肿瘤相关成纤维细胞（CAF）对肿瘤微环境形成具有重要作用，且形成了阻碍药物递送的物理屏障。利用CAF进行肿瘤微环境调节，解除免疫抑制，同时克服CAF屏障实现药物的肿瘤深层穿透，是提高肿瘤治疗效果的有效措施。本课题基于CAF调控，构建了智能化CAF和深部肿瘤细胞双靶向的程序性药物递释系统。将小粒径树突状聚赖氨酸（DGL）纳米粒通过基质金属蛋白酶（MMP）底物肽修饰于胶束表面，在肿瘤部位MMP酶的作用下，DGL纳米粒和胶束分离，其中胶束包载TGF-β抑制剂滞留于肿瘤基质部位，调节CAF，解除免疫抑制，克服CAF屏障，进而促进包载促肿瘤细胞凋亡药物miR-34a的小粒径DGL实现肿瘤深层穿透，从源头上杀灭肿瘤细胞。这种程序性药物递释系统实现了肿瘤免疫微环境调节，同时克服了CAF屏障促进抗肿瘤药物的深层穿透，为肿瘤治疗提供了新思路，有望提高肿瘤治疗效果，对于降低肿瘤转移和复发具有重要的科学意义。

Cancer associated fibroblasts (CAFs) play important roles in the tumor microenvironment, however, they form an obstacle for the deep penetration of anticancer drugs. Therefore, it remains a challenge to achieve the tumor microenvironment modulation via CAFs as well as the deep penetration of anticancer drugs. Hereby we design a multistage dual targeting drug delivery system which targets CAF and deep tumor cells at the same time. The DGL@PEG-PCL nanoparticles accumulate at tumor site via EPR effect, and are consequently digested by matrix metalloproteinase-2 (MMP-2) into PEG-PCL micelle and smaller DGL nanoparticles. The TGF-β-loaded PEG-PCL micelle targets CAFs, modulates the tumor microenvironment and overcomes the CAF barrier, which consequently facilitates the deep penetration of miR-34a loaded smaller DGL nanoparticles. In conclusion, the multistage CAFs and deep tumor cells dual targeting drug delivery system relieves the tumor immune tolerance as well as overcomes the CAF barrier, facilitating the deep penetration of anticancer therapeutics. This stategy provides a new idea for the treatment of tumors, and will be a beneficial trail for preventing the recurrence and metastasis of tumors.