Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), has limited clinical application due to severe side effects and drug resistance. To overcome these challenges, we developed a bismuth-based nanomaterial (BOS) for thermal injury-assisted continuous targeted therapy in HCC. Initially, the mesoporous nanomaterial was loaded with SOR, forming the BOS@SOR nano-carrier system for drug delivery and controlled release. Notably, compared to targeted or photothermal therapy alone, the combination therapy using this nano-carrier system significantly impaired cell proliferation and increased apoptosis. In vivo efficacy evaluations demonstrated that BOS@SOR exhibited excellent biocompatibility, confirmed through hemolysis and biochemical analyses. Additionally, BOS@SOR enhanced contrast in computed tomography, aiding in the precise identification of HCC size and location. The photothermal therapeutic properties of bismuth further contributed to the synergistic anti-tumor activity of BOS@SOR, significantly reducing tumor growth in an orthotopic xenograft HCC model. Taken together, encapsulating SOR within a bismuth-based mesoporous nanomaterial creates a multifunctional and environmentally stable nanocomposite (BOS@SOR), enhancing the therapeutic effect of SOR and presenting an effective strategy for HCC treatment.

Ferroptosis-mediated tumor treatment is constrained by the absence of single-component, activatable multifunctional inducers. Given this, a topological synthesis strategy is employed to develop an efficient bismuth-based semiconductor nano-photocatalyst (Bi2O3:S) for tumor ferroptosis therapy. Photo-excited electrons can participate in the reduction reaction to produce harmful reactive oxygen species (ROS) when exposed to near-infrared light. Meanwhile, photo-excited holes can contribute to the oxidation reaction to utilize extra glutathione (GSH) in tumors. In the acidic tumor microenvironment, bismuth ions generated from Bi2O3:S may further cooperate with GSH to amplify oxidative stress damage and achieve biodegradation. Both promote ferroptosis by downregulating glutathione peroxidase 4 (GPX4) expression. Besides, sulfur doping optimizes its near-infrared light-induced photothermal conversion efficiency, benefiting its therapeutic effect. Thus, bismuth ions and holes synergistically drive photo-activable ferroptosis in this nanoplatform, opening up new avenues for tumor therapy.

Sonodynamic tumor therapy is limited by inefficient sonosensitizers and complex tumor microenvironments. Given this, a concept of metal-sensitized sonocatalyst is proposed and defined as a catalyst based on the metal sensitization effect of noble metals to advance semiconductor sonocatalytic activity. We load Au nanorods onto wide-bandgap semiconductor bismuth oxide to favor its sonocatalytic properties for supporting the concept's practicality. In the catalytic nano-system, Au nanorods improve the ability of bismuth oxide to separate electrons and holes under ultrasound, promoting multifarious reactive oxygen species (ROS) generation and enhancing the photothermal effect. Synergistically, bismuth oxide can consume intratumoral overexpressed glutathione, further disrupting the redox balance. Thus, ROS and heat can directly induce immunogenic cell death, reversing tumor immunosuppressive microenvironment in concert and promoting dendritic cell maturation and CD8+ T cell infiltration. The proposed metal-sensitized sonocatalyst will open up new avenues for sonocatalytic therapy.

Sonodynamic therapy (SDT) represents a promising, noninvasive, and precise treatment modality for tumors, demonstrating significant potential in clinical applications. However, the efficiency of sonosensitizers in generating reactive oxygen species (ROS) is often limited by rapid electron-hole recombination. In this study, BiF 3 @BiOI is synthesized via a co-precipitation method, followed by in-situ reduction to decorate it with Pt nanoparticles, resulting in BiF 3 @BiOI@Pt-PVP (BBP) nanocomposite for enhancing SDT efficacy. The formation of the BiF 3 @BiOI heterojunction enhances charge separation ability. The decoration of Pt nanoparticles narrows the bandgap and alters the band positions and Fermi level of BBP, which can effectively mitigate the rapid recombination of electron-hole pairs and facilitate a cascade reaction of ROS, thereby improving ROS generation efficiency with ultrasound excitation. Additionally, bismuth ions in BBP and the generated holes consume glutathione, exacerbating cellular oxidative damage, and triggering PANoptosis and ferroptosis. Furthermore, Pt nanoparticles demonstrate peroxidase-like activity, catalyzing endogenous hydrogen peroxide to oxygen. These functions are helpful against tumors for alleviating hypoxic conditions, reshaping the microenvironment, modulating immune cell infiltration capacity, and enhancing the efficacy of immunotherapy. The dual strategy of forming heterojunctions and sensitization with noble metals effectively enhances the efficacy of sono-catalytic therapy-induced immune activation in tumor treatment.

