Inflammation-responsive dual-modulation nanotherapy: Reprograming neutrophil recruitment and survival for the alleviation of rheumatoid arthritis

An inflammation-responsive and endothelial cell-targeting R/HTM prodrug micelle nanotherapeutic system was developed for the effective management of rheumatoid arthritis. • R/HTM micelles realized dual modulation of neutrophil recruitment and survival via blocking P-selectin/PSGL-1-mediated adhesion cascade and ROS-triggered site-specific co-release of R-rsc and methylprednisolone. • R/HTM micelles comprehensively regulated the pathological synovial microenvironment, including clearing excess ROS, and inhibiting fibroblast-like synoviocyte invasion. • R/HTM micelles markedly mitigated synovial inflammation, cartilage damage and bone erosion in AIA rat models, holding broad translational potential for neutrophil-dominated inflammatory diseases. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, wherein aberrant neutrophil infiltration and prolonged neutrophil survival drive the amplification of inflammatory cascades. To disrupt these pathological processes, an inflammation-responsive, endothelial cell-targeting nanotherapeutic platform was constructed for dual modulation of neutrophil recruitment and survival. This system is composed of a heparin-thioketal-methylprednisolone (HTM) prodrug that self-assembles into HTM micelles, and it is loaded with the cyclin-dependent kinase inhibitor R-roscovitine (R-rsc) to produce R/HTM (R-rsc/HTM micelles). R/HTM micelle treatment effectively inhibited neutrophil recruitment in vitro by blocking P-selectin/PSGL-1-mediated adhesion to inflamed vascular endothelial cells. In the reactive oxygen species-enriched joint synovial microenvironment of the adjuvant-induced arthritis rat model, R/HTM micelle disassembly enabled co-release of R-rsc and methylprednisolone, which synergistically induced neutrophil apoptosis through Bcl-2 downregulation and Bax/Caspase-3 upregulation. This dual-phase strategy also suppressed neutrophil extracellular trap formation, reprogrammed macrophage polarization (toward an anti-inflammatory M2 phenotype), inhibited fibroblast-like synoviocyte invasion, and cleared excess ROS. Moreover, R/HTM treatment significantly alleviated joint inflammation, repaired cartilage damage, ameliorated bone erosion, and suppressed the levels of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Collectively, these findings establish R/HTM micelles as a potent nanotherapeutic system with a dual-phase mechanism that targets the key pathological checkpoints of neutrophil-mediated inflammation, offering a promising approach for the effective management of RA.