Metal-Organic Frameworks as Candidates for Tumor Sonodynamic Therapy: Designable Structures for Targeted Multifunctional Transformation

Sonodynamic therapy (SDT), utilizing ultrasound (US) as the trigger, has gained popularity recently as a therapeutic approach with significant potential for treating various diseases. Metal-organic frameworks (MOFs), characterized by structural flexibility, are prominently emerging in the SDT realm as an innovative type of sonosensitizer, offering functional tunability and biocompatibility. However, due to the inherent limitations of MOFs, such as low reactivity to reactive oxygen species and challenges posed by the complex tumor microenvironment, MOF-based sonosensitizers with singular functions are unable to demonstrate the desired therapeutic efficacy and may pose risks of toxicity, limiting their biological applications to superficial tissues. MOFs generally possess distinctive crystalline structures and properties, and their controlled coordination environments provide a flexible platform for exploring structure-effect relationships and guiding the design and development of MOF-based nanomaterials to unlock their broader potential in biological fields. The primary focus of this paper is to summarize cases involving the modification of different MOF materials and the innovative strategies developed for various complex conditions. The paper outlines the diverse application areas of functionalized MOF-based sonosensitizers in tumor synergistic therapies, highlighting the extensive prospects of SDT. Additionally, challenges confronting SDT are briefly summarized to stimulate increased scientific interest in the practical application of MOFs and the successful clinical translation of SDT. Through these discussions, we strive to foster advancements that lead to early-stage clinical benefits for patients.Contents Statement of Significance 1. An overview for the progresses in SDT explored from a novel and fundamental perspective. 2. Different modification strategies to improve the MOFs-mediated SDT efficacy are provided. 3. Guidelines for the design of multifunctional MOFs-based sonosensitizers are offered. 4. Powerful tumor ablation potential is reflected in SDT-led synergistic therapies. 5. Future challenges in the field of MOFs-based SDT in clinical translation are suggested.