免疫抑制性微环境严重限制了肿瘤免疫治疗的临床应用，可调控肿瘤微环境的纳米技术将为肿瘤免疫治疗提供新策略。我们前期工作证实免疫激活纳米制剂可通过增加钙网蛋白（CRT）表达来提高免疫疗效，但肿瘤细胞可通过上调CD47表达来拮抗CRT的促吞噬作用以逃避免疫监视，我们推测提高CRT表达的同时下调CD47表达或可引起更强的免疫应答。本项目拟构建表面偶联CD47蛋白的抗吞噬纳米递释系统共输送阿霉素和shCD47，在原位乳腺癌模型中评价肿瘤靶向性、免疫治疗效果及免疫激活机理。表面包被的CD47蛋白可保证纳米递释系统避免吞噬清除而高效靶向肿瘤，克服目前纳米递释系统易被免疫清除和肿瘤靶向能力弱的问题；阿霉素可增加肿瘤细胞表面CRT的暴露，shCD47则下调CD47表达，二者协同增强肿瘤免疫原性，最终激活肿瘤特异性免疫应答。本项目有望在抗吞噬纳米递释系统的研究方面做出贡献，并为乳腺癌的免疫治疗提供一种新探索。

The immunosuppressive microenvironment severely limits the clinical application of tumor immunotherapy, and nanotechnology that can improve tumor microenvironment will provide a new strategy for tumor immunotherapy. Our previous work has confirmed the exposure of calreticulin caused by immunostimulatory nanoparticles potentiates immunotherapy, but tumors can antagonize the pro-phagocytic effect of CRT and evade immune surveillance by upregulating the expression of CD47. We hypothesize that downregulation of CD47 expression in addition to calreticulin exposure might induce a stronger immune response. We will construct an CD47 protein-mediated anti-phagocytic nanoparticular delivery system to co-deliver shCD47 and doxorubicin, investigate tumor targeting, evaluate immunotherapeutic effects and explore the mechanism of immune activation in in-situ breast cancer models. The surface-coated CD47 protein can ensure that the nanoparticular delivery system avoid phagocytic clearance to highly accumulate in tumor tissue, thus overcoming the current problems that nanoparticular delivery system is easy to be cleared by immunity and hard to target tumors; doxorubicin can increase the exposure of calreticulin, while shCD47 can down-regulated the expression of CD47 on the surface of tumor cells, which synergistically enhances tumor immunogenicity and ultimately activates tumor-specific immune response. This project is expected to make contribution to the construction of the anti-phagocytotic nanoparticular delivery system and provide an innovative exploration for the immunotherapy of breast cancer.