A Phase Engineering Strategy of Perovskite-Type ZnSnO3:Nd for Boosting the Sonodynamic Therapy Performance

The sensitization performance of sonosensitizers plays a key role in the sonodynamic therapy (SDT) effect. Herein, ZnSnO₃:Nd nanoparticles with R3c phase/amorphous heterogeneous structure are developed by phase engineering strategy and applied as an ideal sonosensitizer. In the crystalline perovskite-type ZnSnO₃:Nd, the substitution of the Zn²⁺ with Nd³⁺ causes the O 2p non-bonded state to move toward the Fermi level, which optimizes the band structure for ultrasound sensitization by reducing bandgap. Meanwhile, the unequal charge substitution can also form electron traps and oxygen vacancies to shorten the electron migration distance, which accelerates the electron–hole separation and inhibits carrier recombination, thus improving the acoustic sensitivity. Moreover, the dangling bonds exposed on the surface of amorphous ZnSnO₃:Nd provide more active sites, and the localized states of the amorphous phase may also promote carrier separation, resulting in synergistic SDT effect. In particular, the Zn²⁺ released from ZnSnO₃:Nd in the acidic tumor microenvironment (TME) reduces the adenosine triphosphate production by inhibiting the electron transport chain , which promotes the tumor cell apoptosis through destroying the redox balance of TME. Combining the inherent second near infrared and computed tomography imaging capabilities, this ZnSnO₃:Nd nanoplatform shows a promising perspective in clinic SDT field.     

压电半导体纳米材料在声动力疗法中的应用进展

随着纳米医学的发展, 利用纳米材料在外源超声波的刺激下催化产生过量的活性氧物种(Reactive Oxygen Species, ROS)以治疗疾病的方法, 被称为声动力疗法(Sonodynamic Therapy, SDT), 已引起人们的广泛关注。目前, 开发可用于SDT的高效声敏剂用于提高ROS产率, 仍然是当前研究和未来临床转化的最大挑战之一。近年来, 得益于压电电子学和压电光电子学的兴起, 基于压电半导体纳米材料的新型声敏剂在SDT中崭露头角, 显示出良好的应用前景。本文从压电半导体的结构出发, 介绍了压电半导体纳米材料应用于SDT的机理研究, 以及利用压电半导体纳米材料作为声敏剂在声动力学癌症治疗及相关抗菌性能方面所取得的研究进展。最后, 本文对该领域存在的问题以及未来的发展趋势进行了展望。     

Fe(III)‐Porphyrin Sonotheranostics: A Green Triple‐Regulated ROS Generation Nanoplatform for Enhanced Cancer Imaging and Therapy

To address the urgent need for effective sonodynamic therapy (SDT), a facile and efficient strategy is developed for fabricating a new class of sonotheranostics. Herein, a Fe(III)‐porphyrin nano‐sonosensitizer is prepared by a one‐step coordination synthesis, and then anchored with Bis(DPA‐Zn)‐RGD and manganese superoxide dismutase (SOD2) siRNA. Benefiting from the delicate interactions of the Fe(III)‐coordinated nanoformulations, a highly potent sono/gene combinational therapy guided by fluorescence/magnetic resonance imaging is achieved. Importantly, this sonotheranostics significantly enhances the SDT effect of porphyrin through the cancer‐targeted delivery capability and enhanced reactive oxygen species production via triple‐regulated approaches, including down‐regulation of SOD2, depletion of glutathione, and generation of Fenton reaction. This work opens up new perspectives for developing versatile sonotheranostics to overcome the clinical challenges of SDT.     

Ultrasound-Responsive Microneedles Eradicate Deep-Layered Wound Biofilm Based on TiO2 Crystal Phase Engineering

Wound biofilm infection has an inherent resistance to antibiotics, requiring physical debridement combined with chemical reagents or antibiotics in clinical treatment, but it is invasive and may exist as incomplete debridement. So, a new type of noninvasive and efficient treatment is needed to address this problem. Here, the crystal phase engineering of TiO₂ is presented to explore the sonocatalytic properties of TiO₂ nanoparticles with different phases, and find that the anatase-brookite TiO₂ (AB) has the best antibacterial efficiency of 99.94% against S. aureus under 15 min of ultrasound (US) irradiation. The type II homojunction of AB not only enhances the adsorption and decreases the activation energy of O₂, respectively, but also has a great interfacial charge transfer efficiency under US, which can produce more reactive oxygen species than other types of TiO₂. The microneedles (MN) penetrate the biofilm in wound tissue and quickly disperse the loaded AB into the biofilm because the ultrasonic cavitation accelerates the dissolution of microneedles, which non-invasively and efficiently eradicates the deep-layered biofilm under US. This work explores the relationship between the phase composition of TiO₂ and sonocatalytic property for the first time, and provides a new treatment strategy for wound biofilm infection through US-assisted microneedles therapy.     

