siRNA-based nanotherapeutics as emerging modalities for immune-mediated diseases: A preliminary review

Abstract

Immune-mediated diseases (IMDs) are chronic conditions that have an immune-mediated etiology. Clinically, these diseases appear to be unrelated, but pathogenic pathways have been shown to connect them. While inflammation is a common occurrence in the body, it may either stimulate a favorable immune response to protect against harmful signals or cause illness by damaging cells and tissues. Nanomedicine has tremendous promise for regulating inflammation and treating IMIDs. Various nanoparticles coated with nanotherapeutics have been recently fabricated for effective targeted delivery to inflammatory tissues. RNA interference (RNAi) offers a tremendous genetic approach, particularly if traditional treatments are ineffective against IMDs. In cells, several signaling pathways can be suppressed by using RNAi, which blocks the expression of particular messenger RNAs. Using this molecular approach, the undesirable effects of anti-inflammatory medications can be reduced. Still, there are many problems with using short-interfering RNAs (siRNAs) to treat IMDs, including poor localization of the siRNAs in target tissues, unstable gene expression, and quick removal from the blood. Nanotherapeutics have been widely used in designing siRNA-based carriers because of the restricted therapy options for IMIDs. In this review, we have discussed recent trends in the fabrication of siRNA nanodelivery systems, including lipid-based siRNA nanocarriers, liposomes, and cationic lipids, stable nucleic acid-lipid particles, polymeric-based siRNA nanocarriers, polyethylenimine (PEI)-based nanosystems, chitosan-based nanoformulations, inorganic material-based siRNA nanocarriers, and hybrid-based delivery systems. We have also introduced novel siRNA-based nanocarriers to control IMIDs, such as pulmonary inflammation, psoriasis, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, etc. This study will pave the way for new avenues of research into the diagnosis and treatment of IMDs.

Keywords: autoimmunity; drug delivery; inflammation; nanotechnology; nanotherapeutics; siRNA.

Figure 1

siRNA can be modulated for localized and targeted delivery through airways by inhalation via nasal route. siRNA, short‐interfering RNA

Figure 2

Schematic of siRNA/miRNA silencing pathway. RISC, RNA‐induced silencing complex (Sioud, 2019). miRNA, microRNA; mRNA, messenger RNA; siRNA, small interfering RNA; TRBP, TAR RNA‐binding protein

Figure 3

Schematic representation of boosting the immune responses by combining siRNAs with DC vaccinations. For this purpose, DCs may be electroporated with siRNAs. The assembly process is found to be easy and does not add any additional manufacturing expenses (Sioud, 2019). DC, dendritic cell; siRNA, small interfering RNA; TLR7/8, Toll‐like receptors 7 and 8

Figure 4

Schematic representation of lipid‐based siRNA nanocarriers. siRNA, small interfering RNA

Figure 5

(a) Schematic representation of the cationic lipid (lipoplex) coating with anionic polymers for siRNA delivery. (b) Schematic representation of anionic polymers chemical structure added in siRNA lipoplexes. siRNA, small interfering RNA

Figure 6

Schematic of the SNALP delivery system. Reprinted from ref (Alabi et al., 2012) (Copyright 2022 Elsevier). SNALP, stable nucleic acid‐lipid particle

Figure 7

Schematic illustration of PAMAM‐mediated siRNA and pDNA delivery for EGFR‐targeted tumor therapy. Specific binding to the EGFR overexpressing receptors on the tumor cells causes receptor‐mediated endocytosis captured by the lysosomes, lysosomal escape, gene release, and induces apoptosis. Reprinted from ref (Li et al., 2018) (Copyright 2022 Elsevier). siRNA, small interfering RNA

Figure 8

Schematic structures of various modified PEIs in LPPs formulations. (a) Unmodified branched polyethylenimine (bPEI); (b) bromohexane‐modified bPEI; (c) hexyl acrylate‐modified linear polyethylenimine (lPEI); (d) hexyl acrylate‐modified bPEI; (e) poly l‐lysine (PLL) conjugated bPEI; (f) reversible conjugation of hexadecenal to PEI. Reprinted from ref (Rezaee et al., 2016) (Copyright 2022 Elsevier). PEI, polyethylenimine

Figure 9

Scheme of cationic polymer‐based siRNA nanocarriers. siRNA, small interfering RNA

Figure 10

(a) The siRNA immobilization strategies onto the surface of INPs. (b) Schematic illustration for polyelectrolyte complexes formed from amine‐functionalized gold nanoparticles (AF‐AuNPs) with siRNA and siRNA–PEG conjugate. Reprinted from ref (Lee et al., 2008) (Copyright 2022 Elsevier). siRNA, small interfering RNA

Figure 11

Overview of the classification, functional abilities, applications, and biological fate of the MSNPs in drug delivery research. Reprinted from ref (Barkat et al., 2021) (Copyright 2022 Elsevier)

Figure 12

Model for the structural characteristics of siRNA‐loaded LPNs and their release dynamics. For LPNs the siRNA is loaded in (1) surface lamellar layers, (2) surface‐grafted DOTAP–siRNA complexes, and (3) matrix‐entrapped siRNA–DOTAP complexes (a). The release from these structures occurs as the release of siRNA–DOTAP complexes by disassembly of surface structures (b), sustained release of siRNA–DOTAP complexes by diffusion (c), and matrix erosion (d). Reprinted from ref (Colombo et al., 2015) (Copyright 2022 Elsevier). siRNA, small interfering RNA

Figure 13

(a) Molecular structure of TPPS2a. (b) Graphic scheme of the PLN‐TPPS2a‐siRNA NPs. Reprinted from ref (Suzuki et al., 2021). siRNA, small interfering RNA

Figure 14

Schematic illustration of the process of fabricating Dy734‐labeled and siRNA‐loaded calcium phosphate NPs (CaP/PEI‐Dy734/siRNA/SiO₂) for suppressing the NF‐κB p65 gene in mice. TEOS: tetraethoxysilane; CaP: calcium phosphate; Dy: Dyomics; PEI—polyethyleneimine; siRNA: short‐interfering RNA (Müller et al., 2022). siRNA, small interfering RNA