Defect-Engineered Tin Disulfide Nanocarriers as "Precision-Guided Projectile" for Intensive Synergistic Therapy.

Nanoformulations with endogenous/exogenous stimulus-responsive characteristics show great potential in tumor cell elimination with minimal adverse effects and high precision. Herein, an intelligent nanotheranostic platform (denoted as TPZ@Cu-SnS2-x /PLL) for tumor microenvironment (TME) and near-infrared light (NIR) activated tumor-specific therapy is constructed. Copper (Cu) doping and the resulting sulfur vacancies can not only improve the response range of visible light but also improve the separation efficiency of photogenerated carriers and increase the carrier density, resulting in the ideal photothermal and photodynamic performance. Density functional theory calculations revealed that the introduction of Cu and resulting sulfur vacancies can induce electron redistribution, achieving favorable photogenerated electrons. After entering cells through endocytosis, the TPZ@Cu-SnS2-x /PLL nanocomposites show the pH responsivity property for the release of the TPZ selectively within the acidic TME, and the released Cu2+ can first interact with local glutathione (GSH) to deplete GSH with the production of Cu+ . Subsequently, the Cu+ -mediated Fenton-like reaction can decompose local hydrogen peroxide into hydroxyl radicals, which can also be promoted by hyperthermia derived from the photothermal effect for tumor cell apoptosis. The integration of photoacoustic/computed tomography imaging-guided NIR phototherapy, TPZ-induced chemotherapy, and GSH-elimination/hyperthermia enhanced chemodynamic therapy results in synergistic therapeutic outcomes without obvious systemic toxicity in vivo.

CeO2 and Glucose Oxidase Co-Enriched Ti3C2Tx MXene for Hyperthermia-Augmented Nanocatalytic Cancer Therapy.

Foreseen as foundational in forthcoming oncology interventions are multimodal therapeutic systems. Nevertheless, the tumor microenvironment (TME), marked by heightened glucose levels, hypoxia, and scant concentrations of endogenous hydrogen peroxide could potentially impair their effectiveness. In this research, two-dimensional (2D) Ti3C2 MXene nanosheets are engineered with CeO2 nanozymes and glucose oxidase (GOD), optimizing them for TME, specifically targeting cancer therapy. Following our therapeutic design, CeO2 nanozymes, embodying both peroxidase-like and catalase-like characteristics, enable transformation of H2O2 into hydroxyl radicals for catalytic therapy while also producing oxygen to mitigate hypoxia. Concurrently, GOD metabolizes glucose, thereby augmenting H2O2 levels and disrupting the intracellular energy supply. When subjected to a near-infrared laser, 2D Ti3C2 MXene accomplishes photothermal therapy (PTT) and photodynamic therapy (PDT), additionally amplifying cascade catalytic treatment via thermal enhancement. Empirical evidence demonstrates robust tumor suppression both in vitro and in vivo by the CeO2/Ti3C2-PEG-GOD nanocomposite. Consequently, this integrated approach, which combines PTT/PDT and enzymatic catalysis, could offer a valuable blueprint for the development of advanced oncology therapies.

Mitochondria-targeting Cu3VS4 nanostructure with high copper ionic mobility for photothermoelectric therapy.

Thermoelectric therapy has emerged as a promising treatment strategy for oncology, but it is still limited by the low thermoelectric catalytic efficiency at human body temperature and the inevitable tumor thermotolerance. We present a photothermoelectric therapy (PTET) strategy based on triphenylphosphine-functionalized Cu3VS4 nanoparticles (CVS NPs) with high copper ionic mobility at room temperature. Under near-infrared laser irradiation, CVS NPs not only generate hyperthermia to ablate tumor cells but also catalytically yield superoxide radicals and induce endogenous NADH oxidation through the Seebeck effect. Notably, CVS NPs can accumulate inside mitochondria and deplete NADH, reducing ATP synthesis by competitively inhibiting the function of complex I, thereby down-regulating the expression of heat shock proteins to relieve tumor thermotolerance. Both in vitro and in vivo results show notable tumor suppression efficacy, indicating that the concept of integrating PTET and mitochondrial metabolism modulation is highly feasible and offers a translational promise for realizing precise and efficient cancer treatment.

Nanozyme: a rising star for cancer therapy.

