Ultrasound Irradiation Research Articles

Enhancing the Antitumor Efficacy of Oncolytic Adenovirus Through Sonodynamic Therapy-Augmented Virus Replication.

The therapeutic efficacy of oncolytic adenoviruses (OAs) relies on efficient viral transduction and replication. However, the limited expression of coxsackie-adenovirus receptors in many tumors, along with the intracellular antiviral signaling, poses significant obstacles to OA infection and oncolysis. Here, we present sonosensitizer-armed OAs (saOAs) that potentiate the antitumor efficacy of oncolytic virotherapy through sonodynamic therapy-augmented virus replication. The saOAs could not only efficiently infect tumor cells via transferrin receptor-mediated endocytosis but also exhibit enhanced viral replication and tumor oncolysis under ultrasound irradiation. We revealed that the sonosensitizer loaded on the viruses induced the generation of ROS within tumor cells, which triggered JNK-mediated autophagy, ultimately leading to the enhanced viral replication. In mouse models of malignant melanoma, the combination of saOAs and sonodynamic therapy elicited a robust antitumor immune response, resulting in significant inhibition of melanoma growth and improved host survival. This work highlights the potential of sonodynamic therapy in enhancing the effectiveness of OAs and provides a promising platform for fully exploiting the antitumor efficacy of oncolytic virotherapy.

Ultrasound-Activated PROTAC Prodrugs Overcome Immunosuppression to Actuate Efficient Deep-Tissue Sono-Immunotherapy in Orthotopic Pancreatic Tumor Mouse Models.

The degradation of oncoproteins mediated by proteolysis-targeting chimera (PROTAC) has emerged as a potent strategy in cancer therapy. However, the clinical application of PROTACs is hampered by challenges such as poor water solubility and off-target adverse effects. Herein, we present an ultrasound (US)-activatable PROTAC prodrug termed NPCe6+PRO for actuating efficient sono-immunotherapy in a spatiotemporally controllable manner. Specifically, US irradiation, which exhibits deep-tissue penetration capability, results in Ce6-mediated generation of ROS, facilitating sonodynamic therapy (SDT) and inducing immunogenic cell death (ICD). Simultaneously, the generated ROS cleaves the thioketal (TK) linker through a ROS-responsive mechanism, realizing the on-demand activation of the PROTAC prodrug in deep tissues. This prodrug activation results in the degradation of the target protein BRD4, while simultaneously reversing the upregulation of PD-L1 expression associated with the SDT process. In the orthotopic mouse model of pancreatic tumors, NPCe6+PRO effectively suppressed tumor growth in conjunction with US stimulation.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

Potential application of wet-phase modified expandable graphite particles as a novel in-depth profile control agent in carbonate reservoirs

Novel wet-phase modified expandable graphite (WMEG) particles were developed for in-depth profile control in carbonate reservoirs. The harsh environment of carbonate reservoirs (≥ 130 °C, ≥ 22 × 104 mg/L) brings significant challenges for existing profile control agents. WMEG particles were developed to address this problem. WMEG particles were synthesized via intercalation with ultrasound irradiation and chemical oxidation. The critical expansion temperature of WMEG particles is 130 °C, and these particles can effectively expand 3–8 times under high temperature and high salinity water. The core flow experiments show that WMEG particles exhibit a good plugging capacity, profile control capacity, and a better-enhanced oil recovery (EOR) capacity in deep carbonate reservoirs. WMEG particles can be expanded in the formation and form larger particles that bridge the upper and lower end faces of the fracture. Then the high-permeability zones are effectively plugged, and the heterogeneity is improved, resulting in an obvious increase in oil recovery. This research provides a novel insight into future applications of profile control agents for in-depth profile control treatment in carbonate reservoirs.

