Regulatory Fibroblast‐Like Synoviocytes Cell Membrane Coated Nanoparticles: A Novel Targeted Therapy for Rheumatoid Arthritis

Abstract

Fibroblast-like synoviocytes (FLS) are the main cell component in the inflamed joints of patients with rheumatoid arthritis (RA). FLS intimately interact with infiltrating T cells. Fibroblasts have potent inhibitory effects on T cells, leading to the resolution of inflammation and immune tolerance. However, this "regulatory" phenotype is defect in RA, and FLS in RA instead act as "proinflammatory" phenotype mediating inflammation perpetuation. Signals that orchestrate fibroblast heterogeneity remain unclear. Here, it is demonstrated that different cytokines can induce distinct phenotypes of FLS. Interferon-gamma (IFN-𝜸) is pivotal in inducing the regulatory phenotype of FLS (which is termed FLS reg ) characterized by high expressions of several inhibitory molecules. Rapamycin enhances the effect of IFN-𝜸 on FLS. Based on the characteristics of FLS reg , a novel biomimetic therapeutic strategy for RA is designed by coating cell membrane derived from FLS reg induced by IFN-𝜸 and rapamycin on nanoparticles, which is called FIRN. FIRN show good efficacy, stability, and inflammatory joint targeting ability in an RA mouse model. The findings clarify how fibroblast phenotypes are modulated in the inflammatory microenvironment and provide insights into novel therapeutic designs for autoimmune diseases based on regulatory fibroblasts.

Neutrophil‐Mimetic, ROS Responsive, and Oxygen Generating Nanovesicles for Targeted Interventions of Refractory Rheumatoid Arthritis

“…Cytotoxicity and Hemolysis Assay: RAW 264.7 and MH7A cells were cultured in 96 well plates at a density of 1 × 10 4 per well and incubated with Leo@CAT@NM-Lipo at different concentrations (1,10,20,50,100,200,500, and 1000 μg mL −1 ), or incubated with Leo, Leo@CAT@Lipo and Leo@CAT@NM-Lipo (equivalent Leo dose at 10 μM) at 37 °C for 24 h. Afterward, each well was rinsed gently with PBS, replenished with 90 μL of fresh medium and 10 μL of CCK-8, and incubated for another 4 h at 37 °C. The absorbance of each well was measured at 450 nm by a microplate reader (SpectraMax ID5, Molecule Devices, USA).…”

“…[19] So far, FLS, leukocytes, platelets, erythrocytes, or their combinations have been adopted for biomimetic nanomedicine construction targeting RA treatments. [20] Among them, neutrophils are the first responders to inflammation and infiltrate into the cartilage-pannus junction by intimate interactions between the upregulated adhesion molecules, overexpressed cytokines, and excessive chemokines in the lesion and the membrane antigens of neutrophils. [21] Subsequently, the recruited neutrophils further release proinflammatory cytokines, proteases, ROS, chemokines, and neutrophil extracellular traps (NETs) to aggravate joint degeneration.…”

Chemically Modified Platforms for Better RNA Therapeutics

“…Bioinspired vesicle-based nanoparticles have shown potential in organ-specific RNA delivery while decreasing toxicity. These nanoparticles consist of biological elements, such as extracellular vehicles (EVs) and liposomes, mimicking the processes of biological systems. − EVs, which are membrane-coated nanoparticles, are derived from prokaryotic and eukaryotic cells and can carry RNA, proteins, lipids, and DNA. The application of EVs as delivery vehicles for RNA and other biological molecules shows promise in preventing degradation in vivo and delivering them to targeted cells without immune activation.…”

Targeting pathogenic fibroblast-like synoviocyte subsets in rheumatoid arthritis

“…Similarly, our study showed that FLSs stimulated by IFN-γ can upregulate the expression of several inhibitory molecules, such as PD-L1 and galectin-9, on the cell membrane, which might be negative feedback mechanisms of inflammatory cytokines. FLS cell membranes with high expression of inhibitory molecules ameliorated inflammation and bone damage in CIA [ 76 ]. These data suggest that the introduction of fibroblasts with immunosuppressive/pro-resolving effects may help restore the balance of FLS subsets.…”