A Functional "Key" Amplified Piezoelectric Effect Modulates ROS Storm with an Open Source for Multimodal Synergistic Cancer Therapy.

Chemodynamic therapy (CDT) is a non-invasive strategy for generating reactive oxygen species (ROS) and is promising for cancer treatment. However, increasing ROS in tumor therapy remains challenging. Therefore, exogenous excitation and inhibition of electron-hole pair recombination are attractive for modulating ROS storms in tumors. Herein, a Ce-doped BiFeO3 (CBFO) piezoelectric sonosensitizer to modulate ROS generation and realize a synergistic mechanism of CDT/sonodynamic therapy and piezodynamic therapy (PzDT) is proposed. The mixed Fe2+ and Ce3+ can implement a circular Fenton/Fenton-like reaction in the tumor microenvironment. Abundant ·OH can be generated by ultrasound (US) stimulation to enhance CDT efficacy. As a typical piezoelectric sonosensitizer, CBFO can produce O2 - owing to the enhanced polarization by the US, resulting in the motion of charge carriers. In addition, CBFO can produce a piezoresponse irradiated upon US, which accelerates the migration rate of electrons/holes in opposite directions and results in energy band bending, further achieving toxic ROS production and realizing PzDT. Density functional theory calculations confirmed that Ce doping shortens the diffusion of electrons and improves the conductivity and catalytic activity of CBFO. This distinct US-enhanced strategy emphasizes the effects of doping engineering and piezoelectric-optimized therapy and shows great potential for the treatment of malignant tumors.

Engineering Sonosensitizer-Derived Nanotheranostics for Augmented Sonodynamic Therapy.

Sonodynamic therapy (SDT), featuring noninvasive, deeper penetration, low cost, and repeatability, is a promising therapy approach for deep-seated tumors. However, the general or only utilization of SDT shows low efficiency and unsatisfactory treatment outcomes due to the complicated tumor microenvironment (TME) and SDT process. To circumvent the issues, three feasible approaches for enhancing SDT-based therapeutic effects, including sonosensitizer optimization, strategies for conquering hypoxia TME, and combinational therapy are summarized, with a particular focus on the combination therapy of SDT with other therapy modalities, including chemodynamic therapy, photodynamic therapy, photothermal therapy, chemotherapy, starvation therapy, gas therapy, and immunotherapy. In the end, the current challenges in SDT-based therapy on tumors are discussed and feasible approaches for enhanced therapeutic effects are provided. It is envisioned that this review will provide new insight into the strategic design of high-efficiency sonosensitizer-derived nanotheranostics, thereby augmenting SDT and accelerating the potential clinical transformation.

Sonodynamic Cancer Therapy by Mn(I)-tricarbonyl complexes via Ultrasound-triggered CO release and ROS generation.

A novel ferrocene conjugated Mn(I)-tricarbonyl complex viz [Mn(Fc-tpy)(CO)3Br] (Mn2) where, Fc-tpy = 4'-ferrocenyl-2,2':6',2''-terpyridine was synthesized and fully characterized along with its non-ferrocene analog [Mn(Ph-tpy)(CO)3 Br] Ph-tpy = 4'-phenyl-2,2':6',2''-terpyridine (Mn1) for ultrasound (US) activated anticancer applications. The X-ray structure of Mn2 confirmed its distorted octahedral geometry. Mn1 and Mn2, for the first time, showed US-triggered release of CO and ROS generation (1O2 and •OH) in an aqueous solution from any Mn(I)-tricarbonyl complexes, indicating its potential for synergetic CO gas therapy and sonodynamic therapy. The above-mentioned in-solution chemistry was successfully translated into in vitro cellular models. These complexes showed unprecedented US-triggered toxicity against T-cell lymphoma and human breast cancer cells (IC50 for Mn2 < 1 µM) while were minimally toxic without US or against normal spleen cells. Mn2 was ca. 12 fold more anticancer active than Mn1, indicating that the ferrocene conjugation augmented the US sensitivity. The apoptotic sonotoxicity of Mn2 was due to US-promoted mitochondrial depolarization via ROS generation and CO release. The apoptosis was triggered by caspase 3 activation. This is the first report of Mn(I)-tricarbonyl-based sonosensitizers for cancer SDT. Overall, this study, for the first time, establishes the effectiveness of 3d metal carbonyls in SDT.