Novel nickel-immobilized-SiO2-TiO2 fine particles in the presence of cetyltrimethylammonium bromide as a catalyst for ultrasound-assisted-Kumada cross-coupling reaction

Kumada cross-coupling reaction is useful for producing biphenyls, where nickel and copper have been widely investigated as catalysts but mainly homogeneous ones. In this study, we investigated ultrasound-assisted-Kumada cross-coupling reaction over the heterogeneous catalysts in which Ni2+, Cu2+, or both was immobilized on aminopropylsilane-functionalized-SiO2-TiO2 prepared in the presence of cetyltrimethylammonium bromide (CTAB). The presence of CTAB effectively prevented the particle growth and therefore SiO2–TiO2 fine particles with high surface area (502 m2 g−1) were formed. The Ni2+-immobilized catalyst showed high catalytic activity for the ultrasound-assisted-Kumada cross-coupling reaction of a wide variety of substrates and was reusable three times. Performing the reaction under ultrasound irradiation was very effective in significantly accelerating the reaction rate compared with the conventional mechanical method. In contrast to Ni2+, Cu2+ was deposited on the support as crystalline Cu(OH)2 and the resulting catalysts with Cu2+ and Ni2+-Cu2+ were less active and less stable under the reaction conditions.

Immunomodulating Sonocatalytic Nanoagents with Dual‐Functional Ir‐N Centers and Narrow Bandgap for Reversing Immunosuppression and Potentiating Ovarian Cancer Immunotherapy

AbstractThe heterogeneity and immunosuppression microenvironment of ovarian cancer seriously restrict the efficiency of monomodal treatment. Emerging multimodal therapy strategies based on sonodynamic therapy with enhanced antitumor effects have attracted intensive attention in the quest to combat cancer. However, exploring highly efficient sonosensitizers integrating chemodynamic/sonodynamic/immunotherapies with reversing immunosuppressive tumor microenvironment (TME) capacity is urgently desired but remains challenging. Here, a facile strategy is designed to synthesize immunomodulating sonocatalytic nanoagents (IrT‐SCN) with dual‐functional Ir‐N centers and narrow bandgap for reversing immunosuppression and potentiating ovarian cancer immunotherapy. IrT‐SCN with dual‐functional centers Ir‐N2 and Ir‐N4 and conjugated networks show a reduced bandgap, moderate interaction with H2O2, and efficient production of reactive oxygen species (ROS). Such ROS capabilities include: 1) utilizing H2O2 in TME to catalytically generate potent O2, as well as abundant superoxide anion (•O2−) and singlet oxygen (1O2) radicals; 2) external ultrasound (US) irradiation can also boost the production of 1O2 simultaneously; 3) M1 polarization of tumor‐associated macrophages and enhanced immune effect can promote the outcome of cancer treatment. This finding provides proof‐of‐concept evidence for the future development of immunomodulating sonocatalytic nanoagents for oncological treatments and other ROS‐related biomedical fields.

Boron Dipyrromethene-Based Nanotheranostic System for Sonophotoassisted Therapy and Simultaneous Monitoring of Tumor Immune Microenvironment Reprogramming.

Therapy-induced modulation of the tumor microenvironment (TME) to overcome the immunosuppressive TME is considered to be an opportunity for cancer treatment. However, monitoring of TME modulation during the therapeutic process to accurately determine immune responses and adjust treatment plans in a timely manner remains to be challenging. Herein, we report a carrier-free nanotheranostic system (CANPs) assembled by two boron dipyrromethene (BODIPY) dyes, a sonophotosensitizer C-BDP, and a nitric oxide (NO) probe amino-BODIPY (A-BDP). CANPs can exert combined sonophototherapeutic effects of C-BDP under ultrasound and light irradiation and simultaneously induce inflammatory TME, as well as emit bright fluorescence via A-BDP by monitoring tumor-associated macrophages (TAMs) repolarization through the released NO in vitro and in vivo. Of note, transforming growth factor-β (TGF-β) could be the key cytokine involved in the sonophototherapy-induced TME reprogramming. By virtue of high physiological stability, good biocompatibility, and effective tumor targetability, CANPs could be a potential nanotheranostic system for the simultaneous induction and detection of TME reprogramming triggered by sonophototherapy.

Synthesis of Ceiba pentandra biodiesel using ultrasound and infrared radiation: Comparison and fuel characterisation.