In recent years, nanozymes have attracted enormous attention due to their effectiveness in promoting various catalytic reactions. To date, thousands of nanozymes have been discovered, including oxidase-like nanozymes, peroxidase-like nanozymes, and catalase-like nanozymes, covering noble metal, transition metal, and carbon nanomaterials. These nanozymes have been widely applied in various fields, including environmental protection, biosensing and nanomedicine. There are many reviews about this rising star being used in analytical chemistry. However, few works about nanozymes were related to cancer therapy. In this study, we comprehensively summarize the latest research advances on the strategies for cancer therapy based on different nanozymes. With traditional cancer treatment (including chemotherapy, radiotherapy, phototherapy), nanozyme catalytic therapy exhibited a synergistic effect for limiting the growth of tumors. Opportunities and trends for nanozymes in future cancer therapy are also discussed.

Theoretical simulation and experimental design of selenium and gold incorporated polymer-based microcarriers for ROS-mediated combined photothermal therapy.

Recently, multi-modal combined photothermal therapy (PTT) with the use of photo-active materials has attracted significant attention for cancer treatment. However, drug carriers enabling efficient heating at the tumor site are yet to be designed: this is a fundamental requirement for broad implementation of PTT in clinics. In this work, we design and develop hybrid carriers based on multilayer capsules integrated with selenium nanoparticles (Se NPs) and gold nanorods (Au NRs) to realize reactive oxygen species (ROS)-mediated combined PTT. We show theoretically and experimentally that cooperative interaction of Se NPs with Au NRs improves the heat release efficiency of the developed capsules. In addition, after uptake by tumor cells, intracellular ROS level amplified by Se NPs inhibits the tumor growth. As a consequence, the synergy between Se NPs and Au NRs exhibits the advantages of hybrid carriers such as (i) improved photothermal conversion efficiency and (ii) dual-therapeutic effect. The results of in vitro and in vivo experiments demonstrate that the combination of ROS-mediated therapy and PTT has a higher tumor inhibition efficiency compared to the single-agent treatment (using only Se-loaded or Au-loaded capsules). Furthermore, the developed hybrid carriers show negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys and spleen. This study not only provides a potential strategy for the design of multifunctional "all-in-one" carriers, but also contributes to the development of combined PTT in clinical practice.

"Electron Transport Chain Interference" Strategy of Amplified Mild-Photothermal Therapy and Defect-Engineered Multi-Enzymatic Activities for Synergistic Tumor-Personalized Suppression.

Arming activatable mild-photothermal therapy (PTT) with the property of relieving tumor thermotolerance holds great promise for overcoming traditional mild PTT limitations such as thermoresistance, insufficient therapeutic effect, and off-target heating. Herein, a mitochondria-targeting, defect-engineered AFCT nanozyme with enhanced multi-enzymatic activity was elaborately designed as a tumor microenvironment (TME)-activatable phototheranostic agent to achieve remarkable anti-tumor therapy via "electron transport chain (ETC) interference and synergistic adjuvant therapy". Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the AFCT nanozymes with excellent catalytic activity. In TME, open sources of H2O2 can be achieved by superoxide dismutase-mimicking AFCT nanozymes. In response to the dual stimuli of H2O2 and mild acidity, the peroxidase-mimicking activity of AFCT nanozymes not only catalyzes the accumulation of H2O2 to generate ·OH but also converts the loaded 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form with strong near-infrared absorption, specifically unlocking its photothermal and photoacoustic imaging properties. Intriguingly, the undesired thermoresistance of tumor cells can be greatly alleviated owing to the reduced expression of heat shock proteins enabled by NADH POD-mimicking AFCT-mediated NADH depletion and consequent restriction of ATP supply. Meanwhile, the accumulated ·OH can facilitate both apoptosis and ferroptosis in tumor cells, resulting in synergistic therapeutic outcomes in combination with TME-activated mild PTT.

Alternative Strategy to Optimize Cerium Oxide for Enhanced X-ray-Induced Photodynamic Therapy.

