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 siTNFαact as not only the gene therapeutics to inhibit TNFαproduction 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 siTNFαto macrophages followed by the significant reduction of TNFαexpression,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.

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),cellfree DNA,and regulating infammation-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 infammatory 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.