A New Sono-Chemo Sensitizer Overcoming Tumor Hypoxia for Augmented Sono/Chemo-Dynamic Therapy and Robust Immune-Activating Response

Novel sonosensitizers with intrinsic characteristics for tumor diagnosis, efficient therapy, and tumor microenvironment regulation are appealing in current sonodynamic therapy. Herein, a manganese (Mn)-layered double hydroxide-based defect-rich nanoplatform is presented as a new type of sono-chemo sensitizer, which allows ultrasound to efficiently trigger reactive oxygen species generation for enhanced sono/chemo-dynamic therapy. Moreover, such a nanoplatform is able to relieve tumor hypoxia and achieve augmented singlet oxygen production via catalyzing endogenous H₂O₂ into O₂. On top of these actions, the released Mn²⁺ ions and immune-modulating agent significantly intensify immune activation and reverse the immunosuppressive tumor microenvironment to the immunocompetent one. Consequently, this nanoplatform exhibits excellent anti-tumor efficacy and effectively suppresses both primary and distant tumor growth, demonstrating a new strategy to functionalize nanoparticles as sono-chemo sensitizers for synergistic combination cancer therapy.     

Enhanced Sonodynamic Cancer Therapy through Iron-Doping and Oxygen-Vacancy Engineering of Piezoelectric Bismuth Tungstate Nanosheets

Sonodynamic therapy (SDT) is regarded as a new-rising strategy for cancer treatment with low invasiveness and high tissue penetration, but the scarcity of high-efficiency sonosensitizers has seriously hindered its application. Herein, the iron-doped and oxygen-deficient bismuth tungstate nanosheets (BWO-Fe NSs) with piezotronic effect are synthesized for enhanced SDT. Due to the existence of oxygen defects introduced through Fe doping, the bandgap of BWO-Fe is significantly narrowed so that BWO-Fe can be more easily activated by exogenous ultrasound (US). The oxygen defects acting as the electron traps inhibit the recombination of US-induced electrons and holes. More importantly, the dynamically renewed piezoelectric potential facilitates the migration of electrons and holes to opposite side and causes energy band bending, which further promotes the production of reactive oxygen species. Furthermore, Fe doping endows BWO-Fe with Fenton reactivity, which converts hydrogen peroxide (H₂O₂) in tumor microenvironment into hydroxyl radicals (•OH), thereby amplifying the cellular oxidative damage and enhancing SDT. Both in vitro and in vivo experiments illustrate their high cytotoxicity and tumor suppression rate against refractory breast cancer in mice. This work may provide an alternative strategy to develop oxygen-deficient piezoelectric sonosensitizers for enhanced SDT via doping metal ions.     

Synergistic Sonodynamic/Chemotherapeutic Suppression of Hepatocellular Carcinoma by Targeted Biodegradable Mesoporous Nanosonosensitizers

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide featured with the poor prognosis and high mortality in affected patients. Given its insensitivity to conventional systemic chemotherapy, the development of novel modalities for HCC management is highly urgent. Sonodynamic therapy (SDT) has gained considerable momentum in cancer therapy. Especially, through synergistic SDT/chemotherapy, SDT would enhance the chemotherapeutic process on inhibiting tumor growth, which holds great potential on combating HCC. In this work, we report on the design/fabrication of targeted biodegradable nanosonosensitizers based on hollow mesoporous organosilica nanoparticles (HMONs), followed by pore‐engineering including covalent anchoring of protoporphyrin (PpIX, HMONs‐PpIX) and conjugation of arginine‐glycine‐aspartic acid in order to specifically targeting HCC cells. Such nanosonosensitizers provide efficient loading and controllable stimuli‐responsive release of chemotherapeutic agents for HCC‐targeting chemotherapy, thus promoting an enhancing chemotherapeutic process via the unique sonotoxicity under ultrasound irradiation. The HMONs matrix with biologically active organic groups in the framework (disulfide bond) are endowed with intrinsic tumor microenvironment‐responsive biodegradability and improved biocompatibility/biosafety. In particular, a synergistic inhibition effect of drug‐loaded HMONs‐PpIX‐arginine‐glycine‐aspartic acid on HCC growth has been systematically demonstrated both in vitro and in vivo (84.7% inhibition rate), which brings insights and meets the versatile therapeutic requirements for HCC management.     

