功能化介孔有机硅纳米颗粒介导梗死心肌miRNA调控及再生修复的研究

Inhibition of miRNA-34a in myocardium is an effective gene therapy strategy to promote regeneration and repair after myocardial infarction. However, there is no suitable vector that can target myocardium and conduct site-specific release of miRNA inhibitor. Publications and our previous studies demonstrated that mesoporous organosilica materials held great potential as nano-vector for drug delivery with their high biocompatibility. In the present study, we aim to functionalize the hollow mesoporous organosilica nanoparticles with large pore size, small particle size and hollow structure, which have been fabricated in our previous studies. The thermosensitive, long-circulating and ultrasound-responsive co-polymers will be grafted onto the surface of nanoparticles as mesoporous gate-valves, which could allow the loading of miRNA-34a inhibitors and subsequent blocking of pores under the control of temperature. After intravenous injection, these long-circulating vectors could target and gather into infarcted myocardium. Afterwards, the ultrasound-sensitive groups in co-polymers can be hydrolyzed by echocardiography and make gate-valves re-open. The miRNA inhibitors will escape from the vectors and modulate cardiac regeneration and repair. Besides that, the non-specific deposition of vectors in other organs wouldn’t open their gate-valves and release miRNA-34a inhibitor in vivo, which prevent these organs from side effect of off-targeted miRNA modulation. This study will expand the applications of mesoporous organosilica nanoparticles-based drug delivery and provide a novel gene therapy strategy for myocardial infarction.

抑制心肌内miRNA-34a表达是一种能有效促进梗死心肌再生、修复的基因治疗方案，但目前仍缺乏合适的载体将miRNA抑制剂进行心肌内靶向递送和定位释放。文献和前期研究工作表明，有机无机杂化的介孔材料有望成为具有良好生物相容性的纳米药物递送载体。本课题基于前期制备的大孔径、小粒径、中空、有机无机杂化的介孔纳米颗粒，拟对其功能化修饰，以温敏、长循环以及超声响应性的聚合物作为介孔阀门，在温度控制下进行miRNA-34a抑制剂装载及孔道关闭，静脉注射后，载体具有长循环特性并可靶向富集于心梗部位，随后体外局部应用的心脏超声可水解介孔阀门内基团，开放孔道释药并抑制miRNA-34a表达，促进梗死心肌再生及修复，而其他器官中非特异性沉积的载体因无超声作用而避免了释药，减少了miRNA治疗在靶器官外的副作用。本项目将拓宽介孔纳米材料介导药物递送的应用领域，并可为心肌梗死的基因治疗提供一种新的方案。

靶向递送基因药物至梗死心肌是一种能有效促心肌再生、修复的基因治疗方案，但目前仍缺乏合适的载体将基因药物进行心肌内靶向递送和定位释放。文献和前期研究工作表明，有机无机杂化的介孔材料有望成为具有良好生物相容性的纳米药物递送载体。本课题基于前期制备的大孔径、小粒径、中空、有机无机杂化的介孔纳米颗粒，对进行其功能化修饰，以温敏、长循环以及超声响应性的聚合物作为介孔阀门，在温度控制下进行基因药物装载及孔道关闭，静脉注射后，载体具有长循环特性并可靶向富集于心梗部位，随后体外局部应用的心脏超声可水解介孔阀门内基团，开放孔道释药并抑制miRNA-34a表达，促进梗死心肌再生及修复，增加微血管密度，减少胶原沉积，减少了miRNA治疗在靶器官外的副作用。本项目将拓宽介孔纳米材料介导药物递送的应用领域，并可为心肌梗死的基因治疗提供一种新的方案。