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Nature nanotechnology
Sep, 2024;19 (9): 1375-1385.

Oral mitochondrial transplantation using nanomotors to treat ischaemic heart disease.

Ziyu Wu, Lin Chen, Wenyan Guo, Jun Wang, Haiya Ni, Jianing Liu, Wentao Jiang, Jian Shen, Chun Mao, Min Zhou, Mimi Wan
Author Information
  1. Ziyu Wu: National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
  2. Lin Chen: National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
  3. Wenyan Guo: National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
  4. Jun Wang: Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  5. Haiya Ni: Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  6. Jianing Liu: Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  7. Wentao Jiang: Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. ORCID
  8. Jian Shen: National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China. ORCID
  9. Chun Mao: National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China. maochun@njnu.edu.cn. ORCID
  10. Min Zhou: Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. zhouminnju@nju.edu.cn. ORCID
  11. Mimi Wan: National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China. wanmimi@njnu.edu.cn. ORCID
PMID: 38802669 DOI: 10.1038/s41565-024-01681-7

Abstract

Mitochondrial transplantation is an important therapeutic strategy for restoring energy supply in patients with ischaemic heart disease (IHD); however, it is limited by the invasiveness of the transplantation method and loss of mitochondrial activity. Here we report successful mitochondrial transplantation by oral administration for IHD therapy. A nitric-oxide-releasing nanomotor is modified on the mitochondria surface to obtain nanomotorized mitochondria with chemotactic targeting ability towards damaged heart tissue due to nanomotor action. The nanomotorized mitochondria are packaged in enteric capsules to protect them from gastric acid erosion. After oral delivery the mitochondria are released in the intestine, where they are quickly absorbed by intestinal cells and secreted into the bloodstream, allowing delivery to the damaged heart tissue. The regulation of disease microenvironment by the nanomotorized mitochondria can not only achieve rapid uptake and high retention of mitochondria by damaged cardiomyocytes but also maintains high activity of the transplanted mitochondria. Furthermore, results from animal models of IHD indicate that the accumulated nanomotorized mitochondria in the damaged heart tissue can regulate cardiac metabolism at the transcriptional level, thus preventing IHD progression. This strategy has the potential to change the therapeutic strategy used to treat IHD.

