Tang Qingshuang, Sun Suhui, Wang Ping, Sun Lihong, Wang Yuan, Zhang Lulu, Xu Menghong, Chen Jing, Wu Ruiqi, Zhang Jinxia, Gong Ming, Chen Qingfeng, Liang Xiaolong
Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, 138673, Singapore.
Adv Mater. 2023 May;35(18):e2300964. doi: 10.1002/adma.202300964. Epub 2023 Mar 23.
Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non-specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)-activated PD-L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD-L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD-L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2-activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD-L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor.
基于免疫检查点阻断（ICB）的肿瘤免疫疗法仍然存在宿主反应率低和免疫检查点抑制剂非特异性分布的问题，这大大降低了治疗效果。在此，通过工程方法构建稳定表达基质金属肽酶2（MMP2）激活的程序性死亡受体配体1（PD-L1）阻断剂的细胞膜，包覆超小钛酸钡（BTO）纳米颗粒，以克服肿瘤的免疫抑制微环境。所得的M@BTO纳米颗粒能显著促进BTO在肿瘤部位的蓄积，而当暴露于肿瘤中高表达的MMP2时，膜上PD-L1抗体的屏蔽结构域会被切割。在超声（US）照射下，M@BTO纳米颗粒可基于BTO介导的压电催化和水分解同时产生活性氧（ROS）和氧，显著促进细胞毒性T淋巴细胞（CTL）在肿瘤内的浸润，并改善对肿瘤的PD-L1阻断治疗，从而在黑色素瘤小鼠模型中有效抑制肿瘤生长并抑制肺转移。这种纳米平台将MMP2激活的基因编辑细胞膜与US响应性BTO相结合，实现免疫刺激和特异性PD-L1抑制，为增强抗肿瘤免疫反应提供了一种安全有效的策略。
