ROS-responsive “Trojan Horse” nanoplatform via homotypic fibroblast-membrane camouflage for precision reprogramming of pathogenic synoviocytes in rheumatoid arthritis

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The clinical management of rheumatoid arthritis (RA) remains hampered by persistent joint destruction driven by aggressive fibroblast-like synoviocytes (RA-FLS). Despite conventional therapies, structural progression often continues due to the lack of stroma-targeted delivery and the metabolic/signaling crosstalk in RA-FLS. Herein, we engineered a multifunctional biomimetic “Trojan Horse” nanoplatform, SK/TK@pAFM, to specifically reprogram pathogenic RA-FLS. This system features a reactive oxygen species (ROS)-responsive thioketal core loaded with the PKM2 inhibitor shikonin, cloaked in inflammation-activated synovial fibroblast membranes (pAFM) engineered with a TGF-β1 inhibitory peptide (TGFi). The results demonstrate that SK/TK@pAFM achieves superior joint accumulation through homotypic self-recognition, effectively evading macrophage clearance and pulmonary sequestration, which was a common drawback of immune-cell mimetics. Upon targeting, the engineered membrane provides immediate TGF-β/Smad2 blockade, while the ROS-responsive core ensures precise intracellular release of shikonin to inhibit glycolysis and induce apoptosis, even in methotrexate-resistant FLS. Notably, single-cell RNA sequencing reveals that this platform significantly reshapes the synovial landscape by depleting pathogenic fibroblast subsets (infFLS and cycFLS) and restoring chondrocyte populations. In zymosan A-induced mice, the nanovesicles significantly attenuated synovitis and cartilage erosion without systemic toxicity. This “active membrane encapsulation” strategy provides a promising blueprint for the precision treatment of stromal-driven inflammatory diseases.