Table 1.
Summary of siRNA nanosystems in IBD treatment
| Delivery system | siRNA target | Formulation | Size and zeta potential | Targeting
|
Route of administration | Characteristics | Ref | ||
|---|---|---|---|---|---|---|---|---|---|
| Moiety | Cell and ligand | Mechanism | |||||||
| Lipid-based nanoparticles | |||||||||
| Neutral liposome–hyaluronan–integrin mAb | Cyclin D1 | siRNA-protamine encapsulated into β7 I-tsNPs by rehydrating and lyophilized | 877±110 nm −4.1±2.1 mV |
FIB504 mAb | β7 integrin on leukocyte | Antibody-targeting integrin | Intravenous injection via tail veins | Protamine is a positively charged protein, which was used to enhance delivery of nucleic acids. Hyaluronan maintains the structural integrity in the cycle of lyophilization and rehydration. | 30 |
| Polysaccharide-based nanoparticles | |||||||||
| Modified chitosan–UAC–PEG–scCD98 | CD98 | Complex coacervation technique | 147–261 nm 7.9–17.3 mV |
Single-chain CD98 Ab | CD98 protein on colonic epithelial cells and macrophages | Antibody-targeting delivery | Oral gavage NPs encapsulated into hydrogel of alginate and chitosan | PEI in NPs functions as “proton sponge” to escape degradation by lysosome. | 41 |
| Galactosylated trimethyl chitosan–cysteine | Map4k4 | Ionic gelation with TPP and siRNA entrapment method | 140–160 nm 20–42 mV |
Galactosyl | MGL on macrophage | MGL-mediated targeting | Oral gavage administration | Trimethyl chitosan improves solubility and gene transfection efficiency in physiological conditions. Cysteine–chitosan enhances bioadhesion capacity via covalently bonding with mucin glycoproteins. Cationic delivery systems spontaneously conjugate with anionic cross-linker TPP without sonication protecting siRNA. | 46 |
| Mannose trimethyl chitosan–cysteine | TNF-α | Ionic gelation with TPP and siRNA entrapment method | 100–150 nm | Mannose | MR on enterocytes and M-cells | MR-mediated targeting | – | Mannose moieties improve intestinal permeation of Peyer’s patches. | 52 |
| SC12-cyclodextrin-click-propylamine | TNF-α | Complex coacervation technique | Without L-PEI: 240 nm +42 mV With L-PEI: 420 nm +24 mV |
– | – | Mucoadhesion | Intrarectal administration | NPs keep stability in simulated colonic fluids and α-amylase. B-PEI has more appropriate electrostatic attraction with siRNA than L-PEI at low N/P ratio. | 57 |
| β-1,3-d-Glucan | Map4k4 | SiRNA absorbs into glucan shell with electrostatic attraction and coated with PEI | 2–4 µm | – | Phagocytosis via dectin-1 receptor on M-cells and macrophages | Mucoadhesion | Oral gavage administration | First report of oral siRNA delivery. The silencing efficiency of NPs up to 250 times compared to previous studies of systemic siRNA delivery in vivo. | 59 |
| PLA-based nanoparticles | |||||||||
| PLA | TNF-α | Double emulsion/solvent evaporation | 380 nm −8 mV |
– | – | Mucoadhesion | Oral gavage administration | Encapsulate NPs into hydrogen of alginate and chitosan at a weight ratio of 7/3 and administered orally to mice. | 63 |
| PLA | Klf4 | Double emulsion/solvent evaporation | – | – | – | Mucoadhesion | Oral gavage administration | DSS increases epithelial permeation efficiency of NPs. NPs uptake more by proliferating cells. | 65 |
| PLA–PEG–maleimide–Ab | TNF-α | Double emulsion/solvent evaporation | Without Fab’: 609±37 nm With Fab’: 379±19 nm |
F4/80 Ab | F4/80 antigens on macrophages | Antibody-targeting delivery | Oral gavage administration | SiRNA-PEI complex decreases the therapeutic dose of siRNA. | 66 |
| CaP/PLGA-based nanoparticles | |||||||||
| CaP/PLGA/PEI | TNF-α IP-10 KC | Rapid precipitation and double emulsion/solvent evaporation | 151.52 nm 22.08 mV |
– | – | Mucoadhesion | Intrarectal administration | B-PEI absorbed on the surface of CaP/PLGA nanoparticles to enhance cell endocytosis and endosomal escape. Intestinal epithelial cells as target of CaP/PLGA nanoparticles. | 72 |
| NiMOS-based microspheres | |||||||||
| NiMOS | TNF-α | Double emulsion-like technique | NPs: 279±3.2 nm MPs: 2.4±0.94 µm |
– | – | Mucoadhesion | Oral gavage administration | Blank NiMOS and scramble siRNA NiMOS show off-target effects. | 80 |
| NiMOS | TNF-α/cyclin D1 | Double emulsion-like technique | – | – | – | Mucoadhesion | Oral gavage administration | Combined siRNA treatment caused stronger downregulated efficiency than single siRNA. Dilution effect in dual siRNA treatment compared to same amount of single siRNA. |
77 |
| Thioketal-based nanoparticles | |||||||||
| PPADT | TNF-α | siRNA-DOTAP/PPADT mixture by emulsification method | 600 nm 5.84+0.8 mV |
– | – | Mucoadhesion | Oral gavage administration | DOTAP enhances siRNA transfection and endosome escapes. Oral TKNs target to disease tissue and perform silencing efficiency in tenfold lower dose than GeRPs. | 83 |
| Polyethylenimine-based nanoparticles | |||||||||
| p(CBA–B-PEI)–PEG–Man | TNF-α | Complex coacervation technique | Without TPP: 302–363 nm With TPP: 211–275 nm |
Mannose | MR on macrophages | MR-mediated targeting | Ex vivo cell culture | TPP is non-toxic, enhances siRNA consideration with polycation and decreases the size of NPs. | 90 |
Note: “–” Indicates data not available.
Abbreviations: Ab, antibody; B-PEI, branched-polyethylenimine; CaP, calcium phosphate; CBA, N,N′-bioreducible cystamine bisacrylamide; DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; GeRPs, β-1,3-d-glucan-encapsulated siRNA particles; IBD, inflammatory bowel disease; Klf4, Krüppel-like factor 4; L-PEI, liner-polyethylenimine; mAb, monoclonal antibody; Man, mannose; MGL, macrophage galactose-type lectin; MPs, microspheres; MR, mannose receptor; NiMOS, nanoparticles-in-microsphere oral system; NPs, nanoparticles; PEG, polyethylene glycol; PEI, polyethylenimine; PLA, polylactide; PLGA, poly(d,l-lactide-co-glycolide acid); Ref, reference; ScCD98, single-chain CD98; siRNA, short interfering RNA; TKNs, thioketal nanoparticles; TNF-α, tumor necrosis factor-alpha; TPP, tripolyphosphate; UAC, urocanic acid; β7 I-tsNPs, β7 antibody-equipped liposome-siRNA complexes.