Ultrasonic-responsive piezoelectric stimulation enhances sonodynamic therapy for HER2-positive breast cancer.

INTRODUCTION: Breast cancer ranks second as the most common malignancy globally, after lung cancer. Among the various subtypes of breast cancer, HER2 positive breast cancer (HER2 BC)poses a particularly challenging prognosis due to its heightened invasiveness and metastatic potential. The objective of this study was to construct a composite piezoelectric nanoparticle based on poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) for imaging and treatment of HER2 BC. METHOD: By reshaping the crystal structure of P(VDF-TrFE) piezoelectric nanoparticles, improving hydrophilicity, and incorporating imaging capabilities, we developed piezoelectric composite nanoparticles (PGd@tNBs) that integrate imaging and therapeutic functions. The in vitro characterization encompassed the assessment of piezoelectric properties, hydrophilicity, imaging performance, and therapeutic efficacy of these particles. The targeting and therapeutic effectiveness of PGd@tNBs particles were further validated in the SK-BR3 cell line and subsequently confirmed in HER2-positive tumor-bearing mice. RESULTS: The nanoparticle demonstrated excellent biocompatibility and impressive multimodal imaging performance. Magnetic resonance imaging (MRI) observations revealed significant accumulation of PGd@tNBs particles in the HER2 positive tumor, exhibiting superior contrast-enhanced ultrasound performance compared to traditional ultrasound contrast agents, and small animal in vivo imaging showed that PGd@tNBs particles were primarily excreted through respiration and urinary metabolism. Piezoforce Microscopy characterization highlighted the outstanding piezoelectric properties of PGd@tNBs particles. Upon targeted binding to HER2-BC, ultrasound stimulation influenced the cell membrane potential, leading to reversible electroporation. This, in turn, affected the balance of calcium ions inside and outside the cells and the mitochondrial membrane potential. Following ingestion by cells, PGd@tNBs, when exposed to ultrasound, triggered the generation of reactive oxygen species (ROS), resulting in the consumption of glutathione and superoxide dismutase and achieving sonodynamic therapy. Notably, repeated ultrasound stimulation, post PGd@tNBs particles binding and entry into cells, increased ROS production and elevated the apoptosis rate by approximately 45%. CONCLUSION: In conclusion, the PGd@tNBs particles developed exhibit outstanding imaging and therapeutic efficacy, holding potential for precise diagnosis and personalized treatment of HER2 BC.

Sonodynamic Therapy for HER2+ Breast Cancer with Iodinated Heptamethine Cyanine-Trastuzumab Conjugate.

The first example of sonodynamic therapy (SDT) with a cyanine dye-antibody conjugate is reported. The aim of this study was to evaluate the sonodynamic efficacy of a trastuzumab-guided diiodinated heptamethine cyanine-based sensitizer, 2ICy7-Ab, versus its non-iodinated counterpart, Cy7-Ab, in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model. In addition, the combined sonodynamic and photodynamic (PDT) effects were investigated. A single intravenous injection of 2ICy7-Ab followed by sonication or combined sonication and photoirradiation in mice resulted in complete tumor growth suppression compared with the nontreated control and showed no detectable toxicity to off-target tissues. In contrast, Cy7-Ab provided only a moderate therapeutic effect (~1.4-1.6-fold suppression). SDT with 2ICy7-Ab resulted in a 3.5-fold reduction in tumor volume within 45 days and exhibited 13-fold greater tumor suppression than PDT alone. In addition, 2ICy7-Ab showed more durable sonostability than photostability. The sonotoxicity of the iodinated versus noniodinated counterparts is attributed to the increased generation of hydroxyl radicals, superoxide, and singlet oxygen. We observed no significant contribution of PDT to the efficacy of the combined SDT and PDT, indicating that SDT with 2ICy7-Ab is superior to PDT alone. These new findings set the stage for the application of cyanine-antibody conjugates for fluorescently monitored targeted sonodynamic treatment of cancer.

