Cheng Wei, Yang Jiaojiao, Pan Yuqing, Qu Haijing, Duan Zhiran, Wu Jie, Chen Han, Wang Chao, Xue Xiangdong
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
ACS Nano. 2025 Aug 5;19(30):27804-27824. doi: 10.1021/acsnano.5c08928. Epub 2025 Jul 23.
Glioblastoma (GBM) presents significant therapeutic challenges due to the blood-brain barrier (BBB), suppressive tumor immune microenvironment (TIME), and systemic immunosuppression with limited T cell reserves. We developed a sequential-targeting sonodynamic nanovaccine (Stars NV) that avoids circulating macrophage uptake, efficiently crosses the BBB, and sequentially targets tumor-associated macrophages (TAMs). Under ultrasound stimulation, Stars NV noninvasively ablates GBM and induces adaptive anti-GBM immunity, functioning as a personalized in situ vaccine. Simultaneously, it releases R848 to reprogram the suppressive TIME. Additionally, Stars NV activates systemic immunity, promoting T cell generation in the thymus, maturation in lymph nodes, circulation in the bloodstream, and recruitment into the reprogrammed TIME. In an intracranial GBM mouse model, Stars NV extended median survival from 23 to over 60 days, elevated the M1/M2 TAM ratio by 31-fold and tumor-infiltrating lymphocytes by 5.2-fold, and lowered the Tregs by 5.5-fold. It also boosted systemic immunity, increasing peripheral CD4 and CD8 T cells by 2.4-fold and 5.4-fold, respectively. The Stars NV initiates a self-reinforcing cycle of local and systemic immunity, offering a promising strategy for GBM that holds substantial potential to enhance therapeutic outcomes.
胶质母细胞瘤（GBM）由于血脑屏障（BBB）、抑制性肿瘤免疫微环境（TIME）以及T细胞储备有限导致的全身免疫抑制，带来了重大的治疗挑战。我们开发了一种序贯靶向声动力纳米疫苗（Stars NV），它能避免循环巨噬细胞摄取，有效穿过血脑屏障，并序贯靶向肿瘤相关巨噬细胞（TAM）。在超声刺激下，Stars NV能无创消融GBM并诱导适应性抗GBM免疫，起到个性化原位疫苗的作用。同时，它释放R848来重编程抑制性TIME。此外，Stars NV激活全身免疫，促进胸腺中T细胞的生成、淋巴结中T细胞的成熟、血液中的循环以及向重编程的TIME中的募集。在颅内GBM小鼠模型中，Stars NV将中位生存期从23天延长至60多天，使M1/M2 TAM比例提高了31倍，肿瘤浸润淋巴细胞增加了5.2倍，调节性T细胞减少了5.5倍。它还增强了全身免疫，使外周CD4和CD8 T细胞分别增加了2.4倍和5.4倍。Stars NV启动了局部和全身免疫的自我强化循环，为GBM提供了一种有前景的策略，具有显著提高治疗效果的潜力。
