Engineered extracellular vesicles for ischemic heart diseases: modification methods, targeted delivery strategies, and multi-modal therapies - A systematic review

Background/purpose Due to the complex pathological process of ischemic heart diseases (IHD), a single treatment strategy had limited efficacy. Multi-targeted synergy, precise delivery, and long-lasting effects were new directions for treatment. Engineering extracellular vesicles (EVs) had become a research hotspot in the field of IHD treatment due to their ability carrying therapeutic signaling molecules, precise tissue targeting capabilities, and excellent biocompatibilities. This systematic review focused on the modification methods, targeting strategies, and combined effects of multi-pathway synergy of engineered EVs in IHD treatment. Methods Systematic searches were conducted in 8 databases. According to strict inclusion and exclusion criteria, the literature was screened, and relevant information was extracted based on the research purpose. Two researchers independently screened the literature, extracted information, and evaluated the quality of literatures. Results A total of 50 animal studies were included. The existing studies mainly achieved the engineering modification of EVs through internal loading/knockdown, surface modification, membrane fusion, combination with biotechnological materials, and pre-treatment; and by using targeting peptides or specific antibodies modification, membrane fusion, and in situ cardiac delivery, to enhance their targeting enrichment abilities for ischemic myocardium. In terms of therapeutic effects, engineered EVs could exert beneficial effects on cardiac function through multiple pathways, such as alleviating myocardial fibrosis, inhibiting inflammatory responses, promoting angiogenesis, reducing cardiomyocyte apoptosis, and improving mitochondrial metabolism. The multi-modal therapy of engineered EVs presented a pyramid structure: improving cardiac function served as the foundation, ameliorating classical cardioprotective pathways constituted the primary pillars, and optimizing metabolic modulation represented supplementary. Conclusion There was an intrinsic association between the multi-association therapeutic effects of engineered EVs and the modification methods. Currently, the modification strategies of engineered EVs formed a composite system of “ internal cargo loading/knockdown of core signaling molecules + surface modification and membrane fusion to enhance targeting specificity + combination with bioengineering materials for local sustained release”, which met the multiple needs of multi-targeted synergy, precise delivery, and long-lasting effects. This systematic review provided key theoretical basis and practical guidance for constructing a multifunctional EVs delivery system for treating IHD and accelerating its clinical translation and application. Systematic Review Registration: https://www.crd.york.ac.uk/ , identifier PROSPERO CRD420261393475.