BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Potential application of biomimetic exosomes in cardiovascular disease: focused on ischemic heart disease

  • Kang, In Sook (Department of Internal Medicine, School of Medicine, Ewha Womans University) ;
  • Kwon, Kihwan (Department of Internal Medicine, School of Medicine, Ewha Womans University)
  • Received : 2021.10.18
  • Accepted : 2021.12.10
  • Published : 2022.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Cardiovascular disease, especially ischemic heart disease, is a major cause of mortality worldwide. Cardiac repair is one of the most promising strategies to address advanced cardiovascular diseases. Despite moderate improvement in heart function via stem cell therapy, there is no evidence of significant improvement in mortality and morbidity beyond standard therapy. The most salutary effect of stem cell therapy are attributed to the paracrine effects and the stem cell-derived exosomes are known as a major contributor. Hence, exosomes are emerging as a promising therapeutic agent and potent biomarkers of cardiovascular disease. Furthermore, they play a role as cellular cargo and facilitate intercellular communication. However, the clinical use of exosomes is hindered by the absence of a standard operating procedures for exosome isolation and characterization, problems related to yield, and heterogeneity. In addition, the successful clinical application of exosomes requires strategies to optimize cargo, improve targeted delivery, and reduce the elimination of exosomes. In this review, we discuss the basic concept of exosomes and stem cell-derived exosomes in cardiovascular disease, and introduce current efforts to overcome the limitations and maximize the benefit of exosomes including engineered biomimetic exosomes.

Keywords

References

  1. Benjamin EJ, Muntner P, Alonso A et al (2019) Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 139, e56-e528
  2. Yellon DM and Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357, 1121-1135 https://doi.org/10.1056/NEJMra071667
  3. Staat P, Rioufol G, Piot C et al (2005) Postconditioning the human heart. Circulation 112, 2143-2148 https://doi.org/10.1161/CIRCULATIONAHA.105.558122
  4. Laskey WK (2005) Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study. Catheter Cardiovasc Interv 65, 361-367 https://doi.org/10.1002/ccd.20397
  5. Hausenloy DJ and Yellon DM (2003) The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 35, 339-341 https://doi.org/10.1016/S0022-2828(03)00043-9
  6. Beltrami AP, Barlucchi L, Torella D et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763-776 https://doi.org/10.1016/S0092-8674(03)00687-1
  7. Smith RR, Barile L, Cho HC et al (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896-908 https://doi.org/10.1161/CIRCULATIONAHA.106.655209
  8. Bergmann O, Bhardwaj RD, Bernard S et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324, 98-102 https://doi.org/10.1126/science.1164680
  9. Cambria E, Pasqualini FS, Wolint P et al (2017) Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types. NPJ Regen Med 2, 17 https://doi.org/10.1038/s41536-017-0024-1
  10. Eschenhagen T, Bolli R, Braun T et al (2017) Cardiomyocyte Regeneration. Circulation 136, 680-686 https://doi.org/10.1161/CIRCULATIONAHA.117.029343
  11. Li Z, Hu S and Cheng K (2019) Chemical engineering of cell therapy for heart diseases. Acc Chem Res 52, 1687-1696 https://doi.org/10.1021/acs.accounts.9b00137
  12. Parizadeh SM, Jafarzadeh-Esfehani R, Ghandehari M et al (2019) Stem cell therapy: a novel approach for myocardial infarction. J Cell Physiol 234, 16904-16912 https://doi.org/10.1002/jcp.28381
  13. Makkar RR, Smith RR, Cheng K et al (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895-904 https://doi.org/10.1016/S0140-6736(12)60195-0
  14. Ostovaneh MR, Makkar RR, Ambale-Venkatesh B et al (2021) Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial. Open Heart 8, e001614 https://doi.org/10.1136/openhrt-2021-001614
