Calcium carbonate-actuated ion homeostasis perturbator for oxidative damage-augmented Ca2+/Mg2+ interference therapy.

Ion homeostasis distortion through exogenous overload or underload of intracellular ion species has become an arresting therapeutic approach against malignant tumor. Nevertheless, treatment outcomes of such ion interference are always compromised by the intrinsic ion homeostasis maintenance systems in cancer cells. Herein, an ion homeostasis perturbator (CTC) is facilely designed by co-encapsulation of carvacrol (CAR) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) into pH-sensitive nano-CaCO3, aiming to disrupt the self-defense mechanism during the process of ion imbalance. Upon the endocytosis of CTC into tumor cells, lysosomal acidity can render the decomposition of CaCO3, resulting in the instant Ca2+ overload and CO2 generation in cytoplasm. Simultaneously, CaCO3 disintegration triggers the release of CAR and TCPP, which are devoted to TRPM7 inhibition and sonosensitization, respectively. The malfunction of TRPM7 can impede the influx of Mg2+ and allow unrestricted influx of Ca2+ based on the antagonism relationship between Mg2+ and Ca2+, leading to an aggravated Ca2+/Mg2+ dyshomeostasis through ion channel deactivation. In another aspect, US-triggered cavitation can be significantly enhanced by the presence of inert CO2 microbubbles, further amplifying the generation of reactive oxygen species. Such oxidative damage-augmented Ca2+/Mg2+ interference therapy effectively impairs the mitochondrial function of tumor, which may provide useful insights in cancer therapy.

A robust Au@Cu2-xS nanoreactor assembled by silk fibroin for enhanced intratumoral glucose depletion and redox dyshomeostasis.

Intracellular redox dyshomeostasis promoted by tumor microenvironment (TME) modulation has become an appealing therapeutic target for cancer management. Herein, a dual plasmonic Au/SF@Cu2-xS nanoreactor (abbreviation as ASC) is elaborately developed by covalent immobilization of sulfur defective Cu2-xS nanodots onto the surface of silk fibroin (SF)-capped Au nanoparticles. Tumor hypoxia can be effectively alleviated by ASC-mediated local oxygenation, owing to the newfound catalase-mimic activity of Cu2-xS. The semiconductor of Cu2-xS with narrow bandgap energy of 2.54 eV enables a more rapid dissociation of electron-hole (e-/h