Synergistic metabolic modulation of fibroblast-like synoviocytes via targeted dual prodrug nanoparticles to mitigate rheumatoid arthritis

Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS' survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (^HAP-1NP_DC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, ^HAP-1NP_DC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, ^HAP-1NP_DC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.