负载巨噬细胞特异性免疫调节因子和抗结核药物的SPEEK新型载药系统靶向治疗脊柱结核的实验性研究

脊柱结核是致残性疾病，结核杆菌（MTB）可抑制巨噬细胞自噬，抵抗免疫清除，使病灶周围硬化，抵御药物作用，是抗结核治疗失败的重要原因。构建同时搭载抗结核药物和巨噬细胞特异性免疫调节因子的局部缓释内植材料是脊柱结核外科治疗的关键。我们前期发现骨髓间充质干细胞与MTB共培养分泌的外泌体可调控巨噬细胞自噬，增强巨噬细胞免疫活性，降低MTB生存率；外泌体circRNA_0021716介导miR-27a/miR-144-3p靶向CACNA2D3/ATG4a激活自噬信号通路是发挥作用的重要机制；课题组成功构建SPEEK负载抗结核药物和基因修饰circRNA_0021716高表达的外泌体控释系统，体外实验展示了良好的生物学释放和抗结核活性。本次课题拟通过基因编辑等技术进一步探索外泌体调控巨噬细胞自噬体内作用机制，分析SPEEK载药系统在体内抗结核作用和生物安全性，为临床治疗脊柱结核开辟新途径，提供新思路。

Spinal tuberculosis is a disabling disease. Tuberculosis bacillus (MTB) can inhibit macrophage autophagy, resist immune clearance, make the lesions hardened, and resist drug action. It is an important reason for the failure of anti-MTB treatment. The key to the surgical treatment of spinal tuberculosis is to construct local slow-release implant materials loaded with anti-MTB drugs and macrophage-specific immune regulatory factors. We previously found that exosomes secreted by bone marrow mesenchymal stem cells co-cultured with MTB can relate macrophage autophagy, enhance the immune activity of macrophage and reduce MTB survival rate. The exosome circRNA_0021716 mediates miR-27a/miR-144-3p to target the CACNA2D3/ATG4a and activates the autophagy signaling pathway, which is an important mechanism. The research group successfully constructed SPEEK exosome controlled release system with high expression of anti-MTB drug and gene modification circRNA_0021716 and demonstrated good biological release and anti-MTB activity in vitro. This project intends to further explore the mechanism of exosomes regulating macrophage autophagy in vivo through gene editing and other technologies, and analyze the anti-MTB effect and biological safety of SPEEK drug carrier system in vivo, so as to open up a new approach and provide new ideas for the clinical treatment of spinal tuberculosis.