He Jinming, Ren Xijiao, Zhang Qiqi, Wang Shuang, Li Zhongjun, Cai Kaiyong, Li Menghuan, Hu Yan, Ran Qian, Luo Zhong
School of Life Science, Chongqing University, Chongqing, 400044, China.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
Biomaterials. 2025 Apr;315:122924. doi: 10.1016/j.biomaterials.2024.122924. Epub 2024 Oct 29.
The insufficient activation and impaired effector functions of T cells in the immunosuppressive tumor microenvironment (TME) substantially reduces the immunostimulatory effects of radiotherapy. Herein, a multifunctional nanoradiosensitizer is established by integrating molecularly engineered aptamer precursors into cisplatin-loaded liposomes for enhancing radio-immunotherapy of solid tumors. Exposure to ionizing radiation (IR) following the nanoradiosensitizer treatment would induce pronounced immunogenic death (ICD) of tumor cells through cisplatin-mediated radiosensitization while also trigger the detachment of the aptamer precursors, which further self-assemble into PD-L1/PD-1-bispecific aptamer-based T cell engagers (CA) through the bridging effect of tumor-derived ATP to direct T cell binding onto tumor cells in the post-IR TME in a spatial-temporally programmable manner. The CA-mediated post-IR tumor-T cell engagement could override the immunosuppressive barriers in TME and enhance T cell-mediated recognition and elimination of tumor cells while minimizing systemic toxicities. Overall, this work offers an innovative approach to enhance the radio-immunotherapeutic efficacy in the clinics.
免疫抑制性肿瘤微环境（TME）中T细胞的激活不足和效应功能受损，大大降低了放射治疗的免疫刺激效果。在此，通过将分子工程化适配体前体整合到载顺铂脂质体中，构建了一种多功能纳米放射增敏剂，用于增强实体瘤的放射免疫治疗。纳米放射增敏剂处理后暴露于电离辐射（IR）会通过顺铂介导的放射增敏作用诱导肿瘤细胞发生明显的免疫原性死亡（ICD），同时还会触发适配体前体的解离，后者通过肿瘤衍生ATP的桥接作用进一步自组装成基于PD-L1/PD-1双特异性适配体的T细胞衔接器（CA），以时空可编程的方式将T细胞定向结合到IR后TME中的肿瘤细胞上。CA介导的IR后肿瘤-T细胞结合可克服TME中的免疫抑制障碍，增强T细胞介导的对肿瘤细胞的识别和清除，同时将全身毒性降至最低。总体而言，这项工作为提高临床放射免疫治疗疗效提供了一种创新方法。