  15. Clifford DM, Fisher SA, Brunskill SJ et al (2012) Stem cell treatment for acute myocardial infarction. Cochrane Data-base Syst Rev 15, Cd006536
  16. Schachinger V AA, Dobert N, Rover R et al (2008) Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium. Circulation 118, 1425-1432 https://doi.org/10.1161/CIRCULATIONAHA.108.777102
  17. Kaiser J (2018) Suspect science leads to pause in stem cell trial. Science 362, 513 https://doi.org/10.1126/science.362.6414.513
  18. Bheri S, Hoffman JR, Park HJ and Davis ME (2020) Biomimetic nanovesicle design for cardiac tissue repair. Nanomedicine (Lond) 15, 1873-1896 https://doi.org/10.2217/nnm-2020-0097
  19. Sluijter JPG, Davidson SM, Boulanger CM et al (2018) Extracellular vesicles in diagnostics and therapy of the ischaemic heart: position paper from the working group on cellular biology of the heart of the European Society of Cardiology. Cardiovasc Res 114, 19-34 https://doi.org/10.1093/cvr/cvx211
  20. Sahoo S and Losordo DW (2014) Exosomes and cardiac repair after myocardial infarction. Circ Res 114, 333-344 https://doi.org/10.1161/CIRCRESAHA.114.300639
  21. Bei Y, Das S, Rodosthenous RS et al (2017) Extracellular vesicles in cardiovascular theranostics. Theranostics 7, 4168-4182 https://doi.org/10.7150/thno.21274
  22. Porto I, Biasucci LM, De Maria GL et al (2012) Intracoronary microparticles and microvascular obstruction in patients with ST elevation myocardial infarction undergoing primary percutaneous intervention. Eur Heart J 33, 2928-2938 https://doi.org/10.1093/eurheartj/ehs065
  23. Barile L, Moccetti T, Marban E and Vassalli G (2017) Roles of exosomes in cardioprotection. Eur Heart J 38, 1372-1379
  24. Lin J, Li J, Huang B et al (2015) Exosomes: novel biomarkers for clinical diagnosis. Sci World J 2015, 657086 https://doi.org/10.1155/2015/657086
  25. Ibrahim A and Marban E (2016) Exosomes: fundamental biology and roles in cardiovascular physiology. Annu Rev Physiol 78, 67-83 https://doi.org/10.1146/annurev-physiol-021115-104929
  26. Thery C, Amigorena S, Raposo G and Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter 3, Unit 3.22
  27. Kowal J, Arras G, Colombo M et al (2016) Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A 113, E968-E977
  28. Sodar BW, Kittel A, Paloczi K et al (2016) Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection. Sci Rep 6, 24316 https://doi.org/10.1038/srep24316
  29. Huda MN, Nafiujjaman M, Deaguero IG et al (2021) Potential use of exosomes as diagnostic biomarkers and in targeted drug delivery: progress in clinical and preclinical applications. ACS Biomater Sci Eng 7, 2106-2149 https://doi.org/10.1021/acsbiomaterials.1c00217
  30. Lotvall J, Hill AF, Hochberg F et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3, 26913 https://doi.org/10.3402/jev.v3.26913
  31. Ratajczak J, Miekus K, Kucia M et al (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20, 847-856 https://doi.org/10.1038/sj.leu.2404132
  32. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ and Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9, 654-659 https://doi.org/10.1038/ncb1596
  33. Marban E (2018) The secret life of exosomes: what bees can teach us about next-generation therapeutics. J Am Coll Cardiol 71, 193-200 https://doi.org/10.1016/j.jacc.2017.11.013
  34. Choi H, Choi Y, Yim HY, Mirzaaghasi A, Yoo JK and Choi C (2021) Biodistribution of exosomes and engineering strategies for targeted delivery of therapeutic exosomes. Tissue Eng Regen Med 18, 499-511 https://doi.org/10.1007/s13770-021-00361-0
  35. Lai CP, Mardini O, Ericsson M et al (2014) Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8, 483-494 https://doi.org/10.1021/nn404945r
  36. Smyth T, Kullberg M, Malik N, Smith-Jones P, Graner MW and Anchordoquy TJ (2015) Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J Control Release 199, 145-155 https://doi.org/10.1016/j.jconrel.2014.12.013