References

  1. Brown, D. A. et al. Mitochondrial function as a therapeutic target in heart failure. Nat. Rev. Cardiol. 14, 238���250 (2017). [PMID: 28004807]
  2. Godoy, L. C. et al. Association of beta-blocker therapy with cardiovascular outcomes in patients with stable ischemic heart disease. J. Am. Coll. Cardiol. 81, 2299���2311 (2023). [PMID: 37316110]
  3. Cohn, P. F., Fox, K. M. & Daly, C. Silent myocardial ischemia. Circulation 108, 1263���1277 (2003). [PMID: 12963683]
  4. Ibanez, B. et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 39, 119���177 (2018). [PMID: 28886621]
  5. Ikeda, G. et al. Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J. Am. Coll. Cardiol. 77, 1073���1088 (2021). [PMID: 33632482]
  6. Sun, M. et al. Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases. J. Transl. Med. 21, 347 (2023). [PMID: 37231493]
  7. Bertero, E., Maack, C. & O���Rourke, B. Mitochondrial transplantation in humans: ���magical��� cure or cause for concern? J. Clin. Invest. 128, 5191���5194 (2018). [PMID: 30371508]
  8. Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. & Russell, O. M. Mitochondrial transplantation���a possible therapeutic for mitochondrial dysfunction? Mitochondrial transfer is a potential cure for many diseases but proof of efficacy and safety is still lacking. EMBO Rep. 21, e50964 (2020). [PMID: 32852136]
  9. Zhang, T. & Miao, C. Mitochondrial transplantation as a promising therapy for mitochondrial diseases. Acta Pharm. Sin. B 13, 1028���1035 (2023). [PMID: 36970208]
  10. McCully, J. D. et al. Injection of isolated mitochondria during early reperfusion for cardioprotection. Am. J. Physiol. Heart Circ. Physiol. 296, H94���H105 (2009). [PMID: 18978192]
  11. Sun, X. et al. Alda-1 treatment promotes the therapeutic effect of mitochondrial transplantation for myocardial ischemia-reperfusion injury. Bioact. Mater. 6, 2058���2069 (2021). [PMID: 33511307]
  12. Hayashida, K. et al. Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest. BMC Med. 21, 56 (2023). [PMID: 36922820]
  13. Baryakova, T. H., Pogostin, B. H., Langer, R. & McHugh, K. J. Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nat. Rev. Drug Discov. 22, 387���409 (2023). [PMID: 36973491]
  14. Chen, W., Huang, T., Shi, K., Chu, B. & Qian, Z. Chemotaxis-based self-accumulation of surface-engineered mitochondria for cancer therapeutic improvement. Nano Today 35, 100966 (2020).
  15. Chen, H. et al. A nitric-oxide driven chemotactic nanomotor for enhanced immunotherapy of glioblastoma. Nat. Commun. 14, 941 (2023). [PMID: 36804924]
  16. Tang, S. et al. Enzyme-powered Janus platelet cell robots for active and targeted drug delivery. Sci. Robot. 5, eaba6137 (2020). [PMID: 33022613]
  17. Lanza, I. R. & Nair, K. S. Functional assessment of isolated mitochondria in vitro. Methods Enzymol. 457, 349���372 (2009). [PMID: 19426878]
  18. Heitzer, T., Schlinzig, T., Krohn, K., Meinertz, T. & M��nzel, T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104, 2673���2678 (2001). [PMID: 11723017]
  19. Li, T. et al. A universal chemotactic targeted delivery strategy for inflammatory diseases. Adv. Mater. 34, e2206654 (2022). [PMID: 36122571]
  20. Somasundar, A. et al. Positive and negative chemotaxis of enzyme-coated liposome motors. Nat. Nanotechnol. 14, 1129���1134 (2019). [PMID: 31740796]
  21. Michela, P., Velia, V., Aldo, P. & Ada, P. Role of connexin 43 in cardiovascular diseases. Eur. J. Pharmacol. 768, 71���76 (2015). [PMID: 26499977]
  22. Bennett, B. C. et al. An electrostatic mechanism for Ca-mediated regulation of gap junction channels. Nat. Commun. 7, 8770 (2016). [PMID: 26753910]
  23. Islam, M. N. et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 18, 759���765 (2012). [PMID: 22504485]
  24. Gadok, A. K. et al. Connectosomes for direct molecular delivery to the cellular cytoplasm. J. Am. Chem. Soc. 138, 12833���12840 (2016). [PMID: 27607109]
  25. Chen, P. et al. A plant-derived natural photosynthetic system for improving cell anabolism. Nature 612, 546���554 (2022). [PMID: 36477541]
  26. Huang, T. et al. Iron oxide nanoparticles augment the intercellular mitochondrial transfer-mediated therapy. Sci. Adv. 7, eabj0534 (2021). [PMID: 34586849]
  27. Massion, P. B., Feron, O., Dessy, C. & Balligand, J.-L. Nitric oxide and cardiac function: ten years after, and continuing. Circ. Res. 93, 388���398 (2003). [PMID: 12958142]
  28. Manders, E. M. M., Verbeek, F. J. & Aten, J. A. Measurement of co-localization of objects in dual-colour confocal images. J. Microsc. 169, 375���382 (1993). [PMID: 33930978]
  29. Zhu, P. et al. Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: a mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol. 16, 157���168 (2018). [PMID: 29502045]
  30. Han, X. et al. Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions. Nat. Nanotechnol. 15, 605���614 (2020). [PMID: 32483319]
  31. Zhou, Y. et al. A pH���triggered self���unpacking capsule containing zwitterionic hydrogel���coated MOF nanoparticles for efficient oral exendin���4 delivery. Adv. Mater. 33, e2102044 (2021). [PMID: 34216408]