Abstract The continuous expending of the economy and population in modern society has caused an increase in energy usage. Currently, fossil fuels and renewable energy are used to generate energy, contributing to greenhouse gas emissions. A significant effort has been made globally to address the issue of rising emissions by boosting the usage of renewable energy. In comparison to fossil fuels, biodiesel has many benefits, including the ability to be produced from a wide range of feedstocks, the ability to be renewable, and the reduction of atmospheric pollution emissions. Besides, advanced technologies can help the biodiesel sector meet the energy demand while producing high-quality biodiesel. The Ceiba pentandra was used for biodiesel production using ultrasound-infrared applications in the present research work. The study aims to produce biodiesel for a better conversion rate and improve fuel properties. Comparisons were conducted using a combination of infrared ultrasound versus ultrasound irradiation. The results show that ultrasound produced the highest yield of 98.76% when the conditions were as follows: methanol/oil ratio: 60%, KOH: 1%, reaction time: 50 minutes. Yet, the addition of infrared on ultrasound has also produced a high conversion yield in a shorter time than ultrasound. A 98.42% biodiesel yield option when using infrared-ultrasound irradiation with conditions as follows: methanol/oil ratio: 60%, KOH: 1%, reaction time: 30 minutes. As both applications were examined, the ultrasound-infrared application was preferable in saving time and energy constraints for biodiesel production. The fuel properties were found to be equivalent to ASTM D6751 and EN 14214 biodiesel standards.

Effects of insonification on repairing the renal injury of diabetic nephropathy rats

IntroductionProlonged hyperglycemia in diabetes mellitus can result in the development of diabetic nephropathy (DN) and increase the susceptibility to kidney failure. Low-intensity pulsed ultrasound (LIPUS) is a non-invasive modality that...

Sonochemical decomposition effects of nickelocene aiming for low-temperature and dispersant-free synthesis of nickel fine particle

Sonochemical decomposition effects of nickelocene, which sublimates easily were investigated to synthesize dispersant-free nickel fine particles at low temperature. In a hydrazine monohydrate and 2-propanol mixed solvent, the reduction of nickelocene was promoted by ultrasound irradiation, and nickel fine particles were synthesized while precluding the sublimation of nickelocene. Unlike the common hydrazine reduction of nickel salts, which requires multiple-step reactions, nickelocene was reduced directly without forming intermediates. The effect of the water-bath temperature (20–60 °C) was investigated, where larger fine particles were synthesized using a higher water-bath temperature (60 °C). When irradiated at 20 °C, the reduction rate of nickelocene was low, leading to the formation of nickel fine particles and organic nanoparticles via the reduction and decomposition of nickelocene. The ultrasound frequency was also investigated, where fine nickel particles were synthesized using low-frequency ultrasound irradiation. The formation of high-temperature hotspots led to the diffusion and growth of nickel on the surface of the nickel fine particles; therefore, raspberry-like nickel fine particles were synthesized. In this study, the difficult-to-handle nature of nickelocene, owing to its sublimation properties, was easily overcome by ultrasound irradiation. Instantaneous and localized reactions at hotspots contributed to inhibiting particle growth. Furthermore, Ni fine particles were synthesized via a direct reduction pathway, which differs from previous reactions. This method represents a new, dispersant-free, low-temperature process for synthesizing Ni fine particles.

Multifaceted Carbonized Metal-Organic Frameworks Synergize with Immune Checkpoint Inhibitors for Precision and Augmented Cuproptosis Cancer Therapy.