Sonodynamic therapy (SDT) is a minimally invasive therapeutic approach that utilizes sonosensitizers to catalyze substrates and generate reactive oxygen species (ROS) under ultrasound stimulation, ultimately inducing tumor cell death. Enhancing the piezoelectric properties of nanomaterials and modulating the semiconductor energy band are effective strategies to improve the catalytic efficiency of sonosensitizers. In this study, we developed a two-dimensional (2D) copper-based piezoelectric metal-organic framework (MOF) sonosensitizer, denoted as CM, through the coordination of copper and dimethylimidazole. The unique 2D MOF structure imparts CM with piezoelectric characteristics, enabling it to enhance SDT efficacy by modulating the semiconductor bandgap and carrier mobility. Upon ultrasound irradiation, CM catalyzes oxygen to undergo a cascade reaction, producing highly toxic singlet oxygen. Additionally, cupric ions in CM can be reduced by glutathione, facilitating the spontaneous catalysis of hydrogen peroxide in tumors to generate hydroxyl radicals and deplete glutathione, thereby inducing oxidative damage. Moreover, cupric ions in CM can trigger tumor cell cuproptosis, which, in combination with the generated ROS, accelerates cell death. Thus, this study establishes a MOF-based system for controllably inducing multi-pathway cancer cell death and provides a foundation for enhancing ultrasound-catalyzed tumor therapy through the optimization of piezoelectric properties.

Chemotherapeutic agents hold significant clinical potential in combating tumors. However, delivering these drugs to the tumor site for controlled release remains a crucial challenge. In this study, we synthesize and construct a glutathione (GSH) and acid dual-responsive bismuth-based nano-delivery platform (BOD), aiming for sonodynamic enhancement of docetaxel (DTX)-mediated tumor therapy. The bismuth nanomaterial can generate multiple reactive oxygen species under ultrasound stimulation. Furthermore, the loading of DTX to form BOD effectively reduces the toxicity of DTX in the bloodstream, ensuring its cytotoxic effect is predominantly exerted at the tumor site. DTX can be well released in high expression of GSH and acidic tumor microenvironment. Meanwhile, ultrasound can also promote the release of DTX. Results from both in vitro and in vivo experiments substantiate that the synergistic therapy involving chemotherapy and sonodynamic therapy significantly inhibits the growth and proliferation of tumor cells. This study provides a favorable paradigm for developing a synergistic tumor treatment platform for tumor microenvironment response and ultrasound-promoted drug release.

Ultrasound and X-rays possess remarkable tissue penetration capabilities, making them promising candidates for cancer therapy. Sonodynamic therapy, which utilizes ultrasound excitation, offers a safer alternative to radiotherapy and can be combined with X-rays to mitigate the adverse effects on normal tissues. In this study, we developed a bismuth-based heterostructure semiconductor (BFIP) to enhance the efficacy of radiotherapy and sonodynamic therapy in treating breast cancer. The semiconductor is fabricated through a two-step process involving the synthesis of porous spherical bismuth fluoride and partially reduced to bismuth oxyiodide. Then, followed by surface modification with amphiphilic polyethylene glycol, BFIP is fabricated. Incorporating heavy atoms in the BFIP enhances radiosensitivity. The BFIP exhibits superior carrier separation efficiency compared to bismuth fluoride, generating a substantial quantity of reactive oxygen species upon ultrasound stimulation. Moreover, the BFIP effectively depletes glutathione through coordination and hole-mediated oxidation pathways, disrupting the tumor microenvironment and inducing oxidative stress. Encouraging results are acquired in both in vitro cell and in vivo tumor models. Our study provides a de-risking strategy by utilizing ultrasound as a partial substitute for X-rays in treating deep-seated tumors, offering a viable research direction for constructing a unified nanoplatform.

