Intra-Articularly Injectable Ion-Coordinated Bionic Lubricants Improve Rheumatoid Arthritis Recession via Pro-Regenerative Reprogramming of Synovial Macrophages.

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes serious joint damage and functional loss, which is predominantly associated with the aberrant activation of synovial macrophages. Herein, we report an injectable ion-coordinated bionic lubricant to efficiently reprogram synovial macrophages into pro-regenerative phenotypes for RA treatment. For this purpose, rhein (Rh)-modified PEGylated liposomes were integrated with coenzyme Q10 (CoQ10) for macrophage-targeted delivery (LipQ10-Rh), which were subsequently embedded into dynamic hyaluronic acid (HA)-based hydrogel matrices cross-linked by acylhydrazone bonding and Zn²⁺ ion-mediated coordination (HALZ). Owing to the intrinsic reversibility of the dynamic bonding network, the HALZ lubricant could be facilely injected into RA-affected joint cavity and provide immediate relief through biolubrication. Meanwhile, the LipQ10-Rh liposomes and Zn ions could be gradually released from the dynamic hydrogels and taken in by synovial macrophages, where the Zn ions could activate the anti-inflammatory metabolism while CoQ10 alleviated mitochondrial ROS stress to restore their reparative functions, which acted in a cooperative manner to reprogram the inflammatory synovial macrophages into pro-regenerative phenotypes. In vivo results evidently suggested that the injectable HALZ biolubricant efficiently abolished RA-associated joint damage on rat models in a durable manner, providing an approach for improving RA recession in the clinic.