Metalloporphyrin MOFs-Based Nanoagent Enabling Tumor Microenvironment Responsive Sonodynamic Therapy of Intracranial Glioma Signaled by NIR-IIb Luminescence Imaging

Noninvasive sonodynamic therapy (SDT) shows promise for brain glioma treatment due to deep tissue-penetrating capabilities (>10 cm) of ultrasound and high spatial resolutions. Yet, this technique is hindered by inefficient production of reactive oxygen species (ROS), resulting from the hypoxic tumor microenvironment (TME), high level of ROS scavenger glutathione (GSH), and the inability to visualize glioma in vivo for precise treatment management and monitoring in current sonosentizers. To address these challenges, we fabricated a core-shell heterostructure sonosensitizer (labeled as DFM), in which meso-tetra (4-carboxyphenyl) porphine (TCPP) porphyrin metal-organic frameworks (MOF, PCN-224(Fe)) serve as a porous shell to contain approved chemotherapeutics sorafenib (SRF) to effectively inhibit GSH synthesis, while NaErF₄:Yb@NaLuF₄ nanoparticles as the core provide TME-responsive NIR IIb (≈1500–1800 nm) luminescence at 1525 for precise optical imaging. Coordination of Fe³⁺ into the macrocycle of TCPP at the MOFs shell is found to, besides triggering ferroptosis, reduce TCPP phosphorescence (23% decrease) and increase the triplet state (T₁) oxygen quenching, substantially promoting the singlet oxygen generation (2.6-fold increase). Furthermore, GSH in TME facilitates the reduction of Fe³⁺ to Fe²⁺, thereby eliminating the luminescence quenching of Fe³⁺ and augmenting the NIR IIb luminescence of Er³⁺ (5-fold increase) for nanoagents accumulation imaging in intracranial glioma, realizing dynamical monitoring of SDT processes. Compared to control groups, in vitro and in vivo experiments confirm the effective ROS generation and results in a 6-fold volume reduction of brain gliomas, reaching a survival rate of 80% at 30 days posttreatment.     

The Synergistic Effects of Multidrug-Loaded Nanocarriers Improve Tumor Microenvironment Responsive Chemo-Sonodynamic Therapy of Hepatocellular Carcinoma

Chemotherapy works synergistically with sonodynamic therapy in a multi-functional system and is employed to improve the therapeutic outcomes of hepatocellular carcinoma. In this study, ultrasound-responsive multi-functional nanoparticles (USFNPs) are loaded with dual drugs, doxorubicin, and a composite ultrasound-sensitive agent, curcumin-gold. The USFNPs are modified with an acid-hydrolyzable polyethylene glycol outermost layer, making it stable in blood and normal tissues while peeling off in the acidic tumor microenvironment. The USFNPs have high specificity to liver tumor cells (Hepa 1–6 cells); can escape from lysosomes following endocytosis, and exhibit better biocompatibility. Moreover, the carriers enhance the nuclear delivery of the drugs and inhibit p-glycoprotein (P-gp) expression of Hepa 1–6 cells. In cancer cells, carriers convert hydrogen peroxide into oxygen, improving the hypoxic microenvironment and generating abundant superoxide anion and hydroxyl radicals. Confocal laser scanning microscopy, ¹H nuclear magnetic resonance, flow cytometry, cytotoxicity, acute toxicity assays, and Western blot analysis are used to demonstrate the results. The findings suggest USFNPs as novel and potential antitumor agents for treating hepatocellular carcinoma.     

Metal–Organic‐Framework‐Derived Carbon Nanostructure Augmented Sonodynamic Cancer Therapy

Sonodynamic therapy (SDT) can overcome the critical issue of depth‐penetration barrier of photo‐triggered therapeutic modalities. However, the discovery of sonosensitizers with high sonosensitization efficacy and good stability is still a significant challenge. In this study, the great potential of a metal–organic‐framework (MOF)‐derived carbon nanostructure that contains porphyrin‐like metal centers (PMCS) to act as an excellent sonosensitizer is identified. Excitingly, the superior sonosensitization effect of PMCS is believed to be closely linked to the porphyrin‐like macrocycle in MOF‐derived nanostructure in comparison to amorphous carbon nanospheres, due to their large highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) gap for high reactive oxygen species (ROS) production. The nanoparticle‐assisted cavitation process, including the visualized formation of the cavitation bubbles and microjets, is also first captured by high‐speed camera. High ROS production in PMCS under ultrasound is validated by electron spin resonance and dye measurement, followed by cellular destruction and high tumor inhibition efficiency (85%). This knowledge is important from the perspective of understanding the structure‐dependent SDT enhancement of a MOF‐derived carbon nanostructure.