The therapeutic efficacy of monotherapy on tumors is often limited due to the constraints of tumor response conditions, significantly impacting clinical treatment outcomes. In this study, we design a collaborative therapeutic nanosystem (BBSP) that combines photodynamic therapy (PDT) and photothermal therapy (PTT). The system is formulated by doping sulfur ions to modulate wide band gap BiF3 semiconductor nanospheres. The introduction of sulfur and its combination with bismuth not only enhance light absorption but also introduce oxygen vacancies and the local surface plasmon resonance effect of bismuth. Compared with BiF3, the band gap is reduced and the carrier separation efficiency is improved. Under the irradiation of a 520 nm laser, electrons reduce oxygen in the process of transition and meanwhile give energy to O-2, producing a large number of reactive oxygen species (ROS). Simultaneously, holes in the valence band oxidize glutathione (GSH), and the coordination effect of the bismuth ion and GSH further depletes GSH. RNA sequencing results reveal the downregulation of GPX4 in tumor cells, inducing ferroptosis. Additionally, sulfide ion doping augmented light absorption, synergizing with light and heat, thereby increasing oxidative damage to the tumor and inhibiting tumor growth. BBSP emerges as a promising strategy for tumor treatment, orchestrating ferroptosis and apoptosis through the combined application of PDT and PTT.

Exogenous stimuli-activated catalytic therapies for cancer, such as photodynamic therapy, have significant clinical potential. Despite the recent progress, the low catalytic production efficiency of reactive oxygen species (ROS) and the overexpression of glutathione (GSH) in the tumor microenvironment (TME) are major challenges for exogenous stimulative catalytic therapy. Bismuth-based heterojunction nanomaterials can generate ROS under various exogenous stimuli. Based on this, we developed an exogenously excited bismuth-based heterojunction nanocatalyst Bi-Bi2O3-xSx-PEG (BOP) for the photocatalytic treatment of tumors with photothermal synergism. The high photocatalytic activity of BOP is attributed to its heterojunction structure, oxygen vacancy, and local surface plasmon resonance effect, which enable suitable band potential and rapid electron transfer. The GSH consumption characteristic of BOP in TME can also enhance oxidative stress damage, amplify the toxicity of ROS, and induce cell apoptosis. BOP's remarkable photothermal conversion ability contributes to local hyperthermia and synergistic enhancement of photodynamic efficacy. This platform provides a method for constructing an efficient photocatalyst and a strategy for synergistically enhancing photocatalytic therapy by thermal damage and oxidative stress.

The physical property tuning of nanomaterials is of great importance in energy, medicine, environment, catalysis, and other fields. Topochemical synthesis of nanomaterials can achieve precise control of material properties. Here, we synthesized a kind of element-doped bismuth-based nanomaterial (BOS) by topochemical-like synthesis and used it for the phototherapy of tumors. In this study, we employed bismuth fluoride nanoflowers as a template and fabricated element-doped bismuth oxide nanoflowers by reduction conditions. The product is consistent with the precursor in crystal structure and nanomorphology, realizing topochemical-like synthesis under mild conditions. BOS can generate reactive oxygen species, consume glutathione, and perform photothermal conversion under 730 nm light irradiation. In vitro and in vivo studies demonstrate that BOS could suppress tumor growth by inducing apoptosis and ferroptosis through phototherapy. Therefore, this study offers a general regulation method for tuning the physical properties of nanomaterials by using a topochemical-like synthesis strategy.