The discovery of cuproptosis, a copper-dependent mechanism of programmed cell death, has provided a way for cancer treatment. However, cuproptosis has inherent limitations, including potential cellular harm, the lack of targeting, and insufficient efficacy as a standalone treatment. Therefore, exogenously controlled combination treatments have emerged as key strategies for cuproptosis-based oncotherapy. In this study, a Cu2-xSe@cMOF nanoplatform was constructed for combined sonodynamic/cuproptosis/gas therapy. This platform enabled precise cancer cotreatment, with external control allowing the selective induction of cuproptosis in cancer cells. This approach effectively prevented cancer metastasis and recurrence. Furthermore, Cu2-xSe@cMOF was combined with the antiprogrammed cell death protein ligand-1 antibody (aPD-L1), and this combination maximized the advantages of cuproptosis and immune checkpoint therapy. Additionally, under ultrasound irradiation, the H2Se gas generated from Cu2-xSe@cMOF induced cytotoxicity in cancer cells. Further, it generated reactive oxygen species, which hindered cell survival and proliferation. This study reports an externally controlled system for cuproptosis induction that combines a carbonized metal-organic framework with aPD-L1 to enhance cancer treatment. This precision and reinforced cuproptosis cancer therapy platform could be valuable as an effective therapeutic agent to reduce cancer mortality and morbidity in the future.

Synthesis of 3,4-dihydropyrimidines and octahydroquinazolinones by SBA-15 supported schiff-base iron (III) complex as durable and reusable catalyst under ultrasound irradiation

Biginelli-type heterocyclic compounds are particularly important due to their several chemical reactivities and various range of pharmacological activity. Therefore Biginelli reaction has witnessed several modification and numerous investigations are continuing in this field to develop more effective and efficient methodologies. In this research, Iron (III) schiff base immobilized SBA-15 has been prepared as a valuable, efficient, and recoverable catalyst for the Biginelli reaction. The morphology of the prepared catalyst was identified by spectroscopic characterization techniques and structural microscopic analysis including Fourier transform infrared (FT-IR) patterns, X-ray diffraction (XRD) by powder crystal method, Energy-dispersive X-ray spectroscopy (EDS) study, Thermogravimetric-Differential thermal analysis (TGA-DTA), Transmission electron microscopy (TEM) and Field emission scanning electron microscopy (FE-SEM) images. Biginelli compounds containing 3,4-dihydropyrimidines and octahydroquinazolinones were conveniently synthesized by this catalyzed protocol from the cycloaddition of aromatic aldehydes with the 1,3-dicarbonyl substrates and urea via ultrasonic waves. The several advantages of the presented approach are high yields and easy isolation of products, shorter reaction times, and milder conditions, structural stability and reusable catalyst. The combination of heterogeneous catalyst and ultrasonic radiation can make catalytic reactions more efficient than traditional ways attractive for academic researchers and application scholars in the industry.

Turning Waste into Wealth: A Potent Sono-Immune Strategy Based on Microcystis.

Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O2 under red light (RL) illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound (US) irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell (DC) maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade (ICB), the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; the similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibits good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic.

MOF-Derived Nanoparticles with Enhanced Acoustical Performance for Efficient Mechano-Sonodynamic Therapy.

Ultrasound (US) generates toxic reactive oxygen species (ROS) by acting on sonosensitizers for cancer treatment, and the mechanical damage induced by cavitation effects under US is equally significant. Therefore, designing a novel sonosensitizer that simultaneously possesses efficient ROS generation and enhanced mechanical effects is promising. In this study, carbon-doped zinc oxide nanoparticles (C-ZnO) are constructed for mechano-sonodynamic cancer therapy. The presence of carbon (C) doping optimizes the electronic structure, thereby enhancing the ROS generation triggered by US, efficiently inducing tumor cell death. On the other hand, the high specific surface area and porous structure brought about by C doping enable C-ZnO to enhance the mechanical stress induced by cavitation bubbles under US irradiation, causing severe mechanical damage to tumor cells. Under the dual effects of sonodynamic therapy (SDT) and mechanical therapy mediated by C-ZnO, excellent anti-tumor efficacy is demonstrated both in vitro and in vivo, along with a high level of biological safety. This is the first instance of utilizing an inorganic nanomaterial to achieve simultaneous enhancement of ROS production and US-induced mechanical effects for cancer therapy. This holds significant importance for the future development of novel sonosensitizers and advancing the applications of US in cancer treatment.

