High‐Efficiency Targeted Mitochondrial Transfer and AUTAC4‐Enhanced Dual Renewal Strategy for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease with limited therapeutic effectiveness of conventional biomaterials, which often lack targeted accuracy, delivery efficiency, and biocompatibility. Here, we present a biomimetically engineered carrier material using mitochondria as "living materials" to restore cell homeostasis in RA. The dual action carrier consists of a folic acid-modified macrophage membrane targeting activated M1 macrophages in RA joints, and it enables in situ mitochondrial transfer with more than twofold increase of delivery efficiency, which is a critical limitation of current approaches. By facilitating precise intracellular transfer of healthy mitochondria, and incorporating autophagy targeting chimera 4 (AUTAC4) in order to selectively destroy dysfunctional mitochondria, this design achieves complete mitochondrial renewal, increasing energy metabolism and homeostasis. In an RA model, the Dual-Action Mitochondrial Renewal Therapy (DAMRT) showed significant therapeutic potential. It could be used as a novel platform for treatment for RA and other mitochondrial dysfunction.