Malignant tumors are characterized by high risk and complexity [1,2]. Various strategies, including surgery, radiotherapy (RT), and chemotherapy (CT), with positive clinical impacts and widespread use, have been developed to address the elevated mortality associated with these tumors [3]. However, conventional therapies are inevitably associated with side effects, immune damage, and suboptimal efficacy for both primary and metastatic tumors [4,5]. Recently, therapeutic approaches, such as photodynamic therapy (PDT), have been proposed [6,7] as a minimally/non-invasive treatment modality [8]. Despite the effectiveness of certain small-molecule photosensitizers with favorable safety profiles in clinical settings, challenges like phototoxicity [9], light avoidance regulations [10], and restrictions on light penetration depth persist [11]. These inherent challenges impede the translation of PDT from basic research to clinical applications [12].

Sonodynamic therapy (SDT) utilizes ultrasound (US), known for its unique high acoustic propagation characteristics in deep tissues, as external energy that is applied to sonosensitizers aggregated in tumor tissues. This process induces the generation of reactive oxygen species (ROS) to trigger apoptosis and necrosis [[13], [14], [15]], with therapeutic mechanisms and effects akin to those of PDT [[17], [18], [19], [20]]. Simultaneously, tumor tissues can absorb US waves, converting them into thermal energy for tumor ablation [16]. While the successful use of SDT has been reported [21], the development of sonosensitizers with high efficiency and low cost remains the primary goal of this non-invasive treatment modality [14,20,22,23].

The chemical/biological instability and low bioavailability of conventional organic sonosensitizers (e.g., hematoporphyrin) [15,39], coupled with the low ROS-producing efficiency of some classical inorganic sonosensitizers (e.g., TiO2 nanoparticles) [40], hinder satisfactory tumor suppression by SDT [[41], [42], [43],55]. Recently, metal-organic frameworks (MOFs) have garnered attention as emerging materials with diverse topologies [24]. The high specific surface area and tunable pore structure provide MOFs with significant potential for multifunctional applications [34], making them promising candidates for various specific platforms [[25], [26], [27]]. Early studies applied MOFs to gas separation [28], chemical catalysis [29,30], tumor therapy, and drug delivery [[31], [32], [33]]. Structurally flexible nano-MOFs (nMOFs) [34] have emerged as functionally tunable and biocompatible sonosensitizers in the field of SDT due to their accumulation at the tumor site through permeability and the enhanced retention effect (EPR) [37,38,35,36]. Nano-modification engineering strategies have further enhanced the sonosensitization effects of MOF nanoparticles (NPs). Studies have devised targeted solutions for different factors in the complex tumor microenvironment (TME) to mitigate the inhibitory effects of undesirable intracellular conditions on SDT or to synergize with other therapeutic modalities for comprehensive tumor growth inhibition and prevention.

Hence, there is a need for a thorough and in-depth description of the latest developments in MOF-based SDT in cancer treatment. This manuscript takes a holistic approach to MOF structure-activity relationships, providing a comprehensive and critical review. We aimed to 1. Introduce the treatment mechanisms of SDT and several fundamental MOF-based sonosensitizers. 2. Systematically analyze enhancement strategies using different materials and methods, highlighting the most important and cutting-edge themes in the field. 3. Provide an overview of SDT-dominated synergistic therapies involving MOFs, emphasizing the potential synergistic mechanisms involved in each combination formulation. 4. Extensively reflect on the application potential of MOFs in clinical cancer treatment, including the existing challenges and emerging opportunities. The review emphasizes the plasticity and modification options of MOF-based sonosensitizers in promoting fundamental research within SDT, which offers opportunities for technological breakthroughs in other types of sonosensitizers. The goal is to contribute to the positive prospects of SDT in all kinds of disease therapeutic applications in the future and provide early relief for clinical patients with tumors and cancer.

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