三元协同的酶敏感纳米载药系统改善肿瘤免疫检查点阻断治疗效果的研究

免疫检查点阻断（ICB）疗法是癌症治疗领域的革命性进展，但仍面临临床阳性反应率低和存在免疫相关不良反应（irAE）等问题。本项目拟通过合成基质金属蛋白酶-2（MMP-2）敏感的聚合物（PEG-M-OE），同时包载程序性死亡蛋白1配体抗体（αPD-L1）、光敏剂吲哚菁绿（ICG）和干扰素基因刺激蛋白（STING）激动剂ADU-S100，获得解除免疫抑制、增强肿瘤免疫原性、活化抗原呈递细胞（APCs）等三元协同的酶敏感性免疫检查点阻断抗体纳米载药系统（PIAN）。PIAN在体内循环中稳定，在过表达MMP-2的肿瘤内释放药物，阻断PD-1/PD-L1通路，利用光动力效应诱导肿瘤相关抗原释放，激活STING，活化APCs。该载药系统从增强肿瘤免疫原性和调节肿瘤微环境的免疫抑制因素同时入手，克服肿瘤对ICB疗法的耐受，减少irAE发生率，研究思路新颖，有望在改善肿瘤ICB免疫治疗效果上取得重大突破。

Immune-checkpoint blockade (ICB) therapy is a revolutionary development in the field of cancer therapy, but it still faces problems such as low clinical positive response rates and the presence of immune-related adverse effects (irAEs). This project aims to synthesize a matrix metalloproteinase-2 (MMP-2)-sensitive polymer (PEG-M-OE) for encapsulating both programmed cell death protein 1 ligand antibody (αPD-L1), a photosensitizer indocyanine green (ICG) and an agonist of stimulator of interferon genes, ADU-S100, to prepare a ternary synergistic enzyme-sensitive immune-checkpoint blockade antibody nano-delivery system (PIDN), which can relieve immunosuppression, increase tumor immunogenicity, and activate antigen-presenting cells (APCs). PIDN is stable in the blood circulation, and release drugs in tumors overexpressing MMP-2. It can block PD-1/PD-L1 pathway, induce tumor-associated antigen release by the photodynamic effect, and activate APCs by activating STING. PIDN overcomes tumor resistance to ICB therapy by increasing tumor immunogenicity and regulating immunosuppressive factors in the tumor microenvironment simultaneously, and reduces the incidence of irAE. The research idea of this project is new and it is expected to make an important breakthrough on improving the effect of tumor ICB immunotherapy.