Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis

Abstract

Although exosome therapy has been recognized as a promising strategy in the treatment of rheumatoid arthritis (RA), sustained modulation on RA specific pathogenesis and desirable protective effects for attenuating joint destruction still remain challenges. Here, silk fibroin hydrogel encapsulated with olfactory ecto-mesenchymal stem cell-derived exosomes (Exos@SFMA) was photo-crosslinked in situ to yield long-lasting therapeutic effect on modulating the immune microenvironment in RA. This in situ hydrogel system exhibited flexible mechanical properties and excellent biocompatibility for protecting tissue surfaces in joint. Moreover, the promising PD-L1 expression was identified on the exosomes, which potently suppressed Tfh cell polarization via inhibiting the PI3K/AKT pathway. Importantly, Exos@SFMA effectively relieved synovial inflammation and joint destruction by significantly reducing T follicular helper (Tfh) cell response and further suppressing the differentiation of germinal center (GC) B cells into plasma cells. Taken together, this exosome enhanced silk fibroin hydrogel provides an effective strategy for the treatment of RA and other autoimmune diseases.

Developing hydrogels for gene therapy and tissue engineering

“…Exotherapy is a recognized and highly promising strategy for RA treatment; however, it still presents serious challenges in the long-term modulation of the specific pathogenesis of RA and the protection of reduced joint damage. Therefore, Rui et al [ 193 ] prepared a photo-cross-linked SF hydrogel and encapsulated olfactory ecto-MSC-derived Exos to form the Exos@SFMA hydrogel for continuous treatment of the immune microenvironment of RA. Hydrogels have flexible mechanical properties, excellent biocompatibility, and adsorption, and are suitable for the protection of joint tissue surfaces.…”

Therapeutic potential of mesenchymal stem cell-derived exosomes in skeletal diseases

“…The potential mechanisms underlying the therapeutic effects of MSC-exosomes in RA include modification of macrophage heterogeneity and autoimmunity. These effects are mediated by regulation of the matrix metalloproteinase 14 (MMP14)/vascular endothelial growth factor (VEGF) (Chen et al, 2018), interleukin 17 receptor A (IL-17RA)/NF-κB activator 1 (Act1)/TNF receptor associated factor 6 (TRAF6)/NF-κB (Tian et al, 2022), protein inhibitor of activated STAT3 (PIAS3)/STAT3/VEGF , and PD-L1/phosphoinositide 3-kinase (PI3K)/AKT (Rui et al, 2023) signaling pathways. In addition, miR-150-5p (Chen et al, 2018), circFBXW7 (Chang and Kan, 2021), fibrinogen-like protein 1 (FGL1) , miR-146a, and miR-155 (Tavasolian et al, 2020) modulate the therapeutic effect of MSC- Overview of the therapeutic application of MSC-exosomes in IDD, including the cell sources of MSC-exosomes, the active components/cargos, and the possible mechanism/pathways during the alleviation of IDD using MSC-exosomes.…”

“…Dermal microvascular endothelial cells (DMECs) ( Zhang et al, 2021 ), fibroblast-like synoviocytes (FLSs) ( Ma et al, 2022 ), and lymphocytes ( Tian et al, 2022 ) have been used to evaluate the role of MSC-exosomes in RA. MSC-exosomes have been shown to modulate the pathogenesis of RA ( You et al, 2021 ; Ma et al, 2022 ; Rui et al, 2023 ). You et al modified the surface of ADSC exosomes to reprogram macrophages.…”

“…), the engineered ADSC exosomes accumulated in diseased joints and modulated the synovial microenvironment, thereby having a marked anti-inflammatory effect in RA ( You et al, 2021 ). Rui et al synthesized silk fibroin hydrogel encapsulated with olfactory ecto-MSCs (OEMSCs)-derived exosomes; their implantation altered T follicular helper cell polarization by regulating programmed cell death ligand 1 (PD-L1), thereby alleviating synovial inflammation and joint destruction ( Rui et al, 2023 ) ( Table 3 ).…”

Hyaluronic Acid in Rheumatology

“…By harnessing the synergistic effects of HA with other therapeutic agents, it is possible to enhance its regenerative, anti-inflammatory, and analgesic properties, opening up new avenues for personalized medicine and tissue engineering approaches [ 161 , 162 , 163 ]. Further research is warranted to elucidate the precise molecular mechanisms and evaluate the efficacy of targeted interventions in clinical settings with respect to long-term safety and cost-effectiveness of combination therapies involving HA.…”