Xu Xuan-Shou, Ren Wei-Wei, Zhang Heng, Huo Dong-Liang, Lyu Qi, Zhan Mei-Xiao, Xu Hui-Xiong, Wang Li-Ying, Huo Min-Feng, Shi Jian-Lin
Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, the Institute for Biomedical Engineering and Nano Science School of Medicine, Tongji University School of Medicine, Shanghai, 200072, China.
Department of Ultrasound, Zhuhai People's Hospital (the Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai, 519000, Guangdong, China.
Mil Med Res. 2025 Jul 30;12(1):40. doi: 10.1186/s40779-025-00629-9.
PANoptosis has been identified as a robust inflammatory cell death pathway triggered upon host defense against invaded pathogens such as bacteria and viruses, however, pathogen-free tumor PANoptosis has not been achieved yet. Reactive oxygen and nitrogen species capable of inducing robust and diverse cell death pathways such as pyroptosis, apoptosis, and necroptosis are supposed to be the potential triggers for tumor PANoptosis by ultrasound (US)-controlled sono-piezodynamic therapy.
S-nitrosothiols (SNO)-zinc peroxide (ZnO)@cyclic dinucleotide (CDN)@mesoporous tetragonal barium titanate (mtBTO) nanoparticles (NZCB NPs) were synthesized by hydrothermal method with subsequent annealing, in situ growth, and finally surface functionalization. Scanning electron microscopy, transmission electron microscopy, X-ray diffraction, atomic force microscopy, Fourier transform infrared spectroscopy, and electron spin resonance were used for materials characterizations. Murine melanoma B16 cells are employed to investigate the in vitro US-initiated tumor PANoptosis by NZCB NPs. In vivo US-initiated tumor PANoptosis was investigated on B16 tumor-bearing C57BL/6J mice.
A "boiling-bubbling" strategy is developed to endow the piezoelectric BTO nanocatalysts, with mesoporous architecture, which enables the encapsulation of the immune-agonist CDN (9.4 wt%) to initiate innate immunity of the host. Then, SNO-functionalized ZnO was further employed to cap the mesoporous nanocatalysts, forming multifunctional piezocatalytic NZCB NPs. Under US irradiation, intracellular massive reactive oxygen and nitrogen species such as superoxide anion radicals, nitric oxide (NO), and peroxynitrite (ONOO) could be produced from the piezoelectric NZCB NPs, which, synergized with CDN-triggered antitumoral immunity, lead to highly immunogenic tumor PANoptosis by NZCB NPs through the tumor microenvironment remodeling. Intratumoral injection of NZCB NPs leads to substantial tumor PANoptosis with immune potentiation, ultimately destroying the tumor xenografts effectively.
The present work presents the mesostructure design of piezocatalytic nanomaterials and the crosstalk between oxidative stress and antitumor immunity within the tumor, facilitating promising tumor PANoptosis by nanocatalytic oxidation with high effectiveness and biocompatibility.
PAN细胞焦亡已被确定为一种强大的炎症性细胞死亡途径，在宿主抵御细菌和病毒等入侵病原体时被触发，然而，无病原体的肿瘤PAN细胞焦亡尚未实现。能够诱导强烈且多样的细胞死亡途径（如细胞焦亡、凋亡和坏死性凋亡）的活性氧和氮物种被认为是超声（US）控制的声压电动力学疗法引发肿瘤PAN细胞焦亡的潜在触发因素。
通过水热法合成亚硝基硫醇（SNO）-过氧化锌（ZnO）@环二核苷酸（CDN）@介孔四方钛酸钡（mtBTO）纳米颗粒（NZCB NPs），随后进行退火、原位生长，最后进行表面功能化。使用扫描电子显微镜、透射电子显微镜、X射线衍射、原子力显微镜、傅里叶变换红外光谱和电子自旋共振对材料进行表征。采用小鼠黑色素瘤B16细胞研究NZCB NPs在体外超声引发的肿瘤PAN细胞焦亡。在荷B16肿瘤的C57BL/6J小鼠上研究体内超声引发的肿瘤PAN细胞焦亡。
开发了一种“沸腾鼓泡”策略，赋予具有介孔结构的压电BTO纳米催化剂，使其能够封装免疫激动剂CDN（9.4 wt%）以启动宿主的先天免疫。然后，进一步使用SNO功能化的ZnO覆盖介孔纳米催化剂，形成多功能压电催化NZCB NPs。在超声照射下，压电NZCB NPs可产生细胞内大量的活性氧和氮物种，如超氧阴离子自由基、一氧化氮（NO）和过氧亚硝酸盐（ONOO），它们与CDN触发的抗肿瘤免疫协同作用，通过肿瘤微环境重塑导致NZCB NPs引发高度免疫原性的肿瘤PAN细胞焦亡。瘤内注射NZCB NPs可导致大量肿瘤PAN细胞焦亡并增强免疫，最终有效破坏肿瘤异种移植。
本研究提出了压电催化纳米材料的介观结构设计以及肿瘤内氧化应激与抗肿瘤免疫之间的相互作用，通过具有高效性和生物相容性的纳米催化氧化促进了有前景的肿瘤PAN细胞焦亡。
