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Near-infrared light-driven metabolic reprogramming of synoviocytes for the treatment of rheumatoid arthritis

ABSTRACT: Rheumatoid arthritis is a common autoimmune disease characterized by chronic synovial inflammation and joint destruction, primarily driven by imbalance cellular metabolism and inflammatory microenvironment. While gene therapy offers a promising therapeutic approach, its effectiveness is limited by the challenges of non-specific gene expression in healthy tissues. In the present study, we developed a gene delivery system (namely APPC), in which near-infrared (NIR)-responsive gold nanorods (AR) were coated with chondroitin sulfate-modified polyethyleneimine (CS-PEI) to facilitate the heat-responsive targeted delivery of heme oxygenase 1 (HO-1) gene. The APPC showed favorable transfection efficiency due to its targeting ability and significantly facilitate the HO-1 expression under NIR irradiation. The combination of APPC/pHO-1 and NIR could effectively reprogram the cellular metabolism and repolarize the macrophages and fibroblast-like synoviocytes (FLSs), thereby inhibiting the inflammation by suppressing the glycolysis. Meanwhile, APPC could specifically enhance the HO-1 expression in inflamed tissues through NIR-mediated the activation of HSP70 promoter, ensuring the precise gene expression via photothermal conversion. In a collagen-induced arthritis (CIA) model, APPC/pHO-1 under NIR irradiation exhibited potent therapeutic efficacy, restoring the articular microenvironmental homeostasis and mitigating the symptoms of RA. These findings highlighted the potential of APPC/pHO-1 nanoparticles in the gene therapy of RA and other inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE294905 | GEO | 2025/04/17

REPOSITORIES: GEO

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Project description:The pathogenesis of rheumatoid arthritis (RA) is complicated and involves both innate and adaptive immunity [5]. The innate immunity such as macrophages or fibroblast-like synoviocytes (FLS) in the synovium can generate inflammatory mediators, including TNF-α, IL-1, IL-6, IL-17, IFN-γ, and chemo kines that lead to synovial inflammation, bone erosion, and cartilage damage [6-8]. The IL-17 signaling mediates the autoantibody production in collagen-induced arthritis (CIA) model [9]. However, the treatment response with an anti-IL17 monoclonal antibody in RA patients shows a high degree of heterogeneity [10]. The inhibitors of the Janus kinase (JAK) pathway are approved for RA patients [11]. These data suggest that the targeted multiple cytokines through the JAK pathway are useful for RA treatment. Disturbance of type I IFNs (IFNs-I) signaling and production drive autoimmune development [12]. The presymptomatic RA patients display an increase of IFNs-I before the onset of symptoms [13]. The RA patients also show the elevation of IFN- α in the synovial fluid and high expression of IFNs-I regulated gene in peripheral blood mononuclear cells (PBMC) [14]. However, the role of IFNs-I in arthritis and bone homeostasis has suggested the accelerating effect of arthritis and bone damage. The interferon-alpha receptor knockout mice develop arthritis severity higher than wild-type mice in the model of antigen-induced arthritis [15]. IFNs-I also affects the bone homeostasis by inhibiting osteoclastogenesis via receptor activator of nuclear factor-kappa B (RANK) pathway, and reduction of c-FOS expression [16-18]. Therefore, the goal of RA treatment with antagonizing the IFNs-I pathway has to be optimized between efficacy and potentially adverse effect. STING is a cytosolic DNA sensor that initiates the production of IFNs-I. STING functions have been reported as both pro-inflammatory signaling and negative regulator against inflammation [19-21]. The mutation in exon 5 of the STING gene results in gain function leading to initiate inflammation and cause the Sting associated vasculopathy with onset in infancy (SAVI) [22]. Loss of STING function rescues DNaseII-deficient mice from lethality and polyarthritis [23]. However, Sting-deficient lupus mice (MRL/Lpr mice) show higher and earlier mortality than Sting-sufficient MRL/Lpr mice [24]. The pathology also shows lymphoid hypertrophy with a higher amount of macrophages and granulocytes infiltration, autoantibodies, and cytokine [24]. The objective of this study was to identify the role of STING in the pathogenesis of rheumatoid arthritis using collagen-induced arthritis (CIA) model as a representative model of the human RA.

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Near-infrared light-driven metabolic reprogramming of synoviocytes for the treatment of rheumatoid arthritis

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