) nanoparticle system for miR-122 in liver cancer. BOMB system is acid-sensitive and will shed PEG surface grafts in tumor microenvironment to enhance interactions of PAMAM dendrimer core with cell membranes. Reproduced with permission. ^[96] Copyright 2019, The Royal Society of Chemistry.

Figure 12.

Biodistribution studies of Cy3-miR-34a loaded nanoparticles at 1, 6 and 24 h after the intravenous injection. Localization of Cy3-miR-34a in the tumor tissue and various organs was measured via in vivo fluorescence. Reproduced with permission.^[97] Copyright 2019, The Royal Society of Chemistry.

Figure 13.

Structures of the different PBAE polymers utilized for the combination therapy of miR-148a and miR-296-5p in glioblastoma. Reproduced with permission.^[98] Copyright 2018, American Chemical Society.

Figure 14.

Peptide-targeted, ROS-responsive nanoparticles were stabilized by electrostatic, hydrogen bond and hydrophobic interactions for enhanced glioblastoma targeting. These nanoparticles exhibited enhanced BBB permeation and successfully co-delivered PLK1 and VEGFR2 siRNA to gliomas. Reproduced with permission.^[101] Copyright 2019, Wiley.