Microfluidic-based biomimetic mitochondrial nanocomposite for targeted immunotherapy of rheumatoid arthritis via mitochondrial transplantation

Rheumatoid arthritis (RA) is a common chronic autoimmune disease and has recently been reported to be closely related to mitochondrial dysfunction. Mitochondrial dysfunction can promote the occurrence and development of rheumatoid arthritis (RA) through increased cellular ROS production, activation of immune cells and production of autoantibodies. Although the mechanism of mitochondrial dysfunction remains uncertain, it offers potential therapeutic strategies for rheumatoid arthritis. Mitochondrial transplantation is an emerging treatment method, aiming to restore the normal function of tissues by replacing abnormal mitochondria in tissues or cells. Here, we propose a novel biomimetic mitochondrial nanocomposite (Mito@G3K) based on microfluidic chips, which can be used for intravenous RA targeted immunotherapy. Based on microfluidic chips, Mito@G3K were efficiently generated by taking advantage of the charge capture effect between mitochondria and cationic peptide dendritic macromolecules. Due to the naturally derived peptide components, the synthetic Mito@G3K have very high biological activity. Even more attractive is that by customizing Mito@G3K with a higher surface charge density, they can achieve rapid targeting ability, high accumulation volume and long-lasting effect in inflamed joints. In vitro experiments have shown that it can effectively inhibit the inflammation caused by pro-inflammatory macrophages. In addition, Mito@G3K have shown good therapeutic effects in the CIA mouse model and can effectively alleviate inflammation in the joint area. Mouse synovial transcriptome sequencing shows that the therapeutic effect may be achieved by improving mitochondrial metabolism.