Effect of ultrasonic degradation on the physicochemical characteristics, GLP-1 secretion, and antioxidant capacity of Polygonatum cyrtonema polysaccharide

This study aimed to evaluate the influence of ultrasonic degradation on the physicochemical and biological characteristics of Polygonatum cyrtonema polysaccharide (PCP, 8.59 kDa). PCP was subjected to ultrasonic treatment for 8, 16, and 24 h and yielded the degraded fractions PCP-8, PCP-16, and PCP-24 (5.06, 4.13, and 3.69 kDa), respectively. Compared with the intact PCP, PCP-8, PCP-16 and PCP-24 had a reduced particle size (decrements of 28.03 %, 46.15 % and 62.54 %, respectively). Although ultrasonic degradation did not alter the primary structure of PCP, its triple helical and superficial structures were disrupted, with degraded fractions demonstrating reduced thermal stability and apparent viscosities compared with those of the intact PCP. Furthermore, the functional properties of the degraded fractions were different. PCP-16 most favourably affected GLP-1 secretion, while PCP-8 and PCP-24 exhibited the strongest antioxidant and enzyme inhibitory activities, respectively. Hence, controlled ultrasound irradiation is an appealing approach for partially degrading PCP and enhancing its bioactivity as a functional agent.

Sonodynamic and sonomechanical effect on cellular stemness and extracellular physicochemical environment to potentiate chemotherapy

BackgroundHypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP.ResultsA HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness.ConclusionsThis work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.Graphical

Microbubble detection on ultrasound imaging by utilizing phase patterned waves

Objective. Super-resolution ultrasonography offers the advantage of visualization of intricate microvasculature, which is crucial for disease diagnosis. Mapping of microvessels is possible by localizing microbubbles (MBs) that act as contrast agents and tracking their location. However, there are limitations such as the low detectability of MBs and the utilization of a diluted concentration of MBs, leading to the extension of the acquisition time. We aim to enhance the detectability of MBs to reduce the acquisition time of acoustic data necessary for mapping the microvessels. Approach. We propose utilizing phase patterned waves (PPWs) characterized by spatially patterned phase distributions in the incident beam to achieve this. In contrast to conventional ultrasound irradiation methods, this irradiation method alters bubble interactions, enhancing the oscillation response of MBs and generating more significant scattered waves from specific MBs. This enhances the detectability of MBs, thereby enabling the detection of MBs that were undetectable by the conventional method. The objective is to maximize the overall detection of bubbles by utilizing ultrasound imaging with additional PPWs, including the conventional method. In this paper, we apply PPWs to ultrasound imaging simulations considering bubble–bubble interactions to elucidate the characteristics of PPWs and demonstrate their efficacy by employing PPWs on MBs fixed in a phantom by the experiment. Main results. By utilizing two types of PPWs in addition to the conventional ultrasound irradiation method, we confirmed the detection of up to 93.3% more MBs compared to those detected using the conventional method alone. Significance. Ultrasound imaging using additional PPWs made it possible to increase the number of detected MBs, which is expected to improve the efficiency of bubble detection.

Echogenic Gold Nanorod Incorporated Hybrid Poly(2-oxazoline) Nanocapsules for Real-Time Ultrasound/Fluorescent Imaging and Targeted Cancer Theranostics.

In recent years, various nanocarrier systems have been explored to enhance the targeting of cancer cells by improving the ligand-receptor interactions between the nanocarrier and cancer cells for selective cancer cell imaging and targeted delivery of anticancer drugs. Herein, we report multifunctional hydrogen-bonded multilayer nanocapsules functionalized with both folic acid-derived quantum dots (FAQDs) and gold nanorods (AuNRs) for targeted cancer therapy and cancer cell imaging using fluorescence microscopy and medical-range ultrasound imaging systems. The encapsulation efficiency of nanocapsules was found to be 49% for 5-fluorouracil (5-FU). The release percentage reached a plateau at 37% after 1 h at pH 7.4 and increased to 57% after 3 h when the release pH was decreased to pH 5.5 (i.e., the pH of the tumor environment). Under ultrasound irradiation, the release was significantly accelerated, with a total release of 52% and 68% after only 6 min at pH 7.4 and pH 5.5, respectively. While the sonoporation process plays an important role in anticancer activity experiments under ultrasound exposure by generating temporary pores, the targeting ability of FAQDs brings the capsules closer to the cell membrane and improves the cellular uptake of the released drug, thereby increasing local drug concentration. In vitro cytotoxicity experiments with HCT-116 and HEp-2 cells demonstrated anticancer activities of 96% and 98%, respectively. The nanocapsules showed enhanced ultrasound scattering signal intensity and bright spots under ultrasound exposure, most likely caused by high scattering ability and internal reflections of preloaded AuNRs in the interior structure of the nanocapsules. Hence, the demonstrated nanocapsule system not only has the potential to be used as an integrated system for early- stage detection and treatment of cancer cells but also has the ability for live tracking and imaging of cancer cells while undergoing treatment with chemotherapy and radiation therapy.

