Biomimetic Liposome Coloaded ES-Cu and PFK15 Amplify Cuproptosis through Inhibition of Glycolysis in Fibroblast-Like Synoviocytes for Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. The pathogenesis is fundamentally driven by the tumor-like proliferation of fibroblast-like synoviocytes of RA (RAFLS), which agitates chronic inflammatory cascades and progressive tissue destruction. Cuproptosis is a new cell death pathway that relies on copper (Cu) ionophores to transport Cu into cells and has emerged as an attractive strategy for disease intervention. Herein, we first revealed hyperactive glycolysis as a key mechanism to resist cuproptosis in RAFLS by single-cell RNA sequencing. Accordingly, we proposed a hypothesis that inhibiting glycolysis could amplify cuproptosis, which was validated by utilizing PFK15 as a glycolysis inhibitor and elesclomol-copper (ES-Cu) as a cuproptosis inducer. Subsequently, a biomimetic liposome (EC/P@L-RFM) was developed to specifically codeliver ES-Cu and PFK15 to RAFLS by the fusion of RAFLS membrane (RFM) with the dual drug-encapsulated liposome. In vitro, ES-Cu-driven cuproptosis was potently boosted by PFK15-mediated glycolysis blockage and specifically induced cell death in RAFLS following the RFM fusion, which was attributed to enhanced tricarboxylic acid cycle flux by activating the glutamine-glutamate-α-ketoglutaric acid metabolic axis. In vivo, EC/P@L-RFM significantly alleviated RA symptoms by simultaneously suppressing glycolysis and amplifying cuproptosis, reaffirming the therapeutic potential of EC/P@L-RFM for RA.