肿瘤炎性微环境是肿瘤细胞赖以存活和抵御治疗的基础，是肿瘤预后不良的关键所在。M2型巨噬细胞（TAM）是肿瘤相关炎症最主要的参与者，抑制TAM活性对重塑肿瘤炎性微环境，改善化疗预后具有重要意义。本项目因此提出联合肿瘤细胞和TAM靶向治疗策略，设计对肿瘤细胞和TAM的特异性legumain酶可激活靶向肽LAT作为配体，辅以legumain酶可裂解PEG链双层修饰，构建高效的具有肿瘤细胞和TAM双靶向响应性的纳米载药系统应用于肿瘤联合治疗，以实现肿瘤与炎性微环境靶向治疗的协同效果。纳米载体利用legumain酶可裂解PEG链外层屏蔽效应和LAT靶向“钝化”作用避免正常单核巨噬细胞系统非特异性吞噬，延长体循环时间；同时利用肿瘤特异性legumain酶裂解脱除PEG链和“活化”LAT靶向作用，有效实现联合靶向肿瘤细胞和TAM递药和治疗效果。通过本项目研究，为联合肿瘤与炎性微环境靶向治疗提供有益思路。

Tumor inflammatory microenvironment is the basis for tumor cells to survive and resist treatment, and plays a key role for poor tumor prognosis. M2 type tumor-associated macrophages (TAMs) are the main participants for tumor inflammation, inhibition of TAMs activity is of great significance to reshape tumor inflammatory microenvironment to improve the prognosis. In this project, a combination therapeutic strategy of dual targeting to both tumor cells and TAMs is therefore raised for anticancer therapy. Based on modification of tumor cells and TAMs-specific legumain-activable targeting peptides (LAT) and legumain-cleavable PEG chain, a tumor cells and TAMs dual-targeting and double layer-responsive nanocarrier delivery system has been constructed for combined anticancer therapy, to achieve synergy of targeted treatment of both tumor cells and tumor-associated inflammatory microenvironment. . The outer layer of PEG shielding effect and the deactivation of LAT targeting effect can enable the nanocarriers to effectively avoid non-specific MPS elimination to extend the blood circulation. After reaching tumor site by EPR effect, the outer PEG layer of nanocarriers was cleaved and the LAT targeting effect was activated specifically by the legumain overexpressed on both tumor cells and TAMs, thus achieving the dually targeted delivery and the combination treatment. Through this study, it can provide beneficial references for the combined anticancer therapy with tumor inflammatory microenvironment.