Lycium barbarum-Derived Extracellular Vesicles Ameliorate Myocardial Hypertrophy in Heart Failure with Preserved Ejection Fraction, Associated with Reduced Cardiomyocyte Apoptosis

Background: Non-invasive therapies for heart failure represent one of the current major focuses in clinical research. Plant-derived extracellular vesicles (PEVs) have recently emerged as a promising therapeutic modality. Objectives: In this study, we investigated the therapeutic potential of PEVs in heart failure with preserved ejection fraction (HFpEF), focusing on extracellular vesicles derived from Lycium barbarum (Gq-EVs). Methods: We first obtained Gq-EVs with high biological activity and high concentration from Lycium barbarum juice and characterized them by using transmission electron microscopy, nanoparticle tracking analysis, and metabolite composition analysis. Results: Our in vivo findings indicate that nebulized inhalation of Gq-EVs for 7, 14, and 21 days improved abnormal cardiac diastolic function, reduced excessive myocardial hypertrophy, and attenuated inflammatory cell infiltration and collagen deposition in HFpEF mice. Further in vivo and in vitro experiments showed that Gq-EVs can reach injured cardiac tissue, improve mitochondrial function, and are associated with reduced cardiomyocyte apoptosis and amelioration of myocardial hypertrophy, potentially involving TP53-related apoptotic signaling. Conclusions: Overall, nebulized delivery of Gq-EVs may be a relatively non-invasive, well-tolerated, and cost-effective therapeutic strategy for HFpEF, highlighting the potential of PEV-based nanotherapies and offering a sustainable approach for the medical utilization of Lycium barbarum resources.