Scientists have developed oral nanorobots that target damaged heart tissue, deliver energy, and repair mitochondrial function, offering a novel approach to treating ischemic heart disease.
(Nanowerk Spotlight) Mitochondria serve as cellular power plants, converting nutrients into adenosine triphosphate (ATP) – the energy molecule that fuels cellular functions. When mitochondria malfunction, energy production falters, causing cellular dysfunction and tissue deterioration across multiple organ systems. This mitochondrial energy failure contributes to cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes, affecting millions of patients globally and presenting a significant therapeutic challenge.
Medical innovation in this area has pursued two main strategies: direct transplantation of functional mitochondria, and the creation of artificial ATP generation systems. Both approaches show theoretical promise but face substantial practical limitations. Mitochondrial transplantation encounters obstacles in isolation protocols, preservation methods, and immune compatibility. Meanwhile, artificial ATP systems typically require external energy inputs such as visible light, which cannot penetrate deeply into body tissues. The field has needed a breakthrough – a stable energy delivery system that functions effectively inside the body without external power sources.
Researchers from Nanjing Normal University have now developed such a system: artificial mitochondrial nanorobots (AMNs) that can be administered orally to deliver energy directly to damaged heart cells. Their work, published in Advanced Materials (“Artificial Mitochondrial Nanorobots Deliver Energy In Vivo by Oral Administration”), demonstrates a novel approach to treating energy-deficient conditions by mimicking and restoring natural cellular energy transport mechanisms.
The research team based their design on the phosphocreatine (PCr) – creatine kinase (CK) energy shuttle, a sophisticated biological system that transports energy from mitochondria to high-demand sites within cells. This natural mechanism involves creatine molecules receiving high-energy phosphate bonds from ATP in the mitochondrial membrane to form PCr. These PCr molecules then travel into the cytoplasm where they transfer their high-energy phosphate bonds to ADP, producing ATP under the action of CK isozymes, thereby delivering energy precisely where needed. During mitochondrial damage, PCr levels can drop by more than 60%, disrupting this energy supply pathway and significantly reducing ATP synthesis efficiency.
Schematic illustration of the preparation and oral administration of the PFMACr AMNs and its basic properties. A) Preparation process of PFMACr AMNs. B) PFMACr AMNs produce NO to promote damaged mitochondrial biogenesis and provide PCr to promote ATP production. C) In vivo delivery and therapeutic routes of oral administration of PFMACr AMNs. (Image: reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
“We developed an orally administered artificial mitochondrial nanorobot that can repair the PCr-CK energy supply system and directly supply ATP in damaged cells,” the researchers explain. They designed these nanorobots using zwitterionic N-methacryl-L-arginine-phosphocreatine (MAPCr) and pentadecafluorooctyl acrylate (PFA) as monomers to create what they named PFMACr AMNs.
These nanorobots integrate three essential functional components working in concert. The motion unit, composed of L-arginine, responds to the elevated expression of inducible nitric oxide synthase (iNOS) in damaged tissues, enabling the nanorobots to move chemotactically toward injured areas. The energy-generating unit contains phosphocreatine, which carries the high-energy phosphate bonds necessary for ATP synthesis. The barrier-crossing unit features fluorinated components that help the nanorobots navigate through the gastrointestinal tract and successfully cross intestinal barriers.
The researchers selected ischemic heart disease (IHD) as their test model, as this condition creates high energy demands where mitochondria must generate substantial energy to maintain normal cardiac contractions. Following oral administration, the nanorobots demonstrated remarkable capabilities in overcoming multiple physiological barriers. The team’s experiments showed the nanorobots remained stable in the acidic gastric environment, effectively penetrated the intestinal mucus layer, crossed the intestinal epithelial barrier, and successfully targeted damaged heart tissue.
In vitro experiments revealed that these AMNs could move at speeds of approximately 5.2 μm/s in cellular environments with elevated iNOS levels, maintaining this mobility for over 24 hours. Using microfluidic models, the researchers demonstrated the nanorobots’ ability to sense iNOS concentration gradients and move preferentially toward affected areas. When introduced to damaged cardiac cells, the nanorobots accumulated near mitochondria, positioning themselves ideally to influence cellular energy production.
Once reaching their destination, the nanorobots provided high-energy phosphate bonds for ATP synthesis continuously for up to 12 hours. The researchers found that 400 μg of AMNs produced comparable amounts of ATP to approximately 10 million natural mitochondria. Beyond energy production, the nanorobots also reduced inflammation and restored cell viability by converting reactive oxygen species (ROS) into nitric oxide (NO). This generated NO further promoted mitochondrial activity and alleviated calcium overload in damaged cardiomyocytes – addressing multiple aspects of mitochondrial dysfunction simultaneously.
In animal studies, oral administration of AMNs at 50 mg per kg matched the therapeutic efficacy of intravenously administered AMNs at 10 mg per kg, offering a more convenient and patient-friendly approach to improving cardiac function. The oral route proved particularly valuable for ischemic heart disease treatment, as this chronic condition requires frequent, long-term administration. The researchers found that maintaining single doses while increasing the frequency of oral administration could halt the deteriorating trend of cardiac function in IHD-affected animals.
Transcriptomic analysis revealed that 200 μg of AMNs functionally emulated approximately 5 million natural mitochondria, restoring energy metabolism and structural function in damaged hearts at the genetic level. The analysis showed upregulation of genes related to mitochondrial matrix, inner membrane function, the TCA cycle, and fatty acid beta-oxidation – all critical components of cellular energy production. Simultaneously, genes associated with apoptosis, inflammatory responses, and fibrosis were downregulated, indicating comprehensive tissue repair beyond simple energy supplementation.
The research team also compared the efficacy of their artificial nanorobots with natural mitochondria by administering both treatments via intramyocardial injection. They found similar improvements in cardiac function, suggesting that the AMNs successfully replicated key aspects of natural mitochondrial function. This functional equivalence, combined with the practical advantages of oral administration and controlled synthesis, positions the technology as a promising alternative to mitochondrial transplantation.
This innovative design opens a new pathway for constructing artificial energy delivery systems that can function effectively in vivo without requiring external energy inputs. The approach demonstrates several advantages over previous methods: stability in the gastrointestinal environment, targeted delivery to damaged tissues, sustained energy production, and simultaneous modulation of the pathological microenvironment. While the current study focused on heart disease, the approach potentially has broader applications for various conditions characterized by mitochondrial dysfunction, including neurodegenerative and metabolic diseases.
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