Artificial mitochondria ameliorates osteoarthritis through restoring cellular energy metabolism homeostasis

Mitochondrial dysfunction under pathological or aging conditions disrupts adenosine triphosphate (ATP) synthesis, exacerbating disease progression by skewing energy metabolism toward catabolism. Current strategies to restore metabolic balance remain limited by complexity or inefficiency. Inspired by the phosphocreatine-creatine kinase (CK) system-a mitochondrial-independent energy pathway, we developed chemotactic artificial mitochondria (CAMs) to address this challenge. CAMs consist of crosslinked phosphocreatine monomers (MPCr) and perfluorooctyl acrylate, designed to exploit CK's chemotactic properties for targeted delivery while resisting biofluid interference. CAMs entered degenerated chondrocytes and meniscus fibrochondrocytes via clathrin-mediated endocytosis, escaped lysosomal degradation, scavenged reactive oxygen species, and restored ATP production. Transcriptomic analysis revealed CAMs upregulated chondrogenic markers (<i>COL2A1</i>, <i>ACAN</i>, <i>SOX9</i>) and suppressed inflammatory pathways (<i>MMP3</i>, <i>IL6</i>), while enhancing extracellular matrix biosynthesis. In a murine knee osteoarthritis (OA) model, intra-articular CAM injections reduced synovial inflammation, preserved cartilage glycosaminoglycan content, and restored gait function by systemic metabolic reprogramming. Histological and radiographic assessments confirmed CAMs mitigated joint space narrowing and cartilage erosion. This study establishes CAMs as a robust, mitochondria-agnostic platform for treating degenerative diseases by rectifying cellular energy imbalance, with immediate translational potential for OA therapy.