Table 3.
siRNA based nanotherapeutics for treatment of OA.
| Carrier | Drug/ Formulation |
Targeted Pathways | Characteristics | Animal Model | Administration Route | Outcomes | Ref |
|---|---|---|---|---|---|---|---|
| Adenoviral vector | Ad-siRNA NF-κBp65 | NF-κBp65 | Optical density: 260 | SD male rats | Intra-articular injection | Decrease NF-κBp65 expression and mitigate synovial inflammation by inhibition of f IL-1β, TNF-α and cartilage degradation. | [149] |
| – | siRNA with phenotypic features of OA Ob. | Inhibitors of leptin signaling TGF-β1 | Final concentration: 100 µg/ml | Human subchondral Ob cell culture | – | Blocking leptin signaling via siRNA decreased the levels of OC, ALP, TGF-β1, Ob Rb in OA Ob expression. Inhibition of leptin production in OA Ob improved the phenotypic expression of Ob. | [150] |
| – | SDF-1, CXCR4 siRNA, or CXCR4 antibody | Signaling between SDF-1 and CXCR4 with AMD3100 | 5 µg pU6RNAi-CXCR4 vector transferred into chondrocyte | Guinea pig OA model. | Small subcutaneous pockets of Alzet mini osmotic pump (44.44 mg/ml of AMD3100) | SDF-1 entered the cartilage, leading to reduced proteoglycan staining. The blocked of SDF-1, CXCR4 signaling reduced the levels of SDF-1, MMPs, GAG and IL-1b in synovial fluid showing promising therapeutics option to decreased cartilage degeneration in OA. | [151] |
| – | Lentivirus-mediated siRNA | ADAMTS-5 knockdown | – | Rat model | Intra-articular injection | Downregulation of ADAMTS-5 protein expression and prevented the degradation of articular cartilage. | [152] |
| Chondrocyte‐homing peptide/PEI nanoparticles | HIF-2α, siRNA | HIF-2α, ADAMTS-4, MMP-13, and MMP-9, VEGF, NF-κB and collagen type X | – | OA-affected mice | Intra-articular injection | Downregulation of catabolic factors, (HIF-2α, MMP-13 and MMP-9, ADAMTS-4, VEGF, collagen type X and NF-κB). Decreased IL-1β levels and cartilage integrity maintained. |
[153] |
| Surgically | MMP-13 or ADAMTS-5 siRNA | IL-1β stimulation, MMP13 mRNA expression in FLS | – | DMM Mouse Model | Intra-articular injection | siRNA-treated all three groups showed significant improvement in histological scores compared to the control siRNA group. | [154] |
| – | siRNA for NR1D1 or BMAL1 | TGF-β pathway. circadian rhythm pathway |
– | Mouse model | – | Knock down of NR1D1 that increased BMAL1 expression, while knock down BMAL1 resulted in decreased NR1D1 levels. These changes also affected the TGF-α signaling pathway. | [155] |
| – | Lipofectamine 2000, siRNA | NLRP1 and NLRP3 siRNA | – | – | – | Blocking NLRP1 and NLRP3, decreased the production of LPS induced pyroptosis and its related cytokines. | [156] |
| – | Lorecivivint | CLK2 and DYRK1A for Wnt pathway inhibition, siRNA, NF-κB and STAT | – | MIA-induced OA rats | Intra-articular injection | Early chondrogenesis due to decreased CLK2. Enhanced mature chondrocyte function by DYRK1A, inhibition of NF-κB and STAT3 via lorecivivint reduced inflammation, cytokines levels and cartilage-degrading enzymes. All the above finding improves cartilage degradation and weight bearing function of joints. | [157] |
| Photothermal-triggered NO (650 nm NIR laser irradiation) nanogenerators | NHsPP nanoparticles, NO, siRNA or PTT | Pro-inflammatory cytokines, macrophage | Particle size: 200 nm |
OA mice model | In situ injections | Inhibits the inflammatory response effectively by reducing the level of pro-inflammatory cytokines and the macrophage response and also prevents cartilage erosion efficiently. | [158] |
| – | YAP siRNA | IL-1β, Hippo/YAP signaling pathway | – | Surgery-induced OA animal models. | Intra-articular injection | Knockdown of IL-1β and prevent cartilage degradation. | [159] |
| Encapsulate PLGA nanoparticles | p66shc- siRNA-loaded nanoparticles | ROS-associated proteins p-p66shc expression levels | Particle Size: 183.7 ± 72.21 nm Zeta potential: 41.1 ± 4.81 mV |
MIA-induced OA rats | Intra-articular injection | Blocking p66shc phosphorylation reduced ROS in chondrocytes, alleviated pain, cartilage damage and inflammation. | [160] |
| PLGA nanoparticles | siRNA p47phox | Oxidative stress and ROS | Particle size: 126 ± 55 nm, Zeta potential: −23 ± 2 mV |
MIA-induced OA rats | Intra-articular injection | Inhibition of ROS generation, chondrocyte cell death can be reduced as well as decrease cartilage degradation | [147] |
| – | siRNA into chondrocyte | Mitofusin 2 (MFN2) is Parkin receptor |
– | Rats with OA | – | Silencing MFN2 using siRNA reversed age-related metabolic alterations, reduced inflammation and increase Parkin level. | [161] |
| Functionalized nanoparticles antibody | MMP13, siRNA Methylprednisolone |
MMP13, type II collagen | Particle size:100 nm Zeta potential: neutral |
Post-traumatic OA. | Intra-articular injection | Gene knockdown of MMP-13 decrease gene clusters linked to tissue remodeling, angiogenesis, immune responses and proteolysis. Reduced disease progression compared to single or weekly methylprednisolone injections. | [162] |
| – | GPER, siRNA silencing Piezo1 |
AP and ARHGAP29, and the YAP nuclear localization, RhoA/LIMK/coflin pathway | – | Rat OA model | Intra-articular injection | GPER suppressed the RhoA/LIMK/coflin pathway, actin polymerization and Piezo1 by upregulating YAP and ARHGAP29 leading to reduced cartilage degeneration. | [163] |
Ad-siRNANF-kBp65: Adenoviral vector-mediated NF-κB; Ob: Osteoblast; OC: Osteocalcin release; ALP: Alkaline phosphatase activity;; SDF-1: Stromal cell-derived factor-1; CXCR4: C-X-C chemokine receptor type 4; GAG: glycosaminoglycans; FLS: Fibroblast-like synoviocyte; DMM: Disproportionate Micromelia; NLRP1 and NLRP3: Inflammasomes; CLK2: CDC-like kinase 2; DYRK1A: Dual-specificity tyrosine phosphorylation- regulated kinase 1A; MIA: Monoiodoacetate; PTT: Photothermal Therapy; NO: Nitric oxide; NHsPP: NO—Hb@siRNA@PLGA-PEG; YAP: Yes-Associated Protein; GPER: G protein coupled oestrogen receptor; ARHGAP29: YAP/Rho GTPase activating protein 29.