自噬是导致肿瘤细胞耐药的一种重要因素，自噬抑制剂能提高肿瘤细胞对化疗药物的敏感性。但这两类药物均存在特异性差、毒性较强、无法深入肿瘤深部的缺陷，并且药物作用顺序与疗效有直接关系。为实现高特异性、滞留性、渗透性和程序性释药，本项目拟将具pH敏感性的PSA和支撑材料交联形成粒径随pH可逆变化的小粒径纳米核心，其外包覆基质金属蛋白酶敏感的明胶壳层，并修饰靶向分子iNGR，得到一种酶与pH双敏感的粒径可智能化调控的纳米递药体系。将化疗药物和自噬抑制剂分别包载于体系核心和壳层。iNGR介导体系靶向至肿瘤，壳层酶解释放自噬抑制剂，预先降低肿瘤细胞自噬水平并实现体系粒径变小，以实现肿瘤深部渗透，而后纳米核心进入细胞内涵体与溶酶体，发生pH响应性的可逆膨胀收缩，释放化疗药物杀死其所在细胞，纳米粒逃逸出死亡细胞，继续进入下一个细胞发挥作用。本项目所构建体系能够实现程序性释药和肿瘤深部递送，发挥高效协同治疗。

Autophagy is one of the key reasons involved in tumor therapeutic resistance, and autophagy inhibitors can improve the sensitivity of tumor cells to chemotherapeutics. But the non-selectivity, severe side effects and incapability of penetrating into tumor center of both of these two classes of drugs overshadowed their combination therapy. More importantly, antitumor efficacy of the combination of autophagy inhibitors and chemotherapeutics was directly related to their administration sequence. Thus, to simultaneously achieve high specificity, enhanced retention and penetration effect and sequential release in tumor tissues, an enzyme and pH dual-sensitive drug delivery system with smartly changeable particle size was established. The system had a crosslinked core, consisting of PSA with pH sensitivity and corbelled materials, along with a metalloproteinase-2 sensitive gelatin shell which was modified with tumor targeting iNGR. Chemotherapeutics and autophagy inhibitors were respectively entrapped in its core and shell. After the particles reached tumor tissue mediated by iNGR, the shell was degraded by metalloproteinase-2 to release autophagy inhibitor firstly for reducing tumor cells' autophagy level and exposing the core with smaller size for deep tumor penetration. Then core was delivered to endosomes and lysosomes, leading to a reversible swelling-shrinking change in response to outside pH variation for a sequential intra-intercellular system delivery. The swelling of the core resulted in the releasing of chemotherapeutics and the killing of host tumor cells. After escaping from the killed cells, the core could re-enter neighboring tumor cells, killing other tumor cells in a chain-like reaction. In a word, the system designed in this project could simultaneously achieve sequential drug release and deep tumor drug delivery to exert effective and synergistic antitumor therapy.