Non-invasive precision tumor dynamic phototherapy has broad application prospects. Traditional semiconductor materials have low photocatalytic activity and low reactive oxygen species (ROS) production rate due to their wide band gap, resulting in unsatisfactory phototherapy efficacy for tumor treatment. Employing the dye -sensitization mechanism can significantly enhance the catalytic activity of the materials. We develop a multifunctional nanoplatform (BZP) by leveraging the benefits of bismuth -based semiconductor nanomaterials. BZP possesses robust ROS generation and remarkable near -infrared photothermal conversion capabilities for improving tumor immune microenvironment and achieving superior phototherapy sensitization. BZP produces highly cytotoxic ROS species via the photocatalytic process and cascade reaction, amplifying the photocatalytic therapy effect. Moreover, the simultaneous photothermal effect during the photocatalytic process facilitates the improvement of therapeutic efficacy. Additionally, BZP-mediated phototherapy can trigger the programmed death of tumor cells, stimulate dendritic cell maturation and T cell activation, modulate the tumor immune microenvironment, and augment the therapeutic effect. Hence, this study demonstrates a promising research paradigm for tumor immune microenvironment-improved phototherapy. Statement of significance Through the utilization of dye sensitization and rare earth doping techniques, we have successfully developed a biodegradable bismuth -based semiconductor nanocatalyst (BZP). Upon optical excitation, the near -infrared dye incorporated within BZP promptly generates free electrons, which, under the influence of the Fermi energy level, undergo transfer to BiF3 within BZP, thereby facilitating the effective separation of electron-hole pairs and augmenting the catalytic capability for reactive oxygen species (ROS) generation. Furthermore, a cascade reaction mechanism generates highly cytotoxic ROS, which synergistically depletes intracellular glutathione, thereby intensifying oxidative stress. Ultimately, this dual activation strategy, combining oxidative and thermal damage, holds significant potential for tumor immunotherapy. (c) 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In recent years, the research of bismuth chalcogenide (Bi2X3, X = O, S, Se, and Te) nanomaterials has expanded from the fields of optics, chemical, and electronic engineering to the biomedical, due to its easy preparation and modification, low cost, high stability, controllable morphology, and low toxicity. As an anti-magnetic heavy metal, Bi2X3 has various characteristics such as good X-ray attenuation coefficient, high near-infrared absorbance, excellent photothermal conversion efficiency, and photocatalytic performance, making it play an important role in diagnostic imaging, photothermal therapy, radiotherapy, synergistic therapy of cancer, antibacterial and biosensor. Bi2X3 can improve biocompatibility and other specific properties by simply modifying its surface to play the desired function. The good anti-tumor and anti-bacterial effects under near-infrared laser irradiation and the photocatalytic performance of biosensors are the main biomedical research fields of Bi2X3, which open opportunities for its future clinical transformation. In this review, we summarize the synthesis of Bi2X3 with different sizes, morphology, and composition and its application in the biomedical field. In addition, the current challenges and opportunities of Bi2X3 are also discussed.

Ultrasound-activated tumor catalytic therapy has great potential in clinical cancer treatment. However, the hypoxic and immunosuppressive tumor microenvironment impairs the efficacy of solid tumor treatment, leading to a high recurrence rate of metastatic cancer. Thus, reversing the tumor microenvironment remains a formidable challenge. To circumvent these critical issues, we employ ultrasound-activable carbon monoxide (CO) gas therapy and reactive oxygen species (ROS) production to trigger immunogenic cell death (ICD) and alleviate tumor hypoxia, achieving a combination of tumor therapy and reversal of immunosuppression to overcome the limitations of monotherapy and control tumor metastasis and recurrence. In brief, we first use copper sulfide (CuS) nanosheet as a highly efficient ultrasound-controllable catalytic nanomaterial, which can catalyze carbon dioxide, water, and oxygen to produce CO, oxygen, and ROS. Moreover, as a Fenton-like catalyst, it can catalyze hydrogen peroxide at tumor sites to generate ROS. The generated CO can attack mitochondria to accelerate their metabolism and produce more ROS, thus inducing ICD. In addition, the generation of oxygen can not only serve as the source of ROS, but it can also relieve tumor hypoxia and normalize the tumor immunosuppressive microenvironment. This results in the maturation of dendritic cells and the enhancement of T-lymphocyte recruitment and infiltration, further stimulating the antitumor immune response, mediating the regression of primary and distal tumors, and inhibiting lung metastasis. This in situ sono-activable catalytic therapy strategy minimizes the toxicity of CO and ROS leakage and provides a novel approach for designing new ICD inducers and improving therapeutic effects.

