Wang Meng-Fei, Guo Jie, Yuan Shen-Jun, Li Ke, Zhang Quan, Lei Hui-Mei, Wu Jia-Lin, Zhao Li, Xu Yong-Hong, Chen Xiao
Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China.
Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China.
Biomaterials. 2025 Apr;315:122913. doi: 10.1016/j.biomaterials.2024.122913. Epub 2024 Oct 28.
In this study, we demonstrated the mechanism of a glioblastoma (GBM)-targeted sonodynamic therapy (SDT) strategy employing platelets loaded with a sonosensitizer based on functionalized boron nitride nanoparticles carrying chlorin e6 (BNPD-Ce6). In the in vitro study, we first found that the BNPD-Ce6-mediated sonodynamic action (SDA) induced remarkable viability loss, DNA damage, and cell death in the GBM cells (GBCs) but not macrophages. Surprisingly, the SDA-exposed GBCs displayed a ferroptotic phenotype while the SDA-exposed macrophages underwent immuno-stimulatory autophagy and potently potentiated the SDA's toxicity to the GBCs. The ferroptotic GBCs induced by the SDA were found to be quasi-immunogenic, characterized by the emission of some alarmins such as ATP, HSP90, and CRT, but absent HMGB1, a potent endogenous adjuvant. As such, the SDA-stressed GBCs were unable to stimulate the BMDMs. This defect, interestingly, could be rescued by platelets as a donor of HMGB1 which markedly enhanced the BNPD-Ce6's sonotoxicity to the GBCs. In the in vivo study, we first employed BNPD-Ce6-loaded platelets to achieve ultrasound-triggered, targeted delivery of BNPD-Ce6 in grafted intra-cranial GBMs and subsequent sonodynamic tumor damage. An SDT regimen designed based on these results slowed the growth of grafted intra-cranial GBMs and significantly increased the survival of the host animals. Pathological examination of the SDT-treated GBMs revealed tissue necrosis and destruction and validated the in vitro observations. Finally, the depletion of macrophages was found to abrogate the efficacy of the SDT in subcutaneous GBC grafts. In conclusion, the BNPD-Ce6@Plt-mediated SDT is a practicable and efficacious anti-GBM therapy. Its therapeutic mechanism critically involves a synergy of tumor cell ferroptosis, macrophage stimulation, and platelet activation induced by the SDA.
在本研究中，我们展示了一种针对胶质母细胞瘤（GBM）的声动力疗法（SDT）策略的机制，该策略采用负载有基于携带二氢卟吩e6的功能化氮化硼纳米颗粒（BNPD-Ce6）的声敏剂的血小板。在体外研究中，我们首先发现BNPD-Ce6介导的声动力作用（SDA）在GBM细胞（GBCs）中诱导了显著的活力丧失、DNA损伤和细胞死亡，但在巨噬细胞中未出现。令人惊讶的是，暴露于SDA的GBCs表现出铁死亡表型，而暴露于SDA的巨噬细胞经历免疫刺激自噬，并有力地增强了SDA对GBCs的毒性。发现由SDA诱导的铁死亡GBCs具有准免疫原性，其特征是释放一些警报素，如ATP、HSP90和CRT，但不存在HMGB1，一种有效的内源性佐剂。因此，SDA应激的GBCs无法刺激骨髓来源的巨噬细胞（BMDMs）。有趣的是，作为HMGB1供体的血小板可以挽救这一缺陷，这显著增强了BNPD-Ce6对GBCs的声毒性。在体内研究中，我们首先使用负载BNPD-Ce6的血小板在移植的颅内GBM中实现超声触发的BNPD-Ce6靶向递送以及随后的声动力肿瘤损伤。基于这些结果设计的SDT方案减缓了移植的颅内GBM的生长，并显著提高了宿主动物的存活率。对接受SDT治疗的GBM进行的病理检查显示组织坏死和破坏，并验证了体外观察结果。最后，发现巨噬细胞的耗竭消除了SDT在皮下GBC移植中的疗效。总之，BNPD-Ce6@Plt介导的SDT是一种可行且有效的抗GBM治疗方法。其治疗机制关键涉及由SDA诱导的肿瘤细胞铁死亡、巨噬细胞刺激和血小板激活的协同作用。
