Ultrasound (US) is a technology that utilizes sound waves above 20 kHz and has extensive applications in medical imaging and therapy. Sonodynamic Therapy (SDT) uses low-intensity US to locally activate sono-responsive molecules or nanomaterials (the sonosensitizer), inducing the production of reactive oxygen species (ROS) in the biological microenvironment, and triggering a biological response. As opposed to light, which is used in photodynamic therapy, US exhibits deep tissue penetration and thus, enables the stimulation of sonosensitizers that undergo accumulation in internal tissues and organs, and making of SDT a minimally invasive intervention. The types and the spatiotemporal release of ROS can be tuned by the rational selection of the sonosensitizer and its dose as well as US parameters such as frequency, intensity, and irradiation time and it can be capitalized on to affect different cellular pathways, including triggering cancer cell apoptosis. The most traditional sonosensitizers are organic small molecules such as porphyrin precursors (e.g., 5-aminolevulinic acid) and porphyrins, though they often display chemical instability, sonobleaching and high cell toxicity. In addition, the ability to control their biodistribution and accumulation in the target body site is low. To overcome this, they are often encapsulated within lipidic or polymeric nanoparticles of controlled size and surface properties. However, their sonodynamic efficiency is jeopardized. To overcome these drawbacks, ceramic, metallic and hybrid ceramic/metallic and ceramic/polymeric nano-sonosensitizers with better physicochemical stability, no sonobleaching and tunable nanostructure, size, surface functionality, and energy bandgap are under extensive investigation. Even though ROS are involved in a broad spectrum of cellular processes in health and disease, SDT has been mainly investigated as a local anticancer treatment with more limited off-target systemic side-effects than chemotherapy. In this scenario, while both the sonosensitizer and the US are harmless, their combination leads to cancer cell death. At the same time, SDT shows promise also in treating soft and especially hard tissue infections where antibiotics are less effective due to their limited penetration, reprogramming of macrophages and promoting wound healing, reducing inflammation, and neuronal stimulation. This review initially describes the use of inorganic sonosensitizers in SDT, while emphasizing their fundamental structural features to effectively produce ROS upon therapeutic US activation. Then, their application in the treatment of disease with focus on less investigated fields such as infections and wound and bone healing, inflammation, and neuronal diseases are overviewed.

中文翻译：

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无机声敏剂纳米材料，用于癌症以外疾病的声动力治疗


超声 （US） 是一种利用 20 kHz 以上声波的技术，在医学成像和治疗中具有广泛的应用。声动力学疗法 （SDT） 使用低强度 US 局部激活声波响应分子或纳米材料（声波增敏剂），诱导生物微环境中活性氧 （ROS） 的产生，并触发生物反应。与光动力疗法中使用的光相反，US 表现出深层组织渗透性，因此能够刺激在内部组织和器官中积累的声敏剂，并使 SDT 成为一种微创干预。ROS 的类型和时空释放可以通过合理选择超声增敏剂及其剂量以及频率、强度和照射时间等 US 参数来调节，并且可以利用它来影响不同的细胞通路，包括触发癌细胞凋亡。最传统的声敏剂是有机小分子，如卟啉前体（例如 5-氨基乙酰丙酸）和卟啉，尽管它们通常表现出化学不稳定性、声波漂白和高细胞毒性。此外，控制它们在目标身体部位的生物分布和积累的能力很低。为了克服这个问题，它们通常被封装在尺寸和表面特性受控的脂质或聚合物纳米颗粒中。然而，它们的声动力学效率受到威胁。为了克服这些缺点，具有更好物理化学稳定性、无声漂白和可调纳米结构、尺寸、表面功能和能带隙的陶瓷、金属和混合陶瓷/金属和陶瓷/聚合物纳米声敏剂正在被广泛研究。 尽管 ROS 参与健康和疾病中的广泛细胞过程，但 SDT 主要作为一种局部抗癌治疗进行研究，与化疗相比，脱靶全身副作用更有限。在这种情况下，虽然超声增敏剂和 US 都是无害的，但它们的组合会导致癌细胞死亡。同时，SDT 在治疗软组织感染，尤其是硬组织感染方面也显示出前景，在这些感染中，抗生素由于渗透性有限、巨噬细胞的重编程和促进伤口愈合、减少炎症和神经元刺激而效果较差。本综述最初描述了无机声敏剂在 SDT 中的应用，同时强调了它们在治疗性 US 激活后有效产生 ROS 的基本结构特征。然后，概述了它们在疾病治疗中的应用，重点是较少研究的领域，例如感染和伤口和骨骼愈合、炎症和神经元疾病。