The emergence of X-ray-induced photodynamic therapy (X-PDT) holds tremendous promise for clinical deep-penetrating cancer therapy. However, the clinical application of X-PDT in cancer treatment is still limited due to the hypoxic property of cancerous tissue, the inherent antioxidant system of tumor cells, and the difficulty in matching the absorption spectra of photosensitizers. Herein, a versatile core-shell radiosensitizer (SCNPs@DMSN@CeOx-PEG, denoted as SSCP) was elaborately designed and constructed to enhance X-PDT by coating tunable mesoporous silica on nanoscintillators, followed by embedding the cerium oxide nanoparticles in situ. The obtained SSCP radiosensitizer demonstrated a distinct blue-shift in the ultraviolet light region, so that it could perfectly absorb the ultraviolet light converted by the SCNPs core, resulting in the formation of photoinduced electron-hole (e--h+) pairs separation to generate reactive oxygen species (ROS). In addition, the cerium oxide exhibits high glutathione consumption to heighten ROS accumulation, and catalase-like activity to alleviate the hypoxia, which further enhances the efficiency of radiotherapy. Benefiting from the abundant Lu and Ce elements, the computed tomography imaging performance of SSCP is about 3.79-fold that of the clinical contrast agent (iohexol), which has great potential in both preclinical imaging and clinical translation.

Combining Cobalt Ferrite Nanozymes with a Natural Enzyme to Reshape the Tumor Microenvironment for Boosted Cascade Enzyme-Like Activities.

Nanozymes with the merits of effective enzyme-mimic activities, tunable catalytic properties, pH/temperature tolerance, and high stability have been consumingly researched for nanocatalytic therapy. Herein, the union nanozymes and a natural enzyme nanoplatform (DMSN@CoFe2O4/GOD-PCM) are elaborately designed by simply depositing an ultrasmall cobalt ferrite (CoFe2O4) bimetallic oxide nanozyme and natural glucose oxidase (GOD) that are loaded into the aperture (∼12 nm) of dendritic mesoporous silica (DMSN) for near-infrared-II-enhanced tumor therapy. Upon irradiation, the hyperthermia generated by CoFe2O4 nanozymes unlocks the "gate" of phase-change material (PCM) for releasing GOD, which reshapes the specific tumor microenvironment (TME) through the glucose metabolism pathway. The resulting strengthened acid condition and a considerable amount of H2O2 efficiently initiate the cascade catalysis reactions. Moreover, highly toxic hydroxyl radicals are generated with a Co/Fe dual-cycle system of ultrasmall CoFe2O4 nanozymes. The in situ glutathione consumption and hypoxia relief further amplify oxidative stress. In addition, chemotherapeutic effects due to the cytotoxicity of cobalt ions enhance the therapeutic performance. Collectively, this study provides a proof of concept for TME-reshaped natural and artificial nanozyme cascade catalysis for combined reactive oxygen species-based therapy and chemotherapy.

Dual Glutathione Depletion Enhanced Enzyme Catalytic Activity for Hyperthermia Assisted Tumor Therapy on Semi-Metallic VSe2/Mn-CS.

Semimetallic nanomaterials as photothermal agents for bioimaging and cancer therapy have attracted tremendous interest. However, the poor photothermal stability, low biocompatibility, and single component limit their therapeutic efficiency in cancer treatment. Here, manganese-doped VSe2 semimetallic nanosheets were prepared and subsequently modified with chitosan (named VSe2/Mn-CS NSs) for combined enzyme catalytic and photothermal therapy. VSe2/Mn-CS NSs show high photothermal property with a photothermal conversion efficiency of 34.61% upon 808 nm near-infrared laser irradiation. In the tumor microenvironment, VSe2/Mn-CS NSs can convert endogenous H2O2 into lethal hydroxyl radicals (•OH) to induce cancer cell apoptosis. The interaction between glutathione (GSH) and Se-Se bonds in VSe2/Mn-CS NSs results in the depletion of GSH level, and the valence states transition of manganese ions is also beneficial for the GSH consumption. This dual depletion of GSH markedly enhances the peroxidase (POD) activity, leading to the high •OH production and the improved therapeutic effect. What is more, the T1-weighted magnetic resonance and photoacoustic imaging endow VSe2/Mn-CS NSs with the ability to guide and track the treatment process. Our study provides a research strategy for the application of semimetallic nanomaterials in cancer diagnosis and treatment.

On-Demand Generation of Peroxynitrite from an Integrated Two-Dimensional System for Enhanced Tumor Therapy.

