Sonodynamic Therapy Research Articles

Photodynamic and Sonodynamic Therapy Synergy: Mechanistic Insights and Cellular Responses Against Glioblastoma Multiforme

Photodynamic and Sonodynamic Therapy Synergy: Mechanistic Insights and Cellular Responses Against Glioblastoma Multiforme

Innovations in intraoperative therapies in neurosurgical oncology: a narrative review.

High-grade gliomas (HGG) represent the most aggressive primary brain tumors in adults, characterized by high recurrence rates due to incomplete resection. This review explores the effectiveness of emerging intraoperative therapies that may extend survival by targeting residual tumor cells. The main research question addressed is: What recent intraoperative techniques show promise for complementing surgical resection in HGG treatment? A comprehensive literature review was conducted, examining recent studies on intraoperative therapeutic modalities that support surgical resection of HGG. Techniques reviewed include laser interstitial thermal therapy (LITT), intraoperative brachytherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), and focused ultrasound (FUS). Each modality was evaluated based on clinical application, evidence of effectiveness, and potential for integration into standard HGG treatment protocols. Findings indicate that these therapies offer distinct mechanisms to target residual tumor cells: LITT provides localized thermal ablation; intraoperative brachytherapy delivers sustained radiation; PDT and SDT activate cytotoxic agents in tumor cells; and FUS enables precise energy delivery. Each method has shown varying levels of clinical success, with PDT and LITT currently more widely implemented, while SDT and FUS are promising but under investigation. Intraoperative therapies hold potential to improve surgical outcomes for HGG by reducing residual tumor burden. While further clinical studies are needed to optimize these techniques, early evidence supports their potential to enhance the effectiveness of surgical resection and improve patient survival in HGG management.

The abscopal effects of sonodynamic therapy in cancer.

The abscopal effect is a phenomenon wherein localised therapy on the primary tumour leads to regression of distal metastatic growths. Interestingly, various pre-clinical studies utilising sonodynamic therapy (SDT) have reported significant abscopal effects, however, the mechanism remains largely enigmatic. SDT is an emerging non-invasive cancer treatment that uses focussed ultrasound (FUS) and a sonosensitiser to induce tumour cell death. To expand our understanding of abscopal effects of SDT, we have summarised the preclinical studies that have found SDT-induced abscopal responses across various cancer models, using diverse combination strategies with nanomaterials, microbubbles, chemotherapy, and immune checkpoint inhibitors. Additionally, we shed light on the molecular and immunological mechanisms underpinning SDT-induced primary and metastatic tumour cell death, as well as the role and efficacy of different sonosensitisers. Notably, the observed abscopal effects underscore the need for continued investigation into the SDT-induced 'vaccine-effect' as a potential strategy for enhancing systemic anti-tumour immunity and combating metastatic disease. The results of the first SDT human clinical trials are much awaited and are hoped to enable the further evaluation of the safety and efficacy of SDT, paving the way for future studies specifically designed to explore the potential of translating SDT-induced abscopal effects into clinical reality.

Enhancing wound healing through sonodynamic silver/barium titanate heterostructures-loading gelatin/PCL nanodressings.

Bacterial infections present a formidable challenge in surgical procedures, and are a major threat to wound healing. Sonodynamic therapy (SDT) is a non-invasive approach for fighting pathogens; however, it is hindered by the efficiency of sonosensitizers and effective antibacterial time. In this study, we developed a biocompatible nanodressing to improve the antibacterial efficacy and accelerate wound healing via SDT. Silver nanoparticles (NPs) were synthesized on tetragonal barium titanate (BTO) NPs to create an Ag@BTO heterostructure of sonosensitizers to improve their piezocatalytic activities, which were then incorporated into gelatin/polycaprolactone (PCL) to form Ag@BTO-gelatin/PCL nanofiber (ABT-gP NFs) dressings. The loading of Ag@BTO NPs resulted in ABT-gP NFs with better mechanical properties and excellent piezocatalysis, which produced reactive oxygen species and Ag+ to kill bacteria during ultrasound (US) irradiation. Additionally, nanodressing released moderate amounts of silver ions without US, prolonging the antibacterial time, while promoting fibroblast migration. This approach was effective in killing Gram-positive and Gram-negative bacteria (100 % and 90.8 %, respectively), promoting cell migration in vitro and accelerating wound healing without adverse effects in vivo. This study extends the potential applications of ultrasound-triggered nanodressing to the field of wound healing.