GSH-activated Porphyrin Sonosensitizer Prodrug for Fluorescence Imaging-guided Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which uses ultrasound to trigger a sonosensitizer to generate reactive oxygen species (ROS), is a promising form of cancer therapy with outstanding tissue penetration depth. However, the sonosensitizer may inevitably spread to surrounding healthy tissue beyond the tumor, resulting in undesired side effects under an ultrasound stimulus. Herein, as glutathione (GSH) is overexpressed in the tumor microenvironment, a GSH-activatable sonosensitizer prodrug was designed by attaching a quencher to tetraphydroxy porphyrin for tumor therapy. The prodrug exhibited poor fluorescence and low ROS generation capacity under ultrasound irradiation but it can be activated by GSH to simultaneously switch on fluorescence emission and ROS generation in tumor site. Compared with the non-quenched sonosensitizer, the designed prodrug exhibited significantly higher tumor/healthy organ fluorescence ratios, due to the specific fluorescence and ROS activation by overexpressed GSH in the tumor. Finally, the prodrug exhibited efficient tumor growth inhibition under ultrasound irradiation, further demonstrating its promise as a GSH-activated sonosensitizer prodrug for highly effective cancer treatment.

Application of sonodynamic technology and sonosensitizers in food sterilization: a review of developments, trends and challenges.

Food safety and food waste have always been hot topics of discussion in recent years. However, the infection of human pathogenic bacteria and the waste of food resources caused by microbial-contaminated food remains common. Although traditional sterilization technology has been very mature, it causes changes in food flavor and excessive energy consumption to a certain extent. Moreover, the widespread bacterial resistance has also sounded a warning for researchers and finding a new alternative to antibiotics is urgently needed. The application of sonodynamic sterilization technology in medical treatment has aroused the interest of researchers. It provides ideas for new food sterilization technology. As a new non-thermal sterilization technology, sonodynamic sterilization technology has strong penetration, safety, less residue and by-products, and will less change the quality of the food itself. Therefore, sonodynamic sterilization technology has great potential applied in food sterilization technology. This review describes the concept of sonodynamic sterilization technology, the sterilization mechanism of sonodynamic sterilization and the inactivation mechanism of various pathogens, the classification and application of sonosensitizers, and the ultrasonic technology in sonodynamic sterilization in the application over the recent years. It provides a scientific reference for the application of sonodynamic sterilization technology in the field of food sterilization.

Ultrasound-dependent RNAi using TatU1A-rose bengal conjugate.

Tat-U1A-rose bengal conjugate (TatU1A-RB) was prepared as an ultrasound-sensitive RNA carrier molecule. This molecule consists of Tat cell-penetrating peptide, U1A RNA-binding protein, and rose bengal as a sonosensitizer. We demonstrated that TatU1A-RB delivered RNA via the endocytosis pathway, which was followed by ultrasound-dependent endosomal escape and cytosolic dispersion of the RNA. A short hairpin RNA (shRNA) delivered by TatU1A-RB mediated RNA interference (RNAi) ultrasound-dependently. Even by ultrasound irradiation through blood cells, RNAi could be induced with TatU1A-RB and the shRNA. This ultrasound-dependent cytosolic RNA delivery method will serve as the basis for a new approach to nucleic acid therapeutics.

Fluorescein-mediated sonodynamic therapy in a rat glioma model.

INTRODUCTION: Malignant gliomas have a dismal prognosis and significant efforts are being made to develop more effective treatments. Sonodynamic therapy (SDT) is an emerging modality for cancer treatment which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect. The aim of this study is to demonstrate the efficacy of SDT with fluorescein (FL) and low-intensity focused ultrasound in inhibiting the growth of ectopic gliomas implanted in the rat's subcutaneous tissue. METHODS: In vivo cytotoxicity of FL-SDT was evaluated in C6 rat glioma cells which were inoculated subcutaneously. Tumor specific extracellular FL extravasation and accumulation was assessed with IVIS imaging in rats receiving systemic FL. Effects of FL-SDT with focused low-intensity ultrasound on tumor growth, and histological features of the rat's tumors were investigated. Treatment related apoptosis and necrosis were analyzed using hematoxylin & eosin, and apoptosis-specific staining. RESULTS: IVIS imaging revealed a high degree of FL accumulation within the tumor, with a nearly threefold increase in tumoral epifluorescence signal over background. SDT significantly inhibited outgrowth of ectopic C6 gliomas across all three FUS exposure conditions. TUNEL and active caspase-3 staining did not reveal conclusive trends across control and SDT condition for apoptosis. CONCLUSION: Our results suggest that SDT with FL and low-intensity FUS is effective in inhibiting the growth of ectopic malignant gliomas in rats. The selective FL extravasation and accumulation in the tumor areas where the blood-brain barrier is damaged suggests the tumor-specificity of the treatment. The possibility to use this treatment in intracranial models and in human gliomas will have to be explored in further studies.

