Reactive oxygen species and nitric oxide scavenging nanoparticles alleviating rheumatoid arthritis through adjusting the seeds and growing soils

Normalizing inflamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inflammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.

Reprogrammed siTNFα/neutrophil cytopharmaceuticals targeting inflamed joints for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovial inflammation and cartilage damage. Despite great progress in RA therapy, there still lacks the drugs to completely cure RA patients. Herein, we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA (siTNFα) as an alternative anti-inflammatory approach for RA treatment. The loaded siTNFα act as not only the gene therapeutics to inhibit TNFα production by macrophages in inflamed synovium, but also the editors to reprogram neutrophils to anti-inflammatory phenotypes. Leveraging the active tendency of neutrophils to inflammation, the reprogrammed siTNFα/neutrophil cytopharmaceuticals (siTNFα/TP/NEs) can rapidly migrate to the inflamed synovium, transfer the loaded siTNFα to macrophages followed by the significant reduction of TNFα expression, and circumvent the pro-inflammatory activity of neutrophils, thus leading to the alleviated synovial inflammation and improved cartilage protection. Our work provides a promising cytopharmaceutical for RA treatment, and puts forward a living neutrophil-based gene delivery platform.

Recent advances and applications of kartogenin in cartilage regeneration and repair / 中国组织工程研究

BACKGROUND: Cartilage defects due to cartilage lesions such as osteoarthritis are difficult to self-regenerate. How to promote cartilage regeneration and restore smooth wound surface is a hot topic in recent years. OBJECTIVE: To review the general concept, mechanism and effect of Kartogenin as well as the current clinical models, profor the regeneration and repair of damaged cartilage. METHODS: WanFang, CNKI, and PubMed were retrieved for studies on Kartogenin combined with tissue engineering in the regeneration and repair published from January 2010 to January 2020. The keywords were “Kartogenin, cartilage regeneratichondrogenesis, chondroprotection” in English and “Kartogenin, cartilage regeneration and repair, cartilage protection, tissue Chinese. After initial screening by reading titles and abstracts, irrelevant literature was excluded and finally 55 articles were ianalysis according to the inclusion criteria and exclusion criteria. RESULTS AND CONCLUSION: As a newly discovered small molecule, Kartogenin has better stability, lower immunogeniciavailability. In addition, Kartogenin plays a synergistic role with growth factors in cartilage regeneration and has great potentiformation and cartilage protection. Through in vitro experiments or animal experiments, it has been proved that Kartogenin prole in promoting cartilage generation, osteoarthritis treatment, repair of tendon and bone injury, and wound healing, and heldegeneration of cartilage and healing of rotator cuff injury. With more basic research and clinical trials on Kartogenin, a breacartilage regeneration and repair will be made in the near future.