Targeted Sonodynamic Therapy Platform for Holistic Integrative Helicobacter pylori Therapy.

Helicobacter pylori (H. pylori) is a primary pathogen associated with gastrointestinal diseases, including gastric cancer. The increase in resistance to antibiotics, along with the adverse effects caused by complicated medication protocols, has made the eradication of H. pylori a more formidable challenge, necessitating alternative therapeutics. Herein, a targeted nanoplatform is reported based on sonodynamic therapy, the chitosan-conjugated fucose loaded with indocyanine green (ICG@FCS). It penetrates the gastric mucosa and homes in on H. pylori through dual targeting mechanisms: molecular via fucose and physical via ultrasound. Upon ultrasound activation, it generates singlet oxygen, effectively attacking planktonic bacteria, disrupting biofilms, and facilitating the clearance of intracellular bacteria by promoting autophagy, including multidrug-resistant strains. The ICG@FCS nanoplatform minimally affects the gut microbiota and aids in gastric mucosa repair. a holistic integrative H. pylori therapy strategy is proposed that targets eradication while preserving gastrointestinal health. This strategy emphasizes the importance of maintaining patient health while eradicating the pathogen. This advancement is set to refine the comprehensive antibacterial approach, offering a promising horizon in the ongoing battle against antibiotic resistance and more effective gastric cancer prevention strategies.

Conjugated oligo (phenylene vinylene) covalently linked porphyrin for sonodynamic therapy

AbstractSonodynamic therapy (SDT) is garnering considerable attention as a promising treatment for deep‐seated tumors because of its strong tissue penetration ability, non‐invasiveness, and controllability. However, the SDT efficiency of traditional sonosensitizers including porphyrins and their derivatives are limited due to their poor water dissolubility, high aggregation, and low reactive oxygen species (ROS) production efficiency. Consequently, it is crucial to develop novel sonosensitizers with high yields of ROS, outstanding water solubility, and good biocompatibility. Herein, we constructed a new platform for SDT based on unimolecular porphyrin derivatives OPV‐C3‐TPP. The probe OPV‐C3‐TPP was synthesized by covalently linking conjugated oligomers (OPV) with 5, 10, 15, 20‐tetra (4‐aminophenyl) porphyrin (TAPP). The introduction of OPV greatly improves the water solubility of the porphyrins and reduces the self‐aggregation of the porphyrins. In addition, OPV‐C3‐TPP has good intramolecular energy transfer efficiency, thus enhancing the yield of ROS. The experimental results show that OPV‐C3‐TPP exhibits excellent ROS generation capacity under ultrasound (US) irradiation, which leads to apoptosis and necrosis of tumor cells. In vivo tumor growth is also significantly inhibited in the OPV‐C3‐TPP + US group, exhibiting better SDT effects than TAPP. Therefore, the unimolecular OPV‐C3‐TPP can be used as a potential sonosensitizer, providing a promising SDT for deep‐tissue tumors.

The Latest Applications of Carbon-Nitride-Based Materials for Combination Treatment of Cancer.

Carbon-nitride-based (CN-based) materials have shown great potential in combination therapy in recent years. Due to their outstanding biocompatibility, ease of modification, and adjustable band-gap position, CN-based materials can be applied as photosensitizers in photodynamic therapy (PDT) and light-driven water-splitting catalysts in gas therapy. After doping with other elements, the photocatalytic performance of CN-based materials will be enhanced, and more interesting functions will be obtained. In addition, the large specific surface area also promotes CN-based materials as drug carriers combined with other therapeutic modalities to achieve combination therapy. This Review analyzes and summarizes the latest research on CN-based materials in combined therapies, such as PDT with photothermal therapy (PTT), PDT with sonodynamic therapy (SDT), PDT with drug therapy, PDT with gene therapy, gas therapy with PDT, and bioimaging-guided combined therapy. In particular, the applications of CN-based materials in gas and gene combination therapy are summarized for the first time. Finally, the current challenges faced by CN-based materials in combination therapy are further discussed.