  37. Lee RH, Kim B, Choi I et al (2004) Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 14, 311-324 https://doi.org/10.1159/000080341
  38. Lai RC, Chen TS and Lim SK (2011) Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med 6, 481-492 https://doi.org/10.2217/rme.11.35
  39. Li TS, Cheng K, Malliaras K et al (2012) Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 59, 942-953 https://doi.org/10.1016/j.jacc.2011.11.029
  40. Lee JW, Lee SH, Youn YJ et al (2014) A randomized, open-label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction. J Korean Med Sci 29, 23-31 https://doi.org/10.3346/jkms.2014.29.1.23
  41. Mayourian J, Ceholski DK, Gorski PA et al (2018) Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility. Circ Res 122, 933-944 https://doi.org/10.1161/CIRCRESAHA.118.312420
  42. Feng Y, Huang W, Wani M, Yu X and Ashraf M (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9, e88685 https://doi.org/10.1371/journal.pone.0088685
  43. Wang B, Komers R, Carew R et al (2012) Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis. J Am Soc Nephrol 23, 252-265 https://doi.org/10.1681/ASN.2011010055
  44. Park H, Park H, Mun D et al (2018) Extracellular vesicles derived from hypoxic human mesenchymal stem cells attenuate GSK3β expression via miRNA-26a in an ischemia-reperfusion injury model. Yonsei Med J 59, 736-745 https://doi.org/10.3349/ymj.2018.59.6.736
  45. Messina E, De Angelis L, Frati G et al (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95, 911-921 https://doi.org/10.1161/01.RES.0000147315.71699.51
  46. Kang IS, Suh J, Lee MN et al (2020) Characterization of human cardiac mesenchymal stromal cells and their extracellular vesicles comparing with human bone marrow derived mesenchymal stem cells. BMB Rep 53, 118-123 https://doi.org/10.5483/bmbrep.2020.53.2.235
  47. Gray WD, French KM, Ghosh-Choudhary S et al (2015) Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 116, 255-263 https://doi.org/10.1161/CIRCRESAHA.116.304360
  48. Moghaddam AS, Afshari JT, Esmaeili SA, Saburi E, Joneidi Z and Momtazi-Borojeni AA (2019) Cardioprotective microRNAs: Lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis 285, 1-9 https://doi.org/10.1016/j.atherosclerosis.2019.03.016
  49. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872 https://doi.org/10.1016/j.cell.2007.11.019
  50. Yasuda S, Kusakawa S, Kuroda T et al (2018) Tumorigenicity-associated characteristics of human iPS cell lines. PLoS One 13, e0205022 https://doi.org/10.1371/journal.pone.0205022
  51. Wang Y, Zhang L, Li Y et al (2015) Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 192, 61-69 https://doi.org/10.1016/j.ijcard.2015.05.020
  52. El Harane N, Kervadec A, Bellamy V et al (2018) Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. Eur Heart J 39, 1835-1847 https://doi.org/10.1093/eurheartj/ehy012
  53. Gupta S and Knowlton AA (2007) HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 292, H3052-H3056 https://doi.org/10.1152/ajpheart.01355.2006
  54. de Jong OG, Verhaar MC, Chen Y et al (2012) Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles 1, 18396 https://doi.org/10.3402/jev.v1i0.18396
  55. Heijnen HFG, Schiel AE, Fijnheer R, Geuze HJ and Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94, 3791-3799 https://doi.org/10.1182/blood.v94.11.3791.423a22_3791_3799
  56. Badimon L, Suades R, Fuentes E, Palomo I and Padro T (2016) Role of platelet-derived microvesicles as crosstalk mediators in atherothrombosis and future pharmacology targets: a link between inflammation, atherosclerosis, and thrombosis. Front Pharmacol 7, 293 https://doi.org/10.3389/fphar.2016.00293
  57. Bouchareychas L, Duong P, Covarrubias S et al (2020) Macrophage exosomes resolve atherosclerosis by regulating hematopoiesis and inflammation via microRNA cargo. Cell Rep 32, 107881 https://doi.org/10.1016/j.celrep.2020.107881
  58. Oerlemans MI, Mosterd A, Dekker MS et al (2012) Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs. EMBO Mol Med 4, 1176-1185 https://doi.org/10.1002/emmm.201201749
