Microfluidic-generated Mito@G3K nanocomposite targets inflamed joints, alleviates rheumatoid arthritis in mice via mitochondrial metabolism.

Rheumatoid arthritis (RA) is a debilitating chronic autoimmune disease characterized by persistent inflammation and progressive joint damage. Current standard-of-care treatments, often relying on systemic immune suppressors, carry significant risks of infection and systemic adverse reactions, highlighting a critical need for targeted therapies. Recent research has increasingly linked RA pathogenesis to mitochondrial dysfunction, which drives disease progression through increased cellular ROS production, immune cell activation, and autoantibody generation. While the precise mechanisms remain under investigation, this connection offers a promising avenue for novel therapeutic strategies, such as mitochondrial transplantation, aimed at restoring cellular function by replacing damaged mitochondria.

Researchers developed a novel biomimetic mitochondrial nanocomposite, Mito@G3K, utilizing microfluidic chips for efficient generation. This process leveraged the charge capture effect between isolated mitochondria and cationic peptide dendritic macromolecules. The resulting Mito@G3K nanocomposites, composed of naturally derived peptide components, were designed for intravenous administration. In vitro experiments assessed their ability to inhibit inflammation in pro-inflammatory macrophages. For in vivo evaluation, the nanocomposite was tested in a collagen-induced arthritis (CIA) mouse model of RA, with therapeutic effects on joint inflammation and synovial transcriptome changes analyzed to elucidate the underlying mechanisms.

The microfluidic-based synthesis successfully produced Mito@G3K nanocomposites with high biological activity due to their naturally derived peptide components. A key finding was the ability to customize Mito@G3K with a higher surface charge density, enabling rapid targeting ability, high accumulation volume, and a long-lasting effect specifically within inflamed joints. This targeted delivery mechanism is crucial for minimizing systemic exposure. > In vitro experiments demonstrated that Mito@G3K could effectively inhibit the inflammation caused by pro-inflammatory macrophages, suggesting a direct anti-inflammatory action at the cellular level. Furthermore, in the CIA mouse model, Mito@G3K exhibited good therapeutic effects, leading to the effective alleviation of inflammation in the joint area. Synovial transcriptome sequencing from treated mice indicated that the observed therapeutic benefits are likely achieved by improving mitochondrial metabolism, pointing to a fundamental cellular mechanism of action.