Interface-Engineered CuxO@Bi2MoO6 Heterojunctions to Inhibit Piezoelectric Screening Effect and Promote Double-Nanozyme Catalysis for Antibacterial Treatment.

Sonodynamic therapy is confronted with the low acoustic efficiency of sonosensitizers, and nanozymes are accompanied by intrinsic low catalytic activity. Herein, to increase the piezopotential of N-type piezoelectric semiconductors, the P-N heterojunction is designed to inhibit the piezoelectric screening effect (PSE) and increase electron utilization efficiency to enhance nanozyme activity. P-type CuxO nanoparticles are in situ grown on N-type piezoelectric Bi2MoO6 (BMO) nanoflakes (NFs) to construct heterostructured CuxO@BMO by interface engineering. CuxO deposition leads to lattice distortion of BMO NFs to improve piezoelectric response, and the strong interface electric field (IEF) suppresses PSE and increases piezopotential. The nonlocal piezopotential, local IEF, and glutathione (GSH) inoculation enhances electron-hole separation and increases peroxidase (POD)-like activity of BMO and GSH oxidase (GSHOx)-like activity of CuxO with high selectivity. The heterojunction formation causes the transfer and rearrangement of interface electrons, and the increased piezopotential accelerates electron transfer at interfaces with bacteria, thus increasing the production of reactive oxidative species and interfering with adenosine triphosphate synthesis. The heterostructured nanozymes produce abundant intracellular ·OH and achieve 4log magnitude reductions in viable bacteria and effective biofilm dispersion. This study elucidates integral mechanisms of nanozyme and acoustic catalysis and opens up a new way to synergize high piezopotential and nanozyme-catalyzed therapy.

Erratum in: TiO2-Nanoparticle-Enhanced Sonodynamic Therapy for Prevention of Posterior Capsular Opacification and Ferroptosis Exploration of Its Mechanism.

Erratum in: TiO2-Nanoparticle-Enhanced Sonodynamic Therapy for Prevention of Posterior Capsular Opacification and Ferroptosis Exploration of Its Mechanism.

CTNI-76. A PHASE 1/2 DOSE ESCALATION AND EXPANSION STUDY OF SONODYNAMIC THERAPY WITH SONALA-001 IN COMBINATION WITH NON-ABLATIVE MR-GUIDED FOCUSED ULTRASOUND IN SUBJECTS WITH PROGRESSIVE OR RECURRENT GLIOBLASTOMA

Abstract Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective standard of care option and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination therapy that utilizes a drug, aminolevulinic acid HCL (SONALA-001, ALA), and a device, the Exablate 4000 Type 2.0 to deliver MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that SDT activates protoporphyrin IX (PpIX) to generate reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of iv SONALA-001 (ALA) in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Dose escalation will include an initial drug and energy dose escalation of ALA SDT utilizing an accelerated titration design with single subject cohorts for dose level cohorts 1 and 2, followed by cohort 3 with 3 + 3 design for additional dose escalation. SONALA-001 is administered 6 to 9 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of ALA SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Preliminary PK and safety results will be presented.

CTNI-74. SONODYNAMIC THERAPY (SDT) USING INTRAVENOUS 5-AMINOLEVULINIC ACID WITH NON-ABLATIVE FOCUSED ULTRASOUND FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS IN PEDIATRICS: INITIAL SAFETY AND OUTCOMES THE MULTICENTER SDT-201 TRIAL

