Tong Lingjun, Wang Qiyue, Zhang Yameng, Lai Fengling, Xu Jiarun, Yin Wenchao, Zhang Sitong, Wei Guoyue, Yin Jie, Yi Huaxi, Storm Gert, Wang Zhaoyang, Huang Rong, Xu Tao, Wang Jiong-Wei
Jinan Central Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250013, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China.
Department of Cardiology, Shandong First Medical Affiliated Shandong Provincial Hospital, Jinan, 250021, China.
Biomaterials. 2025 May;316:122976. doi: 10.1016/j.biomaterials.2024.122976. Epub 2024 Nov 29.
miR30d has been shown to reverse cardiac hypertrophy. However, effective delivery of miR30d to the heart is challenging. Here, we engineered milk-derived extracellular vesicles (mEVs) by surface functionalization with an ischemic myocardium-targeting peptide (IMTP) and encapsulated miR30d to develop a formulation, the miR30d-mEVs, enabling targeted delivery of miR30d to the injured heart. In vitro, the miR30d-mEVs can be effectively internalized by hypoxia-induced H9C2 cells via the endo-lysosomal pathway. In the isoproterenol (ISO)-induced cardiac hypertrophy mice, more miR30d-mEVs accumulated in cardiac tissue than miR30d-mEVs following intravenous administration. As a result, miR30d-mEVs alleviated cardiac hypertrophy and rescued cardiac function in three murine models of hypertrophic heart failure. Mechanistically, we identified GRK5 as an unprecedented target of miR30d in cardiac hypertrophy. Taken together, our findings demonstrate that mEVs conjugated with IMTP effectively deliver miR30d to the pathological heart and thereby ameliorating cardiac hypertrophy and dysfunction via targeting GRK5-mediated signaling pathways.
miR30d已被证明可逆转心肌肥大。然而，将miR30d有效递送至心脏具有挑战性。在此，我们通过用缺血心肌靶向肽（IMTP）进行表面功能化改造了源自牛奶的细胞外囊泡（mEVs），并将miR30d封装起来，开发出一种制剂，即miR30d-mEVs，可实现将miR30d靶向递送至受损心脏。在体外，miR30d-mEVs可通过内吞溶酶体途径被缺氧诱导的H9C2细胞有效内化。在异丙肾上腺素（ISO）诱导的心肌肥大小鼠中，静脉注射后，心脏组织中积累的miR30d-mEVs比未修饰的mEVs更多。结果，在三种肥厚性心力衰竭小鼠模型中，miR30d-mEVs减轻了心肌肥大并挽救了心脏功能。从机制上讲，我们确定GRK5是miR30d在心肌肥大中一个前所未有的靶点。综上所述，我们的研究结果表明，与IMTP缀合的mEVs可有效地将miR30d递送至病理性心脏，从而通过靶向GRK5介导的信号通路改善心肌肥大和功能障碍。
