SS31-functionalized nanovesicles ameliorate rheumatoid arthritis by regulating macrophage autophagy and cGAS-STING signaling

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex pathology and poorly understood etiology, posing significant therapeutic challenges. Current treatments often fall short due to the intricate inflammatory microenvironment. Recent research highlights the critical roles of mitochondrial dysfunction and aberrant activation of the cGAS-STING signaling pathway in driving RA pathogenesis. These pathways contribute to increased cellular reactive oxygen species (ROS) production and sustained inflammation, underscoring a need for targeted interventions that can modulate these specific mechanisms to achieve more effective disease control.

Researchers engineered SS31-CB@MM-FNVs/CLT nanovesicles for targeted RA therapy. These biomimetic nanovesicles were constructed by fusing macrophage membranes, encapsulating celastrol (CLT), and functionalizing them with a chitosan-bilirubin (CS-BR) conjugate and the SS-31 peptide. The design aimed to bypass immune surveillance, prolong circulation, and specifically target macrophage mitochondria via the CS and SS-31 peptide decorations. The therapeutic efficacy of SS31-CB@MM-FNVs/CLT was evaluated both in vitro and in vivo, focusing on its ability to scavenge ROS, activate autophagy, inhibit the STING pathway, and repolarize macrophages from pro-inflammatory M1 to anti-inflammatory M2 subtypes.