Abstract Diffuse intrinsic pontine glioma (DIPG) is the leading cause of mortality amongst pediatric neuro-oncologic diseases. Sonodynamic therapy with non-ablative MR-guided focused ultrasound (MRgFUS) is being investigated in multiple clinical trials. We describe safety outcomes and initial efficacy of SDT with 5-ALA for the treatment of pediatric patients with DIPG. Twelve patients with DIPG were treated from August 2022-April 2024 as part of a dose-escalation protocol with SDT in a multicenter Phase 1/2 clinical trial (NCT05123534). MRgFUS was combined with the prodrug SONALA-001 (5-ALA iv) to activate its metabolite, protoporphyrin IX, and thereby induce apoptosis within tumor cells. Treatment is delivered every 4 weeks for up to 12 treatments. Patient ages ranged from 3-23 years and 60% were male. Twelve patients underwent a total of 45 SDT treatments (range 2-9). When enrolled, median tumor volume was 1,337 cm3 (range, 310-2078 cm3) and duration since diagnosis was 5 months. SONALA-001 doses tested were 5 mg/kg and 10 mg/kg. Delivered ultrasonic acoustic energy ranged from 190-444 joules/cm3. After 6 months of median follow-up (range 2-18), 2 partial responses occurred, and 9 of 12 patients had stable or improved baseline symptoms (Lansky Status), including improved mobility and diplopia. One adverse clinical event included a small non-operative epidural hematoma secondary to a stereotactic frame pin. There have been no grade 3 or worse treatment-related adverse events or dose-limiting toxicities. Ten patients are alive a median of 11 months after diagnosis; 2 have deceased; 4 have discontinued treatment. Maximum percent tumor volume changes throughout treatment ranged from a -68% reduction to over 100% enlargement. Preliminary analysis of twelve pediatric patients treated with SDT for DIPG demonstrates acceptable safety outcomes and promising clinical results. Additional patient enrollment and longer follow-up times are required to determine efficacy.

CTNI-18. RESULTS FROM A PHASE 1 STUDY OF SONODYNAMIC THERAPY WITH WHOLE HEMISPHERIC LOW INTENSITY NON-ABLATIVE ULTRASOUND IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

Abstract We report the first use of a novel device that delivers non-ablative low intensity diffuse ultrasound (LIDU) across the entire hemisphere in combination with the oral sonosensitizing agent 5-ALA for the treatment of recurrent high grade glioma. LIDU in combination with 5-ALA focally targets tumor cells with sonodynamic therapy (SDT), causing selective tumor cell death across the entire hemisphere via 1) direct tumor targeting and 2) stimulation of immunogenic cell death. In this 3x3 clinical trial designed for safety (n=12, NCT05362409), two patients were enrolled after multiple recurrences and seven patients had multifocal or multicentric disease. Treatments were delivered monthly for a minimum of four sessions. A treatment duration of 120 minutes was established after dose escalation and expansion. SDT delivered via a novel device and in conjunction with 5-ALA was well tolerated, with no duration-limiting toxicities or serious related adverse events. Compared to historical data, we observed a significant increase in overall survival (mOS of 14.0+ months, with 7 of 12 patients still alive at the time of this submission and final median OS not yet achieved). A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been planned to commence in 2025 to assess the safety and efficacy of LIDU with sonosensitization in patients with newly diagnosed GBM.

Modulating Pore Wall Chemistry Empowers Sonodynamic Activity of Two‐Dimensional Covalent Organic Framework Heterojunctions for Pro‐Oxidative Nanotherapy

AbstractCovalent organic frameworks (COFs) have garnered growing interest in the field of biomedicine; however, their application in sonodynamic therapy remains underexplored due to limited understanding of their intrinsic activity and structure–property relationships. Here, we present a pore wall chemistry modulation strategy for empowering sonodynamic activity to two‐dimensional (2D) COF heterojunctions through in situ growth of COFs on bismuth oxycarbonate nanosheets (B NSs). Compared to the negligible sonodynamic effects observed in the pristine B NSs, the 2D heterojunction with vinyl‐decorated COF pore walls demonstrates a 3.6‐fold enhancement in sonocatalytic singlet oxygen generation. This performance also significantly outperforms that of isoreticular COFs functionalized with methoxy or non‐substituted groups. Mechanistic studies reveal that the vinyl groups in the B@COF (BC) heterojunction facilitate the separation and transfer of charge carriers while also enhancing the adsorption of oxygen molecules. Furthermore, peroxymonosulfate (PMS) loading into the porous COFs boosts the therapeutic efficacy of antitumor nanotherapy via sonocatalytic dual oxidative species generation. These findings underscore the critical role of pore wall chemistry in modulating the sonocatalytic properties of COFs, and advance the development of COF‐based sonosensitizers for pro‐oxidative applications.

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.

