Engineered Mitochondria-Targeted Biomimetic Hybrid Nanovesicles Ameliorate Rheumatoid Arthritis via Regulating Macrophage Autophagy and cGAS-STING Signaling

Despite decades of intensive investigation, rheumatoid arthritis (RA) remains a therapeutic challenge, primarily attributed to its intricate pathological microenvironment and poorly elucidated etiology. However, mitochondrial dysfunction and abnormal activation of the cGAS-STING signaling pathway play a key role in RA. Herein, we report mitochondria targeted biomimetic nanovesicles (SS31-CB@MM-FNVs/CLT) for the targeted therapy of RA. SS31-CB@MM-FNVs/CLT is constructed by macrophage membrane fusion nanovesicles, which are encapsulated with celastrol (CLT) and functionalized with the chitosan-bilirubin (CS-BR) conjugate and SS-31 peptide. SS31-CB@MM-FNVs/CLT bypasses immune surveillance and prolongs circulatory persistence through macrophage membrane fusion, targets macrophage mitochondria by CS and SS-31 peptide decoration, and scavenges reactive oxygen species (ROS), activates autophagy, and repolarizes macrophages from the M1 to M2 subtypes through the synergistic effects of bilirubin, celastrol, and the nanoplatform. In general, SS31-CB@MM-FNVs/CLT exhibits therapeutic efficacy in vitro and in vivo by scavenging ROS, inhibiting the STING pathway, and enhancing autophagy, thereby regulating macrophage polarization. Taken together, this biomimetic nanoplatform provides a promising basis for safer and more potent therapeutic interventions.