  59. Deddens JC, Colijn JM, Oerlemans MI et al (2013) Circulating microRNAs as novel biomarkers for the early diagnosis of acute coronary syndrome. J Cardiovasc Transl Res 6, 884-898 https://doi.org/10.1007/s12265-013-9493-9
  60. Jansen F, Yang X, Proebsting S et al (2014) MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary artery disease. J Am Heart Assoc 3, e001249 https://doi.org/10.1161/JAHA.114.001249
  61. Bi S, Wang C, Jin Y, Lv Z, Xing X and Lu Q (2015) Correlation between serum exosome derived miR-208a and acute coronary syndrome. Int J Clin Exp Med 8, 4275-4280
  62. Suades R, Padro T, Vilahur G et al (2015) Growing thrombi release increased levels of CD235a(+) microparticles and decreased levels of activated platelet-derived microparticles. Validation in ST-elevation myocardial infarction patients. J Thromb Haemost 13, 1776-1786 https://doi.org/10.1111/jth.13065
  63. Hafiane A and Daskalopoulou SS (2018) Extracellular vesicles characteristics and emerging roles in atherosclerotic cardiovascular disease. Metabolism 85, 213-222 https://doi.org/10.1016/j.metabol.2018.04.008
  64. Milasan A, Tessandier N, Tan S, Brisson A, Boilard E and Martel C (2016) Extracellular vesicles are present in mouse lymph and their level differs in atherosclerosis. J Extracell Vesicles 5, 31427 https://doi.org/10.3402/jev.v5.31427
  65. Jung C, Sorensson P, Saleh N, Arheden H, Ryden L and Pernow J (2012) Circulating endothelial and platelet derived microparticles reflect the size of myocardium at risk in patients with ST-elevation myocardial infarction. Atherosclerosis 221, 226-231 https://doi.org/10.1016/j.atherosclerosis.2011.12.025
  66. Yin M, Loyer X and Boulanger CM (2015) Extracellular vesicles as new pharmacological targets to treat atherosclerosis. Eur J Pharmacol 763, 90-103 https://doi.org/10.1016/j.ejphar.2015.06.047
  67. Agouni A, Lagrue-Lak-Hal AH, Ducluzeau PH et al (2008) Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. Am J Pathol 173, 1210-1219 https://doi.org/10.2353/ajpath.2008.080228
  68. Perrino C, Barabasi AL, Condorelli G et al (2017) Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? position paper of the European Society of Cardiology Working Group on cellular biology of the heart. Cardiovasc Res 113, 725-736 https://doi.org/10.1093/cvr/cvx070
  69. Suades R, Padro T, Alonso R, Mata P and Badimon L (2013) Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells. Thromb Haemost 110, 366-377 https://doi.org/10.1160/TH13-03-0238
  70. Escudier B, Dorval T, Chaput N et al (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med 3, 10 https://doi.org/10.1186/1479-5876-3-10
  71. Vandergriff AC, de Andrade JB, Tang J et al (2015) Intravenous cardiac stem cell-derived exosomes ameliorate cardiac dysfunction in doxorubicin induced dilated cardiomyopathy. Stem Cells Int 2015, 960926 https://doi.org/10.1155/2015/960926
  72. Agarwal U, George A, Bhutani S et al (2017) Experimental, systems, and computational approaches to understanding the microrna-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients. Circ Res 120, 701-712 https://doi.org/10.1161/CIRCRESAHA.116.309935
  73. Trac D, Hoffman JR, Bheri S, Maxwell JT, Platt MO and Davis ME (2019) Predicting functional responses of progenitor cell exosome potential with computational modeling. Stem Cells Transl Med 8, 1212-1221 https://doi.org/10.1002/sctm.19-0059
  74. Man K, Brunet MY, Jones MC and Cox SC (2020) Engineered extracellular vesicles: tailored-made nanomaterials for medical applications. Nanomaterials (Basel) 10, 1838 https://doi.org/10.3390/nano10091838
  75. Armstrong JPK, Holme MN and Stevens MM (2017) Reengineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano 11, 69-83 https://doi.org/10.1021/acsnano.6b07607
  76. Ostrowski M, Carmo NB, Krumeich S et al (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12, 19-30 https://doi.org/10.1038/ncb2000
  77. Wang Y, Lu X, He J and Zhao W (2015) Influence of erythropoietin on microvesicles derived from mesenchymal stem cells protecting renal function of chronic kidney disease. Stem Cell Res Ther 6, 100 https://doi.org/10.1186/s13287-015-0095-0
  78. Palviainen M, Saari H, Karkkainen O et al (2019) Metabolic signature of extracellular vesicles depends on the cell culture conditions. J Extracell Vesicles 8, 1596669 https://doi.org/10.1080/20013078.2019.1596669
  79. Akuma P, Okagu OD and Udenigwe CC (2019) Naturally occurring exosome vesicles as potential delivery vehicle for bioactive compounds. Front Sustain Food Syst 3, 23 https://doi.org/10.3389/fsufs.2019.00023
  80. Vandergriff A, Huang K, Shen D et al (2018) Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide. Theranostics 8, 1869-1878 https://doi.org/10.7150/thno.20524
  81. Li Z, Shen D, Hu S et al (2018) Pretargeting and bioorthogonal click chemistry-mediated endogenous stem cell homing for heart repair. ACS Nano 12, 12193-12200 https://doi.org/10.1021/acsnano.8b05892
  82. Shen D, Li Z, Hu S et al (2019) Antibody-armed platelets for the regenerative targeting of endogenous stem cells. Nano Lett 19, 1883-1891 https://doi.org/10.1021/acs.nanolett.8b04970
  83. Mentkowski KI, Snitzer JD, Rusnak S and Lang JK (2018) Therapeutic potential of engineered extracellular vesicles. AAPS J 20, 50 https://doi.org/10.1208/s12248-018-0211-z
  84. Antes TJ, Middleton RC, Luther KM et al (2018) Targeting extracellular vesicles to injured tissue using membrane cloaking and surface display. J Nanobiotechnology 16, 61 https://doi.org/10.1186/s12951-018-0388-4
  85. Zhang YN, Poon W, Tavares AJ, McGilvray ID and Chan WCW (2016) Nanoparticle-liver interactions: cellular uptake and hepatobiliary elimination. J Control Release 240, 332- 348 https://doi.org/10.1016/j.jconrel.2016.01.020
  86. Wu M, Guo H, Liu L, Liu Y and Xie L (2019) Size-dependent cellular uptake and localization profiles of silver nanoparticles. Int J Nanomedicine 14, 4247-4259 https://doi.org/10.2147/IJN.S201107
  87. Barenholz Y (2012) DoxilⓇ - The first FDA-approved nanodrug: Lessons learned. J Control Release 160, 117-134 https://doi.org/10.1016/j.jconrel.2012.03.020
  88. Sato YT, Umezaki K, Sawada S et al (2016) Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep 6, 21933 https://doi.org/10.1038/srep21933
  89. Moghimi SM, Andersen AJ, Hashemi SH et al (2010) Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. J Control Release 146, 175-181 https://doi.org/10.1016/j.jconrel.2010.04.003
  90. Wolfram J, Nizzero S, Liu H et al (2017) A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery. Sci Rep 7, 13738 https://doi.org/10.1038/s41598-017-14221-2
  91. Wan Z, Zhao L, Lu F et al (2020) Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium. Theranostics 10, 218-230 https://doi.org/10.7150/thno.38198
  92. Yong S-B, Song Y, Kim HJ, Ain QU and Kim Y-H (2017) Mononuclear phagocytes as a target, not a barrier, for drug delivery. J Control Release 259, 53-61 https://doi.org/10.1016/j.jconrel.2017.01.024
  93. Yamada Y, Kobayashi H, Iwasa M et al (2013) Postinfarct active cardiac-targeted delivery of erythropoietin by liposomes with sialyl Lewis X repairs infarcted myocardium in rabbits. Am J Physiol Heart Circ Physiol 304, H1124-H1133 https://doi.org/10.1152/ajpheart.00707.2012
  94. Liu X, Liu H, Zeng Z, Zhou W, Liu J and He Z (2011) Pharmacokinetics of ligustrazine ethosome patch in rats and anti-myocardial ischemia and anti-ischemic reperfusion injury effect. Int J Nanomedicine 6, 1391-1398
  95. Su T, Huang K, Ma H et al (2019) Platelet-inspired nanocells for targeted heart repair after ischemia/reperfusion injury. Adv Funct Mater 29, 1803567 https://doi.org/10.1002/adfm.201803567
  96. Tang J, Shen D, Caranasos TG et al (2017) Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome. Nat Commun 8, 13724 https://doi.org/10.1038/ncomms13724
  97. Liu B, Lee BW, Nakanishi K et al (2018) Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng 2, 293-303 https://doi.org/10.1038/s41551-018-0229-7