Therapeutic potential of ISO-loaded exosomes against mitochondrial damage and oxidative stress in diabetes mellitus-induced erectile dysfunction: a multiomics perspective

Diabetes mellitus-induced erectile dysfunction (DMED), a common complication of diabetes, is closely associated with oxidative stress and mitochondrial dysfunction, yet effective therapeutic strategies that simultaneously address these pathological processes remain limited, particularly in the context of biocompatible nanodelivery systems. Previous studies have demonstrated that isorhamnetin (ISO) can alleviate DMED, however, ISO exhibits poor water solubility and low bioavailability. This study aimed to develop a novel, efficient natural product-based delivery and therapeutic strategy by innovatively isolating Cistanche deserticola-derived exosomes (CD-EXOs) and encapsulating ISO into CD-EXOs via ultrasound-assisted loading technology, resulting in the successful preparation of an isorhamnetin-loaded, plant-derived exosomal nano-delivery system (ISO@CD). In vivo experiments confirmed that ISO@CD effectively improved erectile function in streptozotocin (STZ)-induced DMED rats, repaired endothelial structure and collagen arrangement in penile cavernous tissue, and mitigated oxidative stress and mitochondrial damage in penile tissue. Integrated mRNA and miRNA transcriptomic analysis combined with weighted gene co-expression network analysis (WGCNA) identified the critical roles of the Atg12 and FOXO signaling pathways. In vitro experiments further verified that ISO@CD significantly reduced high glucose (HG)-induced oxidative stress, mitochondrial damage, and apoptosis in corpus cavernosum endothelial cells (CCECs) while restoring mitochondrial respiratory function through modulation of the FOXO1/Atg12 signaling pathway. This study preliminarily confirms the potential biological activity of ISO@CD in DMED and provides new insights and directions for future exploration of DMED treatment strategies.