装载PEDF-34的MSC-exosome在糖尿病视网膜病变中的作用及机制研究

VEGF的过量表达、炎症和氧化应激是糖尿病视网膜病变（DR）的关键致病因素。注射抗VEGF疗效可靠，但易引发视网膜神经萎缩。PEDF是内源性新生血管抑制因子，可同时平衡VEGF的表达。PEDF-34是由PEDF衍生的多肽片段，具有分子量小、水溶性好且免疫原性低等优点，但稳定性较差。我们前期研究显示间充质干细胞（MSC）来源的exosome具有视网膜神经保护作用，同时exosomes还可作为天然药物载体。本课题将采用MSC-exosome作为载体，构建装载PEDF-34多肽的MSC-exosome制剂，提高PEDF-34在组织中的稳定性和穿透性及其在视网膜的生物利用度。并通过一系列体内外实验，验证其在DR中的治疗作用和研究其机制，为PEDF-34和MSC-exosome治疗DR的临床应用转化提供科学依据。

Over-expression of VEGF, inflammation, and oxidative stress are the key pathogenic factors in diabetic retinopathy (DR). Though injection of anti-VEGF drugs generates reliable efficacy, long-term inhibition of VEGF may lead to neurodeatrophia. PEDF is an endogenous inhibitor of neovascularization that can balance VEGF expression without interfering its normal function. PEDF-34 is a PEDF-derived peptide with several merits, including low molecular weight, good water solubility, and low immunogenicity. However, the stability of PEDF-34 is less satisfactory. The results of our preliminary studies have demonstrated that the exosome derived from mesenchymal sem cells (MSC-exosome) exerts neuroprotective effects on retina. In addition, exosome also can serve as a natural drug carrier. In this study, the MSC-exosome will be used as a drug carrier to load PEDF-34 peptide, thereby increasing the stability and permeability of PEDF-34 in tissue, as well as its bioavailalbility in retina. Furthermore, a series of in vitro and in vivo experiments will be conducted to confirm the therapeutic effects of the PEDF-34-carrying MSC-exosome on DR and to investigate the underlying mechanisms. This study will provide the scientific basis for clinical application and translation of PEDF-34 and MSC-exosome in DR treatment.