Zhang Haoqi, Li Yuanke, Kang Helong, Lan Jingping, Hou Lin, Chen Zhengbang, Li Fan, Liu Yanqin, Zhao Jiliang, Li Na, Wan Yajuan, Zhu Yiping, Zhao Zhen, Zhang Hongkai, Zhuang Jie, Huang Xinglu
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, and Frontiers Science Center for Cell Responses, Nankai University, Tianjin, 300071, China.
School of Medicine, Nankai University, Tianjin, 300071, China.
J Nanobiotechnology. 2024 Mar 11;22(1):104. doi: 10.1186/s12951-024-02369-9.
Modulating macrophages presents a promising avenue in tumor immunotherapy. However, tumor cells have evolved mechanisms to evade macrophage activation and phagocytosis. Herein, we introduced a bispecific antibody-based nanoengager to facilitate the recognition and phagocytosis of tumor cells by macrophages. Specifically, we genetically engineered two single chain variable fragments (scFv) onto cell membrane: anti-CD40 scFv for engaging with macrophages and anti-Claudin18.2 (CLDN18.2) scFv for interacting with tumor cells. These nanoengagers were further constructed by coating scFv-anchored membrane into PLGA nanoparticle core. Our developed nanoengagers significantly boosted immune responses, including increased recognition and phagocytosis of tumor cells by macrophages, enhanced activation and antigen presentation, and elevated cytotoxic T lymphocyte activity. These combined benefits resulted in enhancing antitumor efficacy against highly aggressive "cold" pancreatic cancer. Overall, this study offers a versatile nanoengager design for immunotherapy, achieved through genetically engineering to incorporate antibody-anchored membrane.
调节巨噬细胞是肿瘤免疫治疗中一条有前景的途径。然而，肿瘤细胞已经进化出逃避巨噬细胞激活和吞噬的机制。在此，我们引入了一种基于双特异性抗体的纳米接合器，以促进巨噬细胞对肿瘤细胞的识别和吞噬。具体而言，我们在细胞膜上进行基因工程改造，构建了两个单链可变片段（scFv）：用于与巨噬细胞结合的抗CD40 scFv和用于与肿瘤细胞相互作用的抗Claudin18.2（CLDN18.2）scFv。通过将锚定scFv的膜包裹到聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒核心中，进一步构建了这些纳米接合器。我们开发的纳米接合器显著增强了免疫反应，包括巨噬细胞对肿瘤细胞的识别和吞噬增加、激活和抗原呈递增强以及细胞毒性T淋巴细胞活性升高。这些综合益处提高了对高度侵袭性“冷”胰腺癌的抗肿瘤疗效。总体而言，本研究通过基因工程将锚定抗体的膜整合在一起，提供了一种用于免疫治疗的通用纳米接合器设计。
