Plant-derived extracellular vesicles as a promising anti-tumor approach: A comprehensive assessment of effectiveness, safety, and mechanisms

Background: Plant-derived extracellular vesicles (PDEs) are expected to be a compelling alternative for cancer treatment due to their low cytotoxicity, low immunogenicity, high yield, and potential anti-tumor efficacy. Despite the significant advantages of PDEs, the reliable evidence for PDEs as promising anti-tumor approach remains unsystematic and insufficient. Some challenges remain for the clinical application and large-scale industrial production of PDEs. Purpose: Through systematic evaluation and meta-analysis, the objective was to provide scientific, systematic and reliable preclinical evidence to support the clinical use of PDEs in cancer therapy. Methods: The search for relevant literature, conducted up to March 2024, encompassed various databases including Web of Science, the Cochrane Library, Embase, PubMed, CNKI, Wanfang Data, and the China Science and Technology Journal Database. The SYRCLE<acute accent>s risk of bias tool was used to assess the methodological quality of the animal studies. For overall effect analysis and subgroup analysis, RevMan 5.4 and Stata 12.0 were utilized. Results: The analysis incorporated a total of 38 articles, comprising 29 in vivo studies and 9 in vitro studies. Metaanalysis indicated that PDEs significantly reduced cancer cell activity and induced apoptosis, reduced tumor volume and tumor weight when used as therapeutic agents, as well as exhibited synergistic anti-cancer via combination therapy. Additionally, PDEs-drugs exerted stronger inhibition of tumor volume compared to the free drug or commercial liposome-drugs. Their therapeutic effects were closely related to regulating tumor cell biological behavior and remodeling the tumor microenvironment. The safety was associated with administration route of PDEs, oral administration was currently preferred until more in-depth studies on the safety of other methods are conducted. Conclusions: The meta-analysis revealed that PDEs have systematic and reliable preclinical evidence in preclinical studies of cancer therapy, and their efficacy and certain safety could support the clinical application of PDEs in cancer therapy. Of course, further researches are required for large-scale industrial production to meet the needs of clinical applications.