Nucleus-Targeted Sonosensitizer Activates the cGAS-STING Pathway for Tumor Sonodynamic Immunotherapy.

A nucleus is crucial for both sonodynamic therapy (SDT) and antitumor immunity. However, how to burst ROS generation in situ, accurately damage a nucleus, and meanwhile activate a cGAS-STING pathway-induced innate immune response are still a great challenge. Here, we present TBzT-CPi, a small molecule with a D-A-π-A1 structure that simultaneously amplifies nucleus-targeted SDT and cGAS-STING pathway-dependent immune stimulation. TBzT-CPi could accumulate in the nucleus upon ultrasound irradiation and generate ROS in situ, which damages DNA and simultaneously triggers immunogenic cell death (ICD). Stirringly, nucleus-targeting SDT not only efficiently induces apoptosis in tumor cells but also modifies the immunosuppressive tumor microenvironment by activating cytotoxic T lymphocytes, maturing dendritic cells, and secreting cytokines. These findings pave the way for developing nucleus-targeting sonosensitizers for sonodynamic immunotherapy of cancer.

An alternative way to break the matrix barrier: an experimental study of a LIFU-mediated, visualizable targeted nanoparticle synergistic amplification for the treatment of malignant fibroblasts

Malignant fibroblasts (MFs) are widely present in various diseases and are characterized by connective tissue proliferation; these cells act as a physical barrier that severely limits drug delivery and affects disease outcomes. Based on this, we constructed the smart, integrated, theranostic, targeted lipid nanoprobe HMME-RG3@PFH to overcome the bottleneck in the early diagnosis and treatment of MF-related diseases. The protein glucose transporter protein 1 (GLUT-1) is overexpressed on MFs, and its ideal substrate, ginsenoside RG3 (RG3), significantly enhances the targeted uptake of HMME-RG3@PFH by MFs in a hypoxic environment and endows the nanomaterial with stealthiness to prolong its circulation. Perfluorohexane (PFH), a substance that can undergo phase change, was encapsulated in the lipid core and vaporized for ultrasound-enhanced imaging under low-intensity focused ultrasound (LIFU) irradiation. Moreover, hematoporphyrin monomethyl ether (HMME) was loaded into the lipid bilayer for photoacoustic molecular imaging and sonodynamic therapy (SDT) of MFs under the combined effects of LIFU. Additionally, HMME-RG3@PFH instantaneously burst during visualization to promote targeted drug delivery. In addition, the increased number of exposed RG3 fragments can regulate the MFs to enter a quiescent state. Overall, this nanoplatform ultimately achieves dual-modal imaging with targeted and precise drug release for visualization and synergistic amplification therapy, providing a new possibility for the early diagnosis and precise treatment of MF-related diseases.

Nanotechnology‐Based Systems for Enhancing the Efficacy of Sonodynamic Therapy in Cancer Treatment

AbstractSonodynamic therapy (SDT) is a minimally invasive cancer therapeutic modality that utilizes low‐intensity ultrasound to activate sensitizers for the production of cytotoxic reactive oxygen species (ROS) and the site‐specific ablation of tumors. Compared to conventional cancer treatments, SDT has no adverse side effects, has been shown to radically reduce tumor volume, and has the potential to raise antitumor immune response. Ever‐increasing studies have demonstrated that nanotechnology can significantly enhance the efficacy of SDT against certain cancers and improve its therapeutic effects. Nanosystems are developed that can improve the intratumoral delivery and cellular uptake of sensitizers, can reduce intrinsic cancer defenses against ROS, can act synergistically for the production of ROS and can tackle cancer immune tolerance. In this review, the various strategies to enhance SDT performance with the assistance of nanotechnology, and the outstanding research outcomes, are discussed.

Recent Advances in Silica-Based Nanomaterials for Enhanced Tumor Imaging and Therapy.