Photocatalytic therapy (PCT) is a minimally invasive technique that utilizes reactive oxygen species (ROS) to selectively and optically impair tumor cells. However, the limited efficacy of photocatalysts hinders their more comprehensive application. In this study, we successfully synthesized Ce and S-doped Bi2O3 (BOSC) nanosheets through topological synthesis. BOSC exhibits CAT-like and POD-like enzyme activities and can generate ROS and heat upon near-infrared light irradiation, thereby amplifying tumor oxidative stress. Introducing rare earth Ce element enhances light absorption, introduces oxygen vacancies, reduces bandgap, and facilitates charge separation. This Ce-doping also modifies the band position and Fermi level of BOSC, resulting in increased band bending at the solid-liquid interface, enabling a cascade reaction of ROS and enhancing ROS production. Additionally, BOSC demonstrates multiple enzyme activities by depleting GSH and catalyzing the production of ROS and O2 from endogenous H2O2, thereby exacerbating cellular oxidative damage. The synergistic effect of BOSC post-illumination induces panoptosis, thereby improving the therapeutic efficacy against tumors. This strategy, involving the modulation of band structure and band bending through ion doping to introduce oxygen defects into the photosensitizer, provides a viable approach to enhance tumor phototherapy.

Immunogenic cell death (ICD) can activate the body's immune system via dead cell antigens to achieve immunotherapy. Currently, small molecule drugs have been used for ICD treatment in clinical, however, how to precisely control the induced ICD while treating tumors is of great significance for improving therapeutic efficacy. Based on this, a sono/light dual response strategy to tumor therapy and activation of ICD is proposed. A topological synthesis method is used to obtain sulfur-doped bismuth oxide Bi2O3-xSx (BS) using BiF3 (BF) as a template through reduction and a morphology-controllable bismuth-based nano-semiconductor with a narrow bandgap is constructed. Under the stimulation of ultrasound, BS can produce reactive oxygen species (ROS) through the sonocatalytic process, which cooperates with BS to consume glutathione and enhance cellular oxidative damage, further inducing ICD. Due to the introduction of sulfur in the reduction reaction, BS can achieve photothermal conversion under light, and combine with ROS to treat tumors. Further, with the assistance of ivermectin (IVM) to form composite (BSM), combined with sono/light dual strategy, ICD is promoted and DCs maturation is accelerated. The proposed ICD-mediated hyperthermia/sonocatalytic therapy strategy will pay the way for synergetic enhancement of tumor treatment efficacy and provide a feasible idea for controllable induction of ICD.

As a noninvasive treatment, sonodynamic therapy (SDT) has been widely used in the treatment of tumors because of its ability to penetrate deep tissue with few side effects. As the key factor of SDT, it is meaningful to design and synthesize efficient sonosensitizers. Compared with organic sonosensitizers, inorganic sonosensitizers can be easily excited by ultrasound. In addition, inorganic sonosensitizers with stable properties, good dispersion, and long blood circulation time, have great development potential in SDT. This review summarizes possible mechanisms of SDT (sonoexcitation and ultrasonic cavitation) in detail. Based on these mechanisms, the design and synthesis of inorganic nanosonosensitizers can be divided into three categories: traditional inorganic semiconductor sonosensitizers, enhanced inorganic semiconductor sonosensitizers, and cavitation-enhanced sonosensitizers. Subsequently, the current efficient construction methods of sonosensitizers are summarized including accelerated semiconductor charge separation and enhanced production of reactive oxygen species through ultrasonic cavitation. Furthermore, the advantages and disadvantages of different inorganic sonosensitizers and detailed strategies are systematically discussed on how to enhance SDT. Hopefully, this review could provide new insights into the design and synthesis of efficient inorganic nano-sonosensitizers for SDT.

