Inorganic sonosensitizer nanomaterials for sonodynamic therapy of diseases beyond cancer

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.