Novel Class of Ultrasound-Triggerable Drug Delivery Systems for the Improved Treatment of Tumors.

The controlled release of anticancer drugs at the tumor site is a central challenge in treating cancer. To achieve this goal, our strategy was based on tumor-specific targeting and ultrasound-triggered release of an anticancer agent from liposomal nanocarriers. To enhance the ultrasound-triggered drug release, we incorporated a lipophilic sonosensitizer, chlorin e6 (Ce6) ester, into the lipid bilayer of liposomes. Additionally, asparagine-glycine-arginine (NGR) that binds to CD13, which is overexpressed in tumor cells, was introduced into these liposomes. Under the navigation effects of the NGR, the novel ultrasound-triggerable NGR-modified liposomal nanocarrier (NGR/UT-L) accumulates in tumor sites. Once irradiated by ultrasound in tumor tissues, the sonodynamic effect produced by Ce6 could create more efficient disruptions of the lipid bilayer of the liposomal nanocarriers. After encapsulating doxorubicin (DOX) as the model drug, the ultrasound triggered lipid bilayer breakdown can spring the immediate release of DOX, making it possible for ultrasound-responsive chemotherapy with great selectivity. By combining tumor-specific targeting and stimuli-responsive controlled release into one system, NGR/UT-L demonstrated a perfect antitumor effect. Moreover, this report provides an example of controlled-release by means of a novel class of ultrasound triggering systems.

Ultrasound-dependent cytoplasmic internalization of a peptide-sonosensitizer conjugate.

A method to induce cytoplasmic peptide delivery, using ultrasound, was demonstrated using a molecular conjugate of a cell-penetrating peptide (CPP), a functional peptide, and a sonosensitizer. As a model of such molecular conjugates, TatBim-RB, consisting of the Tat CPP, the Bim apoptosis inducing peptide, and the sonosensitizer rose bengal was synthesized. CPPs have been widely used for intracellular delivery of various cargos; however, CPP-fused molecules tend to become entrapped in endosomes, as was observed for TatBim-RB molecules applied to cells. To promote escape of the entrapped TatBim-RB molecules, cells were irradiated with ultrasound, which successfully induced endosomal escape and cytoplasmic dispersion of TatBim-RB, and subsequently apoptosis. Our results suggest that this peptide-sonosensitizer conjugate strategy may facilitate numerous kinds of medicinal chemistry studies, and furthermore, this specific conjugate may exhibit potential as a novel therapeutic agent for the promotion of apoptosis.

Generation of ROS mediated by mechanical waves (ultrasound) and its possible applications.

The thermal decomposition of 9,10 diphenylanthracene peroxide (DPAO2) generates DPA and a mix of triplet and singlet molecular oxygen. For DPAO2 the efficiency to produce singlet molecular oxygen is 0.35. On the other hand, it has shown that many thermal reactions can be carried out through the interaction of molecules with ultrasound. Ultrasound irradiation can create hydrodynamic stress (sonomechanical process), inertial cavitation (pyrolitic process) and long range effects mediated by radicals or ROS. Sonochemical reactions can be originated by pyrolytic like process, shock mechanical waves, thermal reactions and radical and ROS mediated reactions. Sonolysis of pure water can yield hydrogen or hydroxyl radicals and hydrogen peroxide (ROS). When DPAO2 in 1,4 dioxane solution is treated with 20 or 24kHz and different power intensity the production of molecular singlet oxygen is observed. Specific scavengers like tetracyclone (TC) are used to demonstrate it. The efficiency now is 0.85 showing that the sonochemical process is much more efficient that the thermal one. Another endoperoxide, artemisinin was also studied. Unlike the concept of photosensitizer of photodynamic therapy, in spite of large amount of reported results in literature, the term sonosensitizer and the sonosensitization process are not well defined. We define sonosensitized reaction as one in which a chemical species decompose as consequence of cavitation phenomena producing ROS or other radicals and some other target species does undergo a chemical reaction. The concept could be reach rapidly other peroxides which are now under experimental studies. For artemisinin, an important antimalarian and anticancer drug, was established that ultrasound irradiation increases the effectiveness of the treatment but without any explanation. We show that artemisinin is an endoperoxide and behaves as a sonosensitizer in the sense of our definition.