Nanosystem-mediated tumor radiosensitization strategy combining the features of X-ray with infinite penetration depth and high atomic number elements shows considerable application potential in clinical cancer therapy. However, it is difficult to achieve satisfactory anticancer efficacy using clinical radiotherapy for the majority of solid tumors due to the restrictions brought about by the tumor hypoxia, insufficient DNA damage, and rapid DNA repair during and after treatment. Inspired by the complementary advantages of nitric oxide (NO) and X-ray-induced photodynamic therapy, we herein report a two-dimensional nanoplatform by the integration of the NO donor-modified LiYF4:Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO-). By simply adjusting the Ce3+ doping content, the obtained nanoscintillator can realize high radioluminescence, activating photosensitive materials to simultaneously generate NO and superoxide radical for the formation of ONOO- in the tumor. Obtained ONOO- effectively amplifies therapeutic efficacy of radiotherapy by directly inducing mitochondrial and DNA damage, overcoming hypoxia-associated radiation resistance. The level of glutamine synthetase (GS) is downregulated by ONOO-, and the inhibition of GS delays DNA damage repair, further enhancing radiosensitivity. This work establishes a combinatorial strategy of ONOO- to overcome the major limitations of radiotherapy and provides insightful guidance to clinical radiotherapy.

Near Infrared-Triggered Theranostic Nanoplatform with Controlled Release of HSP90 Inhibitor for Synergistic Mild Photothermal and Enhanced Nanocatalytic Therapy with Hypoxia Relief.

Mild photothermal therapy (PTT, <45 °C) can prevent tumor metastasis and heat damage to normal tissue, compared with traditional PTT (>50 °C). However, its therapeutic efficacy is limited owing to the hypoxic tumor environment and tumor thermoresistance owing to the overproduction of heat shock proteins (HSPs). Herein, a near-infrared (NIR)-triggered theranostic nanoplatform (GA-PB@MONs@LA) is designed for synergistic mild PTT and enhanced Fenton nanocatalytic therapy against hypoxic tumors. The nanoplatform is fabricated by the confined formation of Prussian blue (PB) nanoparticles in mesoporous organosilica nanoparticles (MONs), followed by the loading of gambogic acid (GA), an HSP90 inhibitor, and coating with thermo-sensitive lauric acid (LA). Upon NIR irradiation, the photothermal effect (44 °C) of PB not only induces apoptosis of tumor cells but also triggers the on-demand release of GA, inhibiting the production of HSP90. Moreover, the delivered heat simultaneously enhances the catalase-like and Fenton activity of PB@MONs@LA in an acidic tumor microenvironment, relieving the tumor hypoxia and promoting the generation of highly toxic •OH. In addition, the nanoplatform enables magnetic resonance/photoacoustic dual-modal imaging. Thus, this study describes a distinctive paradigm for the development of NIR-triggered theranostic nanoplatforms for enhanced cancer therapy.

Pt Decorated Ti3C2Tx MXene with NIR-II Light Amplified Nanozyme Catalytic Activity for Efficient Phototheranostics.

The clinical application of photothermal therapy (PTT) is severely limited by the tissue penetration depth of excitation light, and enzyme therapy is hampered by its low therapeutic efficiency. As a two-dimensional ultrathin nanosheet with high absorbance in the near-infrared-II (NIR-II) region, the titanium carbide (Ti3C2) nanosheet can be used as a substrate to anchor functional components, like nanozymes and nanodrugs. Here, we decorate Pt artificial nanozymes on the Ti3C2 nanosheets to synthesize Ti-based MXene nanocomposites (Ti3C2Tx-Pt-PEG). In the tumor microenvironment, the Pt nanoparticles exhibit peroxidase-like (POD-like) activity, which can in situ catalyze hydrogen peroxide to generate hydroxyl radicals (•OH) to induce cell apoptosis and necrosis. Meanwhile, the composite shows a desirable photothermal effect upon NIR-II light irradiation with a low power density (0.75 W cm-2). Especially, the POD-like activity is significantly enhanced by the elevated temperature arising from the photothermal effect of Ti3C2Tx. Therefore, satisfactory synergistic PTT/enzyme therapy has been accomplished, accompanied by an applicable photoacoustic imaging capability to monitor and guide the therapeutic process. This work may provide an approach for hyperthermia-amplified nanozyme catalytic therapy, especially based on metal catalysts and MXene nanocomposites.

