Decellularized extracellular matrix hydrogel-mediated EVs therapy alleviates diabetic erectile dysfunction by targeting the miR-203a-3p/TMEM33 Axis.
脱细胞细胞外基质水凝胶介导的EVs疗法通过靶向miR-203a-3p/TMEM33轴缓解糖尿病勃起功能障碍
Hao Liu, Zhenjie Zang, Danfeng Zhao, Jing Zhang, Zhenqing Wang, Qiang Fu, Keqin Zhang (2026) Decellularized extracellular matrix hydrogel-mediated EVs therapy alleviates diabetic erectile dysfunction by targeting the miR-203a-3p/TMEM33 Axis. J Nanobiotechnology (IF: 12.6) 1 区
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Abstract
Diabetic erectile dysfunction (DMED) is a common complication among male patients with diabetes. Therapies primarily based on phosphodiesterase type 5 inhibitors (PDE5Is) often yield suboptimal results. Extracellular vesicles (EVs) have emerged as a promising therapeutic strategy; however, their clinical translation is hindered by rapid in vivo clearance and limited inherent bioactivity. Therefore, we developed an innovative combined therapeutic approach. First, we fabricated an injectable, thermosensitive hydrogel (ECMTA-Hydrogel) by combining a decellularized porcine corpus cavernosum extracellular matrix (ECM) with tannic acid, which exhibits excellent biocompatibility and rapid gelation at body temperature (37 °C), enabling prolonged local retention of EVs within the corpus cavernosum. Second, we pretreated mesenchymal stem cells (MSCs) with pioglitazone to generate engineered EVs (PGZ-EVs) with enhanced bioactivity. Experiments confirmed that the ECMTA-Hydrogel facilitates sustained release of PGZ-EVs, extending their duration of action. In a DMED rat model, the combined ECMTA-PGZ-EVs therapy demonstrated superior efficacy, markedly improving erectile function and effectively reversing pathological phenotypic switching and apoptosis in corpus cavernosum smooth muscle cells (CCSMCs). Mechanistically, we identified that miR-203a-3p, highly enriched in PGZ-EVs, directly targets and suppresses the endoplasmic reticulum transmembrane protein TMEM33, thereby mitigating diabetes-induced endoplasmic reticulum stress (ERS). This pathway represents the key mechanism underlying the cytoprotective effects of PGZ-EVs. In summary, this study not only establishes an efficient natural matrix hydrogel-based delivery system but also augments the therapeutic potential of EVs via engineered modification. Furthermore, we elucidate a novel mechanism involving the miR-203a-3p/TMEM33/ERS axis, offering a promising therapeutic strategy for the clinical management of DMED.© 2026. The Author(s).
糖尿病性勃起功能障碍（DMED）是男性糖尿病患者常见的并发症。目前主要基于5型磷酸二酯酶抑制剂（PDE5Is）的疗法往往效果欠佳。细胞外囊泡（EVs）作为一种有前景的治疗策略，因其体内清除迅速且生物活性有限，限制了其临床转化。因此，我们开发了一种创新的联合治疗方法。首先，我们通过将脱细胞猪阴茎海绵体细胞外基质（ECM）与单宁酸结合，制备了一种可注射的热敏性水凝胶（ECMTA-水凝胶）。该水凝胶具有优异的生物相容性，在体温（37℃）下可快速凝胶化，从而使EVs能够在阴茎海绵体内长期局部滞留。其次，我们用吡格列酮预处理间充质干细胞（MSCs），生成具有增强生物活性的工程化EVs（PGZ-EVs）。实验证实，ECMTA-水凝胶能够促进PGZ-EVs的持续释放，延长其作用时间。在DMED大鼠模型中，ECMTA-PGZ-EVs联合疗法展现出优异的疗效，显著改善勃起功能，并有效逆转阴茎海绵体平滑肌细胞（CCSMCs）的病理表型转换和凋亡。机制研究表明，PGZ-EVs中高表达的miR-203a-3p能够直接靶向并抑制内质网跨膜蛋白TMEM33，从而减轻糖尿病诱导的内质网应激（ERS）。该通路是PGZ-EVs发挥细胞保护作用的关键机制。总之，本研究不仅建立了一种高效的天然基质水凝胶递送系统，而且通过工程化修饰增强了EVs的治疗潜力。此外，我们阐明了一种涉及 miR-203a-3p/TMEM33/ERS 轴的新机制，为 DMED 的临床治疗提供了一种有前景的治疗策略。© 2026. 作者。
Links
http://www.ncbi.nlm.nih.gov/pubmed/41981572http://dx.doi.org/10.1186/s12951-026-04414-1
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