Sonodynamic Therapy: Concept, Mechanism and Application to Cancer Treatment.

Sonodynamic therapy (SDT) represents an emerging approach that offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. It involves the sensitization of target tissues with a non-toxic sensitizing chemical agent and subsequent exposure of the sensitized tissues to relatively low-intensity ultrasound. Essentially, both aspects (the sensitization and ultrasound exposure) are harmless, and cytotoxic events occur when both are combined. Due to the significant depth that ultrasound penetrates tissue, the approach provides an advantage over similar alternative approaches, such as photodynamic therapy (PDT), in which less penetrating light is employed to provide the cytotoxic effect in sensitized tissues. This suggests that sonodynamic therapy may find wider clinical application, particularly for the non-invasive treatment of less accessible lesions. Early SDT-based approaches employed many of the sensitizers used in PDT, although the manner in which ultrasound activates the sensitizer differs from activation events in PDT. Here we will review the currently accepted mechanisms by which ultrasound activates sensitizers to elicit cytotoxic effects. In addition, we will explore the breath of evidence from in-vitro and in-vivo SDT-based studies, providing the reader with an insight into the therapeutic potential offered by SDT in the treatment of cancer.

A telluroviologen-anchored tetraphenylporphyrin as sonosensitizer for periodontitis sonodynamic therapy.

Periodontitis is a chronic disease caused by bacteria (e.g. Porphyromonas gingivalis, P.gingivalis) that currently lacks effective non-invasive treatment options. Sonodynamic therapy (SDT) is an emerging non-invasive antimicrobial therapeutic strategy. Since ultrasonic tooth cleaning is widely used in dental treatments, SDT has significant potential for the facile implementation of treat periodontitis. However, hypoxia in periodontitis severely limits the effectiveness of traditional sonosensitizers. To address this issue, we have developed a new sonosensitizer termed as TPP-TeV, which combines the traditional sonosensitizer tetraphenylporphyrin (TPP) with a new photosensitizer telluroviologen (TeV). Under ultrasound radiation, TPP-TeV can produce numerous cationic free radicals (TPP-TeV•), which subsequently generate ROS free radicals (O2•-, •OH) efficiently via electron transfer mechanism, resulting in the effective killing of anaerobic P.gingivalis both in vivo and in vitro. As a result, the dental environment is improved, and the inhibition rate of alveolar bone loss reaches 80 %. The introduction of tellurium into the viologen molecule induces changes in its reduction potential, resulting in increased rigidity of the molecule. This modification systematically reduces the biotoxicity of our novel sonosensitizer by 75 % at 50 µM based on bacterial experiments. These promising findings could potentially establish new options for sonodynamic therapy (SDT) in periodontitis clinical treatments.

An amplified sonodynamic therapy by a nanohybrid of titanium dioxide-gold-polyethylene glycol-curcumin: HeLa cancer cells treatment in 2D monolayer and 3D spheroid models.

The utilization of ultrasound (US) to activate sonosensitizers for sonodynamic therapy (SDT) has faced challenges such as low activation efficiency and limited therapeutic outcomes, which have hampered its clinical applications. In this study, a nanohybrid of titanium dioxide-gold-polyethylene glycol-curcumin (TiO2-Au-PEG-Cur NH), as a novel US sensitizer, was synthesized, characterized, and applied for SDT of HeLa cancer cells in 2D monolayer model, and also a 3D spheroid model to bridge the gap between 2D cell culture and in vivo future studies. TiO2-Au-PEG-Cur NH contained TiO2 nanoparticles of 36 ± 11 nm in diameter, PEG-curcumin as a filler, and gold nanoparticles of 21 ± 7 nm in diameter with a high purity and a 35:17 of Ti:Au ratio (W/W), and it had a band gap of 2.4 eV, a zeta potential of -23 ± 7 mV, high stability upon US radiation cycles as well as one year storage. SDT of HeLa cells using TiO2-Au-PEG-Cur NH was investigated in the courses of cytotoxicity assessment in vitro, reactive oxygen species (ROS) generation capability, colony formation, cell migration, and the way to form spheroid. IC50 values of 122 and 38 µg mL-1 were obtained for TiO2-Au-PEG-Cur NH without and with US radiation, respectively. TiO2-Au-PEG-Cur NH not only exhibited an inherent capacity to generate ROS, but also represented an excellent therapeutic performance on the cancer cells through ROS generation and enhanced inhibitory effects on cell migration and spheroid formation.