GPC3-targeted and curcumin-loaded phospholipid microbubbles for sono-photodynamic therapy in liver cancer cells.

More effective strategies are needed to improve the treatment of liver cancer. Sono-photodynamic therapy (SPDT) has a more obvious antitumor effect than sonodynamic therapy (SDT) or photodynamic therapy (PDT). We aimed to investigate Glypican-3-targeted, curcumin-loaded microbubbles (GPC3-CUR-MBs)-mediated SPDT in liver cancer cells in vitro and in vivo. GPC3-CUR-MBs were prepared by streptavidin-biotin interactions and the immune ligation method. The characterization and toxicity of GPC3-CUR-MBs and the anti-liver cancer effects of GPC3-CUR-MB-mediated SPDT in vitro and in vivo were studied. We synthetized GPC3-CUR-MBs and found that GPC3-CUR-MBs had no significant toxicity to HepG2 liver cancer cells. In terms of the anti-liver cancer effects in vitro and in vivo, when we used CUR, CUR-MBs or GPC3-CUR-MBs as the sono/photosensitizers, the outcome of SPDT was superior to that of SDT or PDT alone. The outcomes with GPC3-CUR-MBs were better than those with CUR or CUR-MBs in the SDT, PDT or SPDT groups. During the treatment period, the weight of the HepG2 tumor-bearing mice did not decrease significantly, and no significant evidence of lung, heart, liver, spleen and kidney damage was found with H&E staining. Our results indicated that the anti-liver tumor effect of SPDT was better than that of SDT and PDT and that GPC3-CUR-MBs were promising sono/photosensitizers.

Integration of IR-808 and thiol-capped Au-Bi bimetallic nanoparticles for NIR light mediated photothermal/photodynamic therapy and imaging.

Near infrared (NIR) light detonated phototherapy for cancer treatment based on photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted increasing attention owing to its deep tissue penetration. However, the low absorption ability and therapeutic efficiency of the photosensitive drug have restricted the development of phototherapy to a great degree. Herein, a kind of IR808 dye sensitized glutathione (GSH) cladded Au-Bi bimetallic nanoparticles (Au-Bi-GSH@IR808) was prepared to enhance the inhibition effect of tumors. In this nanoplatform, the construction of GSH cladded Au-Bi bimetallic nanoparticles can effectively generate 1O2 while exhibiting outstanding photothermal conversion efficiency (η = 34.2%) upon 808 nm laser irradiation. Furthermore, IR808 as a small molecule dye endows the Au-Bi-GSH@IR808 with a higher 808 nm light absorption ability and stronger photothermal and photodynamic effects. The IR808 sensitized Au-Bi bimetallic nanoparticles with a small size (5 nm), hydrophilia and dispersible nature, exhibit a noticeably enhanced therapeutic peculiarity. Additionally, the prominent CT imaging property of Au-Bi-GSH@IR808 means it is expected to be used as a CT imaging contrast agent in clinical applications. The results of the in vitro and in vivo experiments indicate that the synthesized nanoparticles have an excellent ablation effect on cancer cells, and they are expected to be widely used in the accurate diagnosis and treatment of cancer.

Intelligent Fe-Mn Layered Double Hydroxides Nanosheets Anchored with Upconversion Nanoparticles for Oxygen-Elevated Synergetic Therapy and Bioimaging.

Multimodal synergistic therapy based on photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) has attracted increasing attention in cancer therapy. However, the scant therapeutic efficiency is always a barrier for further application. Herein, a smart tumor microenvironment (TME) responsive nanocatalysts are developed by adopting Fe-Mn layered double hydroxides (FeMn-LDH) as an effective photothermal nanocarrier to load mesoporous silica and chlorin e6 (Ce6)-covalently coated upconversion nanoparticles (UCSP) for multimodal imaging for directed therapy. Under acidic TME, FeMn-LDH degrades into Fe3+ and Mn2+ ions to initiate a Fenton-like reaction inducing CDT and enhancing magnetic resonance imaging. Additionally, Fe3+ can decompose H2 O2 to oxygen (O2 ), enhancing PDT guided by UCSP. As a representative noninvasive imaging probe, the upconversion luminescence will recover after decomposition of FeMn-LDH, and provide high-resolution upconversion luminescent imaging guidance for pinpointed PDT. Moreover, the photothermal properties of FeMn-LDH can further enhance CDT effects. The synergistic therapy and multifunctional imaging can realize the integration of diagnosis and treatment.

