Artificial Mitochondrial Nanorobots Deliver Energy In Vivo by Oral Administration

Abstract Delivering energy in vivo is essential for treating mitochondrial damage‐related diseases. Current methods, including natural mitochondrial transplantation and artificial energy delivery systems, lack non‐destructive, external energy‐free, and clinically viable potential solutions. Here, artificial mitochondrial nanorobots (AMNs) carrying high‐energy phosphate bonds rebuild the in vivo energy supply system to provide energy. Using ischemic heart disease (IHD) as an energy‐deficient disease model and the oral route, which has high patient compliance and facilitates long‐term administration, to investigate the therapeutic efficacy of AMNs. AMNs remain stable in the gastrointestinal tract, cross the intestinal barrier via a barrier‐crossing unit, and target damaged heart tissue and cardiomyocytes using a motion unit chemotactically. Intracellularly, their energy‐generating unit provides high‐energy phosphate bonds for ATP synthesis (duration 12 h), while synergistically reducing inflammation and restoring cell viability. At the same frequency of administration, oral AMNs (50 mg kg −1 ) match intravenous AMNs (10 mg kg −1 ) in therapeutic efficacy, offering a convenient approach to improving cardiac function. Transcriptomics confirm that 200 µg AMNs emulate 5 × 10⁶ natural mitochondria, restoring energy metabolism and structural function in damaged hearts at the genetic level. This innovative design opens a new pathway for the construction of artificial energy delivery systems in vivo.