Sono‐Triggered Cascade Lactate Depletion by Semiconducting Polymer Nanoreactors for Cuproptosis‐Immunotherapy of Pancreatic Cancer

AbstractThe high level of lactate in tumor microenvironment not only promotes tumor development and metastasis, but also induces immune escape, which often leads to failures of various tumor therapy strategies. We here report a sono‐triggered cascade lactate depletion strategy by using semiconducting polymer nanoreactors (SPNLCu) for cancer cuproptosis‐immunotherapy. The SPNLCu mainly contain a semiconducting polymer as sonosensitizer, lactate oxidase (LOx) conjugated via a reactive oxygen species (ROS)‐cleavable linker and chelated Cu2+. Upon ultrasound (US) irradiation, the semiconducting polymer generates singlet oxygen (1O2) to cut ROS‐cleavable linker to allow the release of LOx that catalyzes lactate depletion to produce hydrogen peroxide (H2O2). The Cu2+ will be reduced to Cu+ in tumor microenvironment, which reacts with the produced H2O2 to obtain hydroxyl radical (⋅OH) that further improves LOx release via destroying ROS‐cleavable linkers. As such, sono‐triggered cascade release of LOx achieves effective lactate depletion, thus relieving immunosuppressive roles of lactate. Moreover, the toxic Cu+ induces cuproptosis to cause immunogenic cell death (ICD) for activating antitumor immunological effect. SPNLCu are used to treat both subcutaneous and deep‐tissue orthotopic pancreatic cancer with observably enhanced efficacy in restricting the tumor growths. This study thus provides a precise and effective lactate depletion tactic for cancer therapy.

Sono-Triggered Cascade Lactate Depletion by Semiconducting Polymer Nanoreactors for Cuproptosis-Immunotherapy of Pancreatic Cancer.

The high level of lactate in tumor microenvironment not only promotes tumor development and metastasis, but also induces immune escape, which often leads to failures of various tumor therapy strategies. We here report a sono-triggered cascade lactate depletion strategy by using semiconducting polymer nanoreactors (SPNLCu) for cancer cuproptosis-immunotherapy. The SPNLCu mainly contain a semiconducting polymer as sonosensitizer, lactate oxidase (LOx) conjugated via a reactive oxygen species (ROS)-cleavable linker and chelated Cu2+. Upon ultrasound (US) irradiation, the semiconducting polymer generates singlet oxygen (1O2) to cut ROS-cleavable linker to allow the release of LOx that catalyzes lactate depletion to produce hydrogen peroxide (H2O2). The Cu2+ will be reduced to Cu+ in tumor microenvironment, which reacts with the produced H2O2 to obtain hydroxyl radical (⋅OH) that further improves LOx release via destroying ROS-cleavable linkers. As such, sono-triggered cascade release of LOx achieves effective lactate depletion, thus relieving immunosuppressive roles of lactate. Moreover, the toxic Cu+ induces cuproptosis to cause immunogenic cell death (ICD) for activating antitumor immunological effect. SPNLCu are used to treat both subcutaneous and deep-tissue orthotopic pancreatic cancer with observably enhanced efficacy in restricting the tumor growths. This study thus provides a precise and effective lactate depletion tactic for cancer therapy.