Ultrasound activated probe for disease imaging and therapy In-Vivo.

Sonodynamic therapy (SDT) is the use of ultrasound (US) to excite sonosensitizers to produce reactive oxygen species (ROS) to induce tumor cell death, thereby achieving therapeutic purposes. Based on the strong tissue penetration ability of ultrasound, SDT can realize the treatment of deeper tumors, and it is targeted, can be specifically concentrated at the tumor site, and has little impact on surrounding normal tissues. It has broad clinical transformation prospects. Therefore, sonosensitizers are the key to SDT, and the exploration of sonosensitizers with excellent therapeutic performance has received great attention. We reviewed the development of ultrasound-inspired sound sensitizers for imaging and treatment. First, different types of sonosensitizers are introduced, the construction and performance of inorganic, organic and hybrid types of sonosensitizers are evaluated, followed by a review of different image-guided SDT, and finally the key problems and solutions in this field are discussed in detail.

Nanomedicine/materdicine-enabled sonocatalytic therapy.

The advent of numerous treatment modalities with desirable therapeutic efficacy has been made possible by the fast development of nanomedicine and materdicine, among which the ultrasound (US)-triggered sonocatalytic process as minimal or non-invasive method has been frequently employed for diagnostic and therapeutic purposes. In comparison to phototherapeutic approaches with inherent penetration depth limitations, sonocatalytic therapy shatters the depth limit of photoactivation and offers numerous remarkable prospects and advantages, including mitigated side effects and appropriate tissue-penetration depth. Nevertheless, the optimization of sonosensitizers and therapies remains a significant issue in terms of precision, intelligence and efficiency. In light of the fact that nanomedicine and materdicine can effectively enhance the theranostic efficiency, we herein aim to furnish a cutting-edge review on the latest progress and development of nanomedicine/materdicine-enabled sonocatalytic therapy. The design methodologies and biological features of nanomedicine/materdicine-based sonosensitizers are initially introduced to reveal the underlying relationship between composition/structure, sonocatalytic function and biological effect, in accompany with a thorough discussion of nanomedicine/materdicine-enabled synergistic therapy. Ultimately, the facing challenges and future perspectives of this intriguing sonocatalytic therapy are highlighted and outlined to promote technological advancements and clinical translation in efficient disease treatment.

Application of antimicrobial sonodynamic therapy as a potential treatment modality in dentistry: A literature review.

The accumulation of dental plaque is a precursor to various dental infections, including lesions, inflammation around dental implants, and inflammation under dentures. Traditional cleaning methods involving physical removal and chemical agents often fall short of eliminating bacteria and their protective biofilms. These methods can also inadvertently lead to bacteria that resist drugs and upset the mouth's microbial harmony. To counter these issues, a new approach is needed that can target and clear away dental plaque, minimize biofilms and bacteria, and thus support sustained dental health. Enter antimicrobial sonodynamic therapy (aSDT), a supplementary treatment that uses gentle ultrasound waves to trigger a sonosensitizer compound, destroying bacterial cells. This process works by generating heat, mechanical pressure, initiating chemical reactions, and producing reactive oxygen species (ROS), offering a fresh tactic for managing dental plaque and biofilms. The study reviews how aSDT could serve as an innovative dental treatment option to enhance oral health.

Progress of Piezoelectric Semiconductor Nanomaterials in Sonodynamic Cancer Therapy.

Sonodynamic therapy is an emerging noninvasive tumor treatment method that utilizes ultrasound to stimulate sonosensitizers to produce a large amount of reactive oxygen species, inducing tumor cell death. Though sonodynamic therapy has very promising prospects in cancer treatment, the application of early organic sonosensitizers has been limited in efficacy due to the high blood clearance-rate, poor water solubility, and low stability. Inorganic sonosensitizers have thus been developed, among which piezoelectric semiconductor materials have received increasing attention in sonodynamic therapy due to their piezoelectric properties and strong stability. In this review, we summarized the designs, principles, modification strategies, and applications of several commonly used piezoelectric materials in sonodynamic therapy and prospected the future clinical applications for piezoelectric semiconductor materials in sonodynamic therapy.