  32. Zhu, W. et al. Oral delivery of therapeutic antibodies with a transmucosal polymeric carrier. ACS Nano 17, 4373���4386 (2023). [PMID: 36802527]
  33. Pearce, S. C. et al. Intestinal in vitro and ex vivo models to study host���microbiome interactions and acute stressors. Front. Physiol. 9, 1584 (2018). [PMID: 30483150]
  34. Drucker, D. J. Advances in oral peptide therapeutics. Nat. Rev. Drug Discov. 19, 277���289 (2020). [PMID: 31848464]
  35. Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121���1135 (2007). [PMID: 17855673]
  36. Zhang, A. et al. Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance. Mol. Ther. 31, 1468���1479 (2023). [PMID: 36805084]
  37. Tevaearai, H. T., Walton, G. B., Eckhart, A. D., Keys, J. R. & Koch, W. J. Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated ��-adrenergic signaling modulation. Eur. J. Cardiothorac. Surg. 22, 733���737 (2002). [PMID: 12414039]
  38. Tang, X. et al. Lipophilic NO���driven nanomotors as drug balloon coating for the treatment of atherosclerosis. Small 19, 2203238 (2023).
  39. Zhang, Q. et al. Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis. Nat. Nanotechnol. 13, 1182���1190 (2018). [PMID: 30177807]
  40. Chen, W., Shi, K., Chu, B., Wei, X. & Qian, Z. Mitochondrial surface engineering for multidrug resistance reversal. Nano Lett. 19, 2905���2913 (2019). [PMID: 30935203]
  41. Xie, C. et al. Irisin controls growth, intracellular Ca signals, and mitochondrial thermogenesis in cardiomyoblasts. PLoS One 10, e0136816 (2015). [PMID: 26305684]
  42. Dagda, R. K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843���13855 (2009). [PMID: 19279012]
  43. Vandergriff, A. C., Hensley, M. T. & Cheng, K. Isolation and cryopreservation of neonatal rat cardiomyocytes. J. Vis. Exp. 9, e52726 (2015).
  44. Yamagata, T. et al. Characterization of insulin protection properties of complexation hydrogels in gastric and intestinal enzyme fluids. J. Control. Release 112, 343���349 (2006). [PMID: 16631271]
  45. Rabiolo, A., Bignami, F., Rama, P. & Ferrari, G. VesselJ: a new tool for semiautomatic measurement of corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 56, 8199���8206 (2015). [PMID: 26720472]
  46. Masuzawa, A. et al. Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 304, H966���H982 (2013). [PMID: 23355340]
  47. Cowan, D. B. et al. Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 11, e0160889 (2016). [PMID: 27500955]
  48. Kaza, A. K. et al. Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion. J. Thorac. Cardiovasc. Surg. 153, 934���943 (2017). [PMID: 27938904]
  49. Shin, B. et al. A novel biological strategy for myocardial protection by intracoronary delivery of mitochondria: safety and efficacy. JACC Basic Transl. Sci. 4, 871���888 (2019). [PMID: 31909298]
  50. Blitzer, D. et al. Delayed transplantation of autologous mitochondria for cardioprotection in a porcine model. Ann. Thorac. Surg. 109, 711���719 (2020). [PMID: 31421103]
  51. Guariento, A. et al. Mitochondrial transplantation for myocardial protection in ex-situ-perfused hearts donated after circulatory death. J. Heart Lung Transplant. 39, 1279���1288 (2020). [PMID: 32703639]
  52. Guariento, A. et al. Preischemic autologous mitochondrial transplantation by intracoronary injection for myocardial protection. J. Thorac. Cardiovasc. Surg. 160, e15���e29 (2020). [PMID: 31564546]
  53. Sun, X. et al. Intravenous transplantation of an ischemic-specific peptide-TPP-mitochondrial compound alleviates myocardial ischemic reperfusion injury. ACS Nano 17, 896���909 (2023). [PMID: 36625783]
  54. Emani, S. M., Piekarski, B. L., Harrild, D., Del Nido, P. J. & McCully, J. D. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg. 154, 286���289 (2017). [PMID: 28283239]
  55. Guariento, A. et al. Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg. 162, 992���1001 (2021). [PMID: 33349443]
  56. Kristensen, K. L., Rauer, L. J., Mortensen, P. E. & Kjeldsen, B. J. Reoperation for bleeding in cardiac surgery. Interact. Cardiovasc. Thorac. Surg. 14, 709���713 (2012). [PMID: 22368106]
  57. Zubrzycki, M. et al. Assessment and pathophysiology of pain in cardiac surgery. J. Pain. Res. 11, 1599���1611 (2018). [PMID: 30197534]
  58. Tanner, T. G. & Colvin, M. O. Pulmonary complications of cardiac surgery. Lung 198, 889���896 (2020). [PMID: 33175990]
  59. Kubota, H. et al. Deep sternal wound infection after cardiac surgery. J. Cardiothorac. Surg. 8, 132 (2013). [PMID: 23688324]
  60. Doll, J. A. et al. Management of percutaneous coronary intervention complications: algorithms from the 2018 and 2019 Seattle percutaneous coronary intervention complications conference. Circ. Cardiovasc. Interv. 13, e008962 (2020). [PMID: 32527193]
  61. Stern, S. & Bayes de Luna, A. Coronary artery spasm: a 2009 update. Circulation 119, 2531���2534 (2009). [PMID: 19433770]

MeSH Term

Animals
Myocardial Ischemia
Administration, Oral
Mitochondria
Rats
Myocytes, Cardiac
Mice
Male
Humans
Mitochondria, Heart
Nanoparticles
Journal Article
Article has an altmetric score of 77

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