Nanomaterials-Based Tumor Microenvironment Modulation for Magnifying Sonodynamic Therapy

Conspectus Sonodynamic therapy (SDT) is a noninvasive and more preferable therapeutic modality than photodynamic therapy (PDT) due to deeper tissue penetration, which utilizes sonosensitizers to produce reactive oxygen species (ROS) to kill tumor cells and arouse immune responses. However, it still suffers from low ROS production efficiency and insufficient systematic immune activation, which thus has attracted increasing attention and researchers to engage in this field. In an attempt to address the low production and elevate SDT, great efforts and advances have been made, where different directions were highlighted. From the perspectives of sonosensitizers, defect-enriched inorganic sonosensitizers and exogenous cavitation nuclei are prevalent, and in inorganic sonosensitizers, three types of nanomaterials are dominant, i.e., enhanced charge transfer, nonstoichiometric ratio, and piezoelectricity, imparting these sonosensitizers with high sonocatalytic activity for converting molecular oxygen into ROS. Based on the SDT principle, ultrasound cavitation directly supplies energy for sonocatalytic ROS production. During cavitation, local hyperthermia, excitation, microjets, and ROS ( e.g., hydroxyl radicals) coincide to destroy tumor cells and eliminate tumors, and thereby elevating the cavitation dose via exogenously delivering cavitation nuclei is expected to boost ROS production in SDT. Tumor microenvironment (TME) is a complex system that interferes with various antitumor activities. In this Account, we give a panoramic glimpse at what types of TME can be engineered to enhance SDT and offer potential solutions. It has been accepted that the TME closely correlates with ROS-based antitumor biological activities including hypoxia, inflammation, acidity, etc. Rational designs of SDT-based nanoplatforms armed with various TME modulations have been proposed to liberate TME imprisonment toward ROS birth, consumption, and ROS-induced immune activation and to magnify antitumor SDT. We have made many efforts to modulate different TMEs to magnify SDT after rationally designing the corresponding sonosensitizer-contained nanoplatforms. We also shed light on why TME could influence SDT-based antitumor efficiency, and we have highlighted various TME modulation inspired nanobiotechnologies and nanomaterials, e.g., metabolism, immunity, acidity, hypoxia, redox balance, and nitrogen/oxygen balance. Notably, divergent association stemming from other ROS-based antitumor methods was implemented to enlighten and broaden TME-engineered SDT nanomaterials; e.g., epigenetics and pyroptosis modulations for magnifying PDT are expected to serve as available references to develop new SDT nanomaterials and guide SDT, providing a distinctive insight into SDT-based antitumor efficiency. Also, two other design principles of SDT sensitizers ( i.e., defect-enriched inorganic sonosensitizers and artificial cavitation nuclei) were outlined, which are also expected to be integrated with TME modulation. Despite the achievement of progress in TME modulation enhanced SDT, the complex and interconnected TME needs comprehensive consideration. Therefore, more effort remains to be devoted to unresolved issues, potential solutions, and future direction on TME modulation enhanced SDT.