A porous material excited by near-infrared light for photo/chemodynamic and photothermal dual-mode combination therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are well-developed light therapy methods for cancer; however, both have a few areas that need improvement. A sustained PDT effect depends on the sustained generation of reactive oxygen species (ROS); therefore, adjusting the type of photosensitizer or the reaction mechanism to prolong the duration of the oxidation-reduction reaction is a possible solution for the continuation of the PDT effect. Further, if PTT could be combined with other treatments, it would bring about a more satisfactory therapeutic effect. To increase the treatment effect of the above two therapeutic methods, a collaborative treatment model of photo/chemodynamic therapy (PCDT) and PTT is needed and is the focus of this study. On the one hand, PCDT is a therapy that integrates PDT with Fenton-like reactions, and Fenton-like reactions can help PDT to produce more ROS by making better use of H2O2 in the tumor microenvironment. On the other hand, the PTT effect can also promote PCDT effects to some extent because rising temperature can elevate the redox reaction rate. Therefore, a copper oxide semiconductor photosensitizer was selected in this research to realize the abovementioned therapeutic purposes and experimental concepts. A porous silica carrier can facilitate the uniform attachment of the copper oxide photosensitizer to the SiO2 surface to form a relatively uniform nanostructure, and the nanoporous structure can increase the performance of the whole material to a certain extent. Based on these perspectives, SiO2@CuO nanotube (NT), an agent of both Fenton-like photosensitization and photothermal reagent, is synthesized by the hydrothermal co-precipitation template approach to shrink the tumor through the combined effect of PCDT and PTT. In this system, copper ions can participate in the Fenton-like reactions and make better use of H2O2 to generate more ROS. Herein, 808 nm light was chosen for irradiation because of its suitable excitation ability, applicable penetration and low intrinsic damage. The experimental results show that SiO2@CuO NT is a promising agent that combines PCDT and PTT for cancer treatment. This work provides guidance for the synthesis of Fenton-like photosensitizers for the PCDT effect.

GSH-Depleted Nanozymes with Hyperthermia-Enhanced Dual Enzyme-Mimic Activities for Tumor Nanocatalytic Therapy.

Nanocatalytic therapy, using artificial nanoscale enzyme mimics (nanozymes), is an emerging technology for therapeutic treatment of various malignant tumors. However, the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME) restrains their biomedical applications. Here, a versatile and bacteria-like PEG/Ce-Bi@DMSN nanozyme is developed by coating uniform Bi2 S3 nanorods (NRs) with dendritic mesoporous silica (Bi2 S3 @DMSN) and then decorating ultrasmall ceria nanozymes into the large mesopores of Bi2 S3 @DMSN. The nanozymes exhibit dual enzyme-mimic catalytic activities (peroxidase-mimic and catalase-mimic) under acidic conditions that can regulate the TME, that is, simultaneously elevate oxidative stress and relieve hypoxia. In addition, the nanozymes can effectively consume the overexpressed glutathione (GSH) through redox reaction. Photothermal therapy (PTT) is introduced to synergistically improve the dual enzyme-mimicking catalytic activities and depletion of the overexpressed GSH in the tumors by photonic hyperthermia. This is achieved by taking advantage of the desirable light absorbance in the second near-infrared (NIR-II) window of the PEG/Ce-Bi@DMSN nanozymes. Subsequently the reactive oxygen species (ROS)-mediated therapeutic efficiency is significantly improved. Therefore, this study provides a proof of concept of hyperthermia-augmented multi-enzymatic activities of nanozymes for tumor ablation.

X-ray-triggered NO-released Bi-SNO nanoparticles: all-in-one nano-radiosensitizer with photothermal/gas therapy for enhanced radiotherapy.

