The hypoxic microenvironment induced by sonodynamic therapy (SDT) via sonochemical oxygen consumption usually triggered tumor resistance to SDT, impeding therapeutic efficacy. In this sense, it was highly desired to tackle the hypoxia-related negative issues. Here we provide the therapeutic agents delivery system, TPZ/HMTNPs-SNO, which was constructed by loading tirapazamine (TPZ) into hollow mesoporous titanium dioxide nanoparticles (HMTNPs) with modification of S-nitrosothiol (R-SNO). Upon encountering ultrasound waves, the HMTNPs as sonosensitizers would generate reactive oxygen species (ROS) for SDT. In a sequential manner, the followed SDT-induced hypoxia further activated the “hypoxic cytotoxin”, TPZ, for hypoxia-specific killing effect. Meanwhile, the generated ROS could sensitize -SNO groups for on-demand nitric oxide (NO) release in an “anticancer therapeutic window”, resulting in the NO sensitized SDT effect. This study confirmed that the TPZ/HMTNPs-SNO with multi-mechanisms exploited the merits of synergistic combination of the three therapeutic modes, consequently potentiating the anticancer efficacy of SDT. Moreover, the echogenic property of NO made the nanoplatform as an ultrasound contrast agent to enhance ultrasound imaging. In this sense, we developed a sequential strategy for ultrasound mediated all-in-one nanotheranostic platform of TPZ/HMTNPs-SNO, which highlighted new possibilities of advancing cancer theranostics in biomedical fields.

声动力学疗法（SDT）通过以下途径诱导的低氧微环境声化学耗氧量通常会触发肿瘤对SDT的耐药性，从而阻碍治疗效果。从这个意义上讲，迫切需要解决与缺氧相关的负面问题。在这里，我们提供了治疗剂递送系统TPZ / HMTNPs-SNO，该系统是通过将替拉帕明（TPZ）加载到中空介孔二氧化钛纳米颗粒（HMTNPs）中，并修饰S-亚硝基硫醇（R-SNO）而构建的。遇到超声波时，作为声敏剂的HMTNP将为SDT生成活性氧（ROS）。以顺序的方式，随后的SDT诱导的缺氧进一步激活了“缺氧性细胞毒素” TPZ，以达到缺氧特异性的杀伤作用。同时，产生的ROS可以使-SNO基团在“抗癌治疗窗口”中敏化按需释放的一氧化氮（NO），导致NO致敏SDT效应。这项研究证实了具有多种机制的TPZ / HMTNPs-SNO充分发挥了三种治疗方式协同结合的优势，从而增强了SDT的抗癌功效。此外，NO的回声特性使纳米平台成为增强超声成像的超声造影剂。从这个意义上讲，我们开发了一种针对TPZ / HMTNPs-SNO的超声介导的纳米纳米治疗平台的顺序策略，突显了在生物医学领域推进癌症治疗学的新可能性。NO的回声特性使纳米平台成为超声造影剂以增强超声成像。从这个意义上讲，我们开发了一种针对TPZ / HMTNPs-SNO的超声介导的纳米纳米治疗平台的顺序策略，突显了在生物医学领域推进癌症治疗学的新可能性。NO的回声特性使纳米平台成为超声造影剂以增强超声成像。从这个意义上讲，我们开发了一种针对TPZ / HMTNPs-SNO的超声介导的纳米纳米治疗平台的顺序策略，突显了在生物医学领域推进癌症治疗学的新可能性。