Cancer remains a formidable challenge, inflicting profound physical, psychological, and financial burdens on patients. In this context, silica-based nanomaterials have garnered significant attention for their potential in tumor imaging and therapy owing to their exceptional properties, such as biocompatibility, customizable porosity, and versatile functionalization capabilities. This review meticulously examines the latest advancements in the application of silica-based nanomaterials for tumor imaging and therapy. It underscores their potential in enhancing various cancer imaging modalities, including fluorescence imaging, magnetic resonance imaging, computed tomography, positron emission tomography, ultrasound imaging, and multimodal imaging approaches. Moreover, the review delves into their therapeutic efficacy in chemotherapy, radiotherapy, phototherapy, immunotherapy, gas therapy, sonodynamic therapy, chemodynamic therapy, starvation therapy, and gene therapy. Critical evaluations of the biosafety profiles and degradation pathways of these nanomaterials within biological environments are also presented. By discussing the current challenges and prospects, this review aims to provide a nuanced perspective on the clinical translation of silica-based nanomaterials, thereby highlighting their promise in revolutionizing cancer diagnostics, enabling real-time monitoring of therapeutic responses, and advancing personalized medicine.

Fluorocarbon-Functionalized Polymerization-Induced Self-Assembly Nanoparticles Alleviate Hypoxia to Enhance Sonodynamic Cancer Therapy.

Sonodynamic therapy (SDT) is an ultrasound-based, noninvasive cancer treatment that targets tumor cells by triggering reactive oxygen species production. However, the limited accumulation of sonosensitizers and the insufficient supply of O2 to the hypoxic environment at the tumor site greatly limit the effectiveness of SDT. To address these issues, positively charged porphyrin-containing nanoparticles (NPs) from self-assembling of fluorocarbon/polyethylene glycol amphiphilic block copolymer, which is synthesized through reversible addition-fragmentation chain transfer polymerization, are constructed. The NPs with fluorocarbon core and positively charged hydrophilic shells not only stabilize the sonosensitizer and improve its cellular uptake, but also act as an O2 carrier alleviating the hypoxic tumor environment. In vitro and in vivo experiments demonstrate that the NPs effectively deliver O2 to the tumor and supply sufficient O2 to Renca cells after ultrasound treatment. Consequently, the NPs inhibit hypoxia-induced resistance to SDT and significantly produce reactive oxygen species by activated porphyrin moieties, inducing apoptosis in cancer cells. These oxygen-enhanced sonosensitizer NPs hold promise for cancer therapies such as photodynamic therapy, radiotherapy, and chemotherapy by overcoming hypoxia-induced resistance.

An ultrasound-activated piezoelectric sonosensitizer enhances mitochondrial depolarization for effective treatment of orthotopic glioma

Despite the significant advancements in piezoelectric materials for sonodynamic therapy (SDT), the suppression of orthotopic glioma remains challenging, primarily due to the unclear mechanism and the restriction of blood-brain barrier (BBB). Herein, we proposed that layered piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) could effectively depolarize the mitochondrial membrane potential (ΔΨm) of glioma cells under ultrasound (US) exposure. The US-induced band bending in SBTO NPs enhanced redox ability, promoting an increase in reactive oxygen species (ROS) generation. The in vitro results proved that SBTO NPs selectively accumulated in mitochondria under US and induced apoptosis in a mitochondrial depolarization manner mediated by the generation of ROS and free charges. Furthermore, SBTO NPs could cross the BBB and then accumulate in gliomas through US/microbubbles (MBs) procedure and protein-mediated transport. The therapeutic effect of piezoelectric SBTO NPs mediated SDT was proved in the orthotopic glioma mouse model. As validated by the histopathological observation and the long-term evaluation, the good biocompatibility and biosafety of SBTO NPs make it possible for deep tumor therapy, and worthy for further preclinical study. Statement of significanceEmploying piezoelectric sonosensitizers for sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, the unclear mechanism and blood-brain barrier (BBB) limit the effectiveness of SDT in glioma. Herein, we developed piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) with a built-in electric field for glioma treatment and explored the underlying therapeutic mechanism. Notably, SBTO NPs selectively accumulated in mitochondria under ultrasound (US) and induced apoptosis in a mitochondrial depolarization manner, which is mediated by the generation of reactive oxygen species (ROS) and free charges. In an orthotopic glioma mouse model, SBTO NPs were delivered into the glioma through US/microbubbles and transferrin-mediated transport pathways, inhibiting tumor growth. This work provides a new paradigm for the treatment of orthotopic glioma and other tumor types.