Hypoxia in tumor cells is regarded as the most crucial cause of clinical drug resistance and radio-resistance; thus, relieving hypoxia of tumor cells is the key to enhancing the efficacy of anticancer therapy. As a gas signal molecule of vasodilatation factors, nitric oxide (NO) can relieve the hypoxia status of tumor cells, thereby, enhancing the sensitivity of tumor cells to radiotherapy. However, considering complications of vascular activity, the level of NO required for radiotherapy sensitization cannot be obtained in vivo. In view of this, we design and fabricate a multifunctional bismuth-based nanotheranostic agent, which is functionalized with S-nitrosothiol and termed Bi-SNO NPs. X-rays break down the S-N bond and simultaneously trigger large amount of NO-releasing (over 60 µM). Moreover, the as-prepared Bi-SNO NPs not only possess the capability of absorbing and converting 808 nm NIR photons into heat for photothermal therapy, but also have the ability to increase X-ray absorption and CT imaging sensitivity. In addition, the collaborative radio-, photothermal-, and gas-therapy of Bi-SNO in vivo was further investigated and remarkable synergistic tumor inhibition was realized. Finally, no obvious toxicity of Bi-SNO NPs was observed in the treated mice within 14 days. Therefore, the Bi-SNO developed in this work is an effective nano-agent for cancer theranostics with well-controlled morphology and uniform size (36 nm), which could serve as a versatile CT imaging-guided combined radio-, photothermal- and gas-therapy nanocomposite with negligible side effects.

SiO2@Cu7S4 nanotubes for photo/chemodynamic and photo-thermal dual-mode synergistic therapy under 808 nm laser irradiation.

Photodynamic therapy (PDT) is a light-based modality for tumor treatment that involves the generation of reactive oxygen species (ROS) by the combination of light, a photosensitizer, and molecular oxygen. Nevertheless, the therapeutic effects of PDT are limited by hypoxic conditions that worsen with oxygen consumption during the PDT process. Photo/chemodynamic therapy (PCDT) based on the Fenton reaction is one strategy to improve ROS generation, provided a highly effective Fenton reagent is developed. In this research, SiO2@Cu7S4 nanotubes (NTs) were synthesized as a PCDT agent. This double-valence metal-sulfide composite material can react with H2O2 at the tumor site. SiO2@Cu7S4 NTs can produce more ROS than the traditional PDT agents, and besides, they can also be used as a photothermal therapy (PTT) agent. SiO2@Cu7S4 NTs will trigger the PTT effect under 808 nm irradiation and generate a large amount of heat to eradicate cancer cells. This heat will also promote the PCDT effect by increasing the reaction rate. Thus, the SiO2@Cu7S4 NT is a suitable material for PCDT and PTT synergistic oncotherapy. The 808 nm laser is selected as the appropriate excitation source, providing adequate penetration and minimal harm to normal cells. The experimental data presented herein demonstrate the promising photosensitive, Fenton-like, and photothermal performance of SiO2@Cu7S4 NTs. Furthermore, the findings could promote the development of PCDT and PTT synergistic therapy. Thus, this research provides a feasible method to design a single, multifunctional material for cancer treatment.

Hyperthermia and Controllable Free Radical Coenhanced Synergistic Therapy in Hypoxia Enabled by Near-Infrared-II Light Irradiation.

Tumor cell metabolism and tumor blood vessel proliferation are distinct from normal cells. The resulting tumor microenvironment presents a characteristic of hypoxia, which greatly limits the generation of oxygen free radicals and affects the therapeutic effect of photodynamic therapy. Here, we developed an oxygen-independent free radical generated nanosystem (CuFeSe2-AIPH@BSA) with dual-peak absorption in both near-infrared (NIR) regions and utilized it for imaging-guided synergistic treatment. The special absorption provides the nanosystem with high photothermal conversion efficiency and favorably matched photoactivity in both I and II NIR biological windows. Upon NIR light irradiation, the generated heat could prompt AIPH release and decompose to produce oxygen-independent free radicals for killing cancer cells effectively. The contrastive research results show that the enhanced therapeutic efficacy of NIR-II over NIR-I is principally due to its deeper tissue penetration and higher maximum permission exposure that benefits from a longer wavelength. Hyperthermia effect and the production of toxic free radicals upon NIR-II laser illumination are extremely effective in triggering apoptosis and death of cancer cells in the tumor hypoxia microenvironment. The high biocompatibility and excellent anticancer efficiency of CuFeSe2-AIPH@BSA allow it to be an ideal oxygen-independent nanosystem for imaging-guided and NIR-II-mediated synergistic therapy via systemic administration.