Biomimetic nanosystem rewires microRNA-mediated inflammatory circuits and disrupts ROS crosstalk for multifaceted rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) persists due to the intractable pro-inflammatory M1 macrophage phenotype, sustained by dysregulated cytokine/reactive oxygen species (ROS) production, where conventional single-target therapies fail to achieve durable M1-to-M2 repolarization. To address this, we develop DPPDz@EXO, a biomimetic nanosystem that integrates M1 responsiveness with multi-target therapy functionality. Its core (DPP) consists of redox-sensitive polydopamine nanoparticles modified with dihydrolipoic acid and polyethyleneimine, enabling ROS scavenging and delivery of a miRNA-programmed DNAzyme (Dz). The Dz stays inactive in healthy cells but is selectively activated by M1 macrophage-overexpressed miRNA-155, triggering cleavage of upstream regulator miRNA-342. This initiates a self-amplifying regulatory cascade, in which suppression of pro-inflammatory miRNA-155 leads to inhibition of JAK/STAT signaling, while concurrent upregulation of anti-inflammatory miRNA-let-7e attenuates NF-κB activation. Together, these effects synergistically suppress multiple pro-inflammatory pathways at their root. An outer shell of M2 macrophage-derived exosomes (EXO) provides inflammation-targeted delivery and inherent immunomodulatory signals. By simultaneously rewiring pathogenic miRNA networks, scavenging ROS, and reinforcing M2 polarization, DPPDz@EXO achieves effective and sustained M1-to-M2 repolarization and mitigates RA progression. This study introduces a comprehensive strategy integrating synthetic nanotechnology with endogenous immunoregulatory mechanisms, offering a powerful and adaptable platform for multi-target RA therapy.