Dysferlin肌病是由dysferlin蛋白缺失导致的进行性肌萎缩，严重影响人们的生命和健康。目前临床上未有任何有效的治疗方法。本课题组前期工作中，成功地利用细胞分泌的一种纳米级囊泡结构-exosome，来运输外源寡核苷酸和肝癌抗原分子，并首次证明exosome可作为外源药物运输载体。同时，我们前期研究结果发现：肌肉细胞来源的exosome可负载高丰度、内源性dysferlin蛋白，并将其高效地传递给dysferlin缺失的靶细胞，介导靶细胞膜修复功能恢复。在此基础上，本项目拟测试负载dysferlin蛋白exosome作为功能蛋白运输载体，在dysferlin肌病治疗上的可行性和应用潜力。通过对负载dysferlin蛋白exosome的体外、体内和在dysferlin肌病病人细胞上的详细、系统的功能测试及对其作用机理的阐释，以期为dysferlin肌病靶向治疗提供一种新模式和新思路。

Dysferlinopathy, caused by the absence of dysferlin protein, presents as progressive muscle degeneration and severely affects the quality of life. Currently there is no treatment available in the clinic. Previously our group demonstrated that exosome, a biological nanoparticle secreted by most cells, could deliver externally-loaded siRNAs and hepatocellular carcinoma antigens into targeted tissues, thus providing evidence for the first time that exosomes can be an effective delivery vehicle for exogenous drugs. Meanwhile, our preliminary data showed that exosomes derived from myotubes contained abundant, endogenous dysferlin protein and could effectively transfer dysferlin protein to dysferlin-deficient muscle cells when co-incubated with muscle cells. Importantly, the transfer of dysferlin protein restored the function of targeted cells, suggesting exosomes are likely a viable delivery vehicle for dysferlin protein. Based on these results, in this proposal, we plan to investigate the feasibility and therapeutic potential of exosomes as a delivery vehicle for dysferlin protein in the dysferlinopathy model systematically. We aim to provide a new therapeutic modality and avenue for dysferlinopathy via detailed studies on dysferlin-loaded exosomes in vitro and in vivo, particularly in dysferlinopathy patients’ cells. Moreover, elucidation of the underlying mechanisms will facilitate the understanding and further improvement on exosome-based targeted therapy.