Stimuli-responsive catalytic therapy based on nano-catalysts has attracted much attention in the field of biomedicine for tumor therapy, due to its excellent and unique properties. However, the complex tumor microenvironment conditions and the rapid charge recombination in the catalyst limit catalytic therapy's effectiveness and further development. Effective heterojunction nanomaterials are constructed to address these problems to improve catalytic performance. Specifically, on the one hand, the band gap of the material is adjusted through the heterojunction structure to promote the charge separation efficiency under exogenous stimulation and further improve the catalytic capacity. On the other hand, the construction of a heterojunction structure can not only preserve the function of the original catalyst but also achieve significantly enhanced synergistic therapy ability. This review summarized the construction and functions of stimuli-responsive heterojunction nanomaterials under the excitation of X-rays, visible-near infrared light, and ultrasound in recent years, and further introduces their application in cancer therapy. Hopefully, the summary of stimuli-responsive heterojunction nanomaterials' applications will help researchers promote the development of nanomaterials in cancer therapy.

Nanothermometry could realize stable, efficient, and noninvasive temperature detection at the nanoscale. Unfortunately, most applications of nanothermometers are still limited due to their intricate synthetic process and low-temperature sensitivity. Herein, we reported a kind of novel bismuth-based upconversion nanomaterial with a fast and facile preparation strategy. The bismuth-based upconversion luminophore was synthesized by the co-precipitation method within 1 minute. By optimizing the doping ratio of the sensitizer Yb ion and the activator Er ion and adjusting the synthetic solvent strategy, the crystallinity of the nanomaterials was increased and the upconversion luminescence intensity was improved. Ratiometric upconversion optical measurements of temperature in the range of 278 K to 358 K can be achieved by ratiometric characteristic emission peaks of thermally sensitive Er ion. This method of rapidly constructing nanometer temperature probes provides a feasible strategy for the construction of novel fluorescent temperature probes.

Sonodynamic therapy is a noninvasive treatment method that generates reactive oxygen species (ROS) triggered by ultrasound, to achieve oxidative damage to tumors. However, methods are required to improve the efficiency of ROS generation and achieve continuous oxidative damage. A ternary heterojunction sonosensitizer composed of Bi@BiO2-x @Bi2 S3 -PEG (BOS) to achieve thermal injury-assisted continuous sonodynamic therapy for tumors is prepared. The oxygen vacancy in BOS can capture hot electrons and promotes the separation of hot carriers on the bismuth surface. The local electric field induced by localized surface plasmon resonance also contributes to the rapid transfer of electrons. Therefore, BOS not only possesses the functions of each component but also exhibits higher catalytic activity to generate ROS. Meanwhile, BOS continuously consumes glutathione, which is conducive to its biodegradation and achieves continuous oxidative stress injury. In addition, the photothermal conversion of BOS under near-infrared irradiation helps to achieve thermal tumor damage and further relieves tumor hypoxia, thus amplifying the sonodynamic therapeutic efficacy. This process not only provides a strategy for thermal damage to amplify the efficacy of sonodynamic therapy, but also expands the application of bismuth-based heterojunction nanomaterials as sonosensitizers in sonodynamic therapy.

Reactive oxygen species (ROS) damage is a crucial method with which to inhibit tumor cell proliferation; however, tumor cells can reduce ROS damage by modulating multiple repair mechanisms, thus, reducing the efficacy of ROS damage in tumor therapy. In this study, we built an ultrasound-triggered ROS damage nanoamplifier using a synergistic strategy consisting of ROS damage and decreased tumor self-protection capability to enhance the treatment efficacy of mutant p53 tumors. A ROS damage nanoamplifier (PT@PTGA) was fabricated using amphiphilic polyglutamic acid (PTGA) to load with a sonosensitizer (protoporphyrin IX, PpIX) and an MTH1 inhibitor (TH287). Under ultrasonic excitation, PpIX catalyzes oxygen to produce singlet oxygen and release TH287 to inhibit MTH1 activity, thereby causing the accumulation of 8-oxo-dGTP, which enhances DNA damage and further induces cell apoptosis. In addition, TH287 allies with ROS to eliminate the mutated p53 protein in tumor cells, thus reducing the self-protective capacity of tumor cells. As a result, the "internal and external" aspects were combined to enhance sensitization for mutant p53 tumor therapy. The construction of a ROS nanoamplifier not only provides an effective strategy for the treatment of mutant p53 tumors but also supplies an integrated platform for tumor diagnosis and therapy.