Charge-reversal nanoassembly for rheumatoid arthritis therapy via cell-free DNA scavenging and microenvironment reprogramming.

The clearance of cell-free DNA (cfDNA) in rheumatoid arthritis (RA) represents a promising therapeutic approach for inflammation. While cationic materials are widely utilized for cfDNA capture, their safety during in vivo delivery remains a critical concern. Additionally, macrophage-mediated inflammatory responses exacerbate disease progression. Here, we propose a charge-reversal and enhanced nanoassembly responsive to the inflammatory microenvironment, composed of a block polymer termed polycaprolactone-poly (N, N-dimethylacrylamide)-thioketal-polyethylene glycol (PCL-PDMA-TK-PEG, PPTP), a copolymer methoxy poly (ethylene glycol)-poly-l-lysine-2,3-dimethylmaleic anhydride (mPEG-PLL-DMA, PLM), and 4-octyl itaconate (4-OI). Charge reversal in acidic inflammatory microenvironments and ROS-responsive enhancement of positive surface charge, significantly improving cfDNA capture efficiency within inflammatory sites. Mitochondrial targeting through electrostatic interactions, promoting 4-OI release to inhibit macrophage-driven inflammation. Reduced protein shielding during systemic circulation, enabling precise accumulation in inflamed joints. The 4-OI@PPTP/PLM nanoassembly effectively suppresses inflammatory cytokine production, mitigates synovial hyperplasia, and attenuates bone erosion in collagen-induced arthritis models. This strategy integrates cfDNA scavenging with microenvironment reprogramming, offering a dual-action therapeutic platform for RA management.