Cardiovascular diseases (CVDs), including myocardial infarction, heart failure, and atherosclerosis, are a leading cause of global morbidity and mortality, posing a severe threat to human health. Conventional treatments such as pharmacological interventions and surgical procedures are limited by low bioavailability and postoperative complications, while cell-based therapies face challenges like poor cell engraftment and ethical concerns. In search of more effective therapeutic strategies, researchers have turned their attention to cell-free therapies centered on extracellular vesicles (EVs), a breakthrough that is reshaping the landscape of cardiovascular disease treatment.
In a landmark comprehensive review published by an international research team led by Professor Junjie Xiao from the Institute of Cardiovascular Sciences at Shanghai University, the team systematically elaborates on the biological properties of EVs, their intricate interplay with the cardiovascular system, and the latest advances in bioengineering technologies to enhance EV therapeutic functionality. The research team includes collaborators from prestigious institutions such as Massachusetts General Hospital/Harvard Medical School, Albert Einstein College of Medicine in the United States, and Carol Davila University of Medicine and Pharmacy in Romania, bringing together multidisciplinary expertise in cardiovascular medicine, nanotechnology, and synthetic biology.
EVs are nanoscale lipid bilayer vesicles secreted by almost all cell types, carrying a diverse array of bioactive cargos including proteins, nucleic acids, and lipids. As key mediators of intercellular communication, they play a pivotal role in maintaining vascular homeostasis, modulating immune responses, and promoting myocardial repair in the cardiovascular system. Healthy donor-derived EVs have been proven in preclinical models to alleviate myocardial injury, reduce inflammation, and inhibit adverse cardiac remodeling, laying a solid foundation for their clinical application. The review also traces the decades-long development of EV research: from the first observation of EV-like structures in blood plasma in 1946 to the Nobel Prize in Physiology or Medicine awarded for vesicular trafficking research in 2013, and the release of international research guidelines by the International Society for Extracellular Vesicles in 2014, EV research has moved from basic discovery to standardized development, and now has entered the clinical trial stage for cardiovascular diseases.
A core focus of the review is the cutting-edge bioengineering strategies for EVs that have emerged in recent years. To overcome the limitations of natural EVs such as non-specific targeting and low cargo loading efficiency, researchers have developed a variety of modification methods, including surface engineering to enhance cardiac tissue targeting, tracking detection engineering for real-time in vivo monitoring, and genetic engineering to optimize cargo sorting and delivery. These bioengineered EVs can precisely target injured cardiac tissue, efficiently deliver therapeutic cargos, and significantly improve therapeutic efficacy in preclinical models of myocardial infarction, heart failure, and pulmonary arterial hypertension. For example, EVs modified with cardiac-homing peptides can specifically accumulate in infarcted myocardial areas, while EVs loaded with anti-inflammatory microRNAs can effectively regulate the immune microenvironment and reduce post-infarction inflammation.
The review further expounds on the clinical potential of bioengineered EVs in cardiovascular homeostasis, metabolic regulation, and tissue regeneration. Bioengineered EVs can promote angiogenesis in ischemic cardiac tissue, inhibit cardiomyocyte apoptosis and myocardial fibrosis, and even regulate cardiac metabolic pathways to restore the energy supply of damaged cardiomyocytes. Advanced delivery systems, such as embedding EVs in injectable hydrogels, can achieve sustained and localized release in the heart, further enhancing their regenerative effect on injured myocardium. The review also summarizes ongoing global clinical trials of EV-based therapies for cardiovascular diseases, showing the promising translational prospect from preclinical research to clinical application.
Despite the exciting therapeutic potential, the clinical translation of bioengineered EVs still faces several key challenges, including the lack of universal isolation and characterization standards, the difficulty of large-scale GMP-compliant production, and the need for more large-scale multicenter clinical trials to verify safety and efficacy. The research team points out that the integration of emerging technologies such as artificial intelligence, 3D bioreactors, and nanobiomimetic engineering will be the key to solving these problems. AI-driven analysis of EV multi-omic data can accelerate the discovery of disease-specific biomarkers, while 3D culture systems can significantly improve the yield and quality of EVs, laying the foundation for their large-scale clinical application.
"Bioengineered EVs represent a paradigm shift in cardiovascular therapeutics, offering a unique cell-free delivery platform that combines high biocompatibility, low immunogenicity, and precise targeting," said Professor Junjie Xiao, the corresponding author of the review. "With the continuous optimization of bioengineering strategies and the establishment of standardized production and detection protocols, EVs are expected to become a mainstream precision therapeutic tool for cardiovascular diseases in the near future, bringing new hope to millions of patients worldwide."
This research was supported by the National Key Research and Development Project of China (2022YFA1104500), the National Natural Science Foundation of China (8225005 and 82302401), and the Science and Technology Commission of Shanghai Municipality (25J22800800 and 23410750100), among other important funding programs, which provided strong financial and technical support for the in-depth research of EVs in the field of cardiovascular medicine.
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