Fuxiao Wang, Hao Zhang, Dongyang Zhou, Xuan Tang, Jian Wang, Han Liu, Xiuhui Wang, Yuanwei Zhang, Z. Li, Yingying Jiang, Qin Zhang, Xiao Chen, Yingying Jing, Y. Jun Xu, Yan Hu, Lu Bai, Jiacan Su
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.