肺是癌症转移的最常见部位之一。肺中的胶原提供了允许的微环境,其支持播散的肿瘤细胞的定植和生长。因此,下调胶原蛋白的产生可能有助于抑制肺转移。已经表明miR-29通过负调节胶原蛋白的表达而表现出有效的抗纤维化活性。的确,我们的肺肿瘤临床数据显示,miR-29a-3p表达与肺肿瘤中I型胶原表达呈负相关,与患者预后呈正相关.然而,需要选择合适的载体以将该治疗性miRNA递送至肺。在这项研究中,我们发现化疗药物顺铂促进miR-29a-3p在肺肿瘤细胞外泌体中的积累,这种类型的外泌体表现出特定的肺靶向作用和有希望的胶原蛋白下调。为了扩大准备范围并简化输送系统,我们设计了一个靶向肺的脂质体纳米囊泡(通过将DOTAP/胆固醇-miRNA的摩尔比调整为4:1)来携带miR-29a-3p并模拟外泌体.这种脂质体纳米囊泡递送系统在体内显著下调肺成纤维细胞I型胶原的分泌,从而缓解循环肺肿瘤细胞的促转移环境的建立。
The lung is one of the most common sites for cancer metastasis. Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells. Therefore, down-regulating the production of collagens may contribute to the inhibition of lung metastasis. It has been suggested that miR-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens. Indeed, our clinical lung tumor data shows that miR-29a-3p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients\' outcomes. However, suitable carriers need to be selected to deliver this therapeutic miRNA to the lungs. In this study, we found that the chemotherapy drug cisplatin facilitated miR-29a-3p accumulation in the exosomes of lung tumor cells, and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation. To scale up the preparation and simplify the delivery system, we designed a lung-targeting liposomal nanovesicle (by adjusting the molar ratio of DOTAP/cholesterol-miRNAs to 4:1) to carry miR-29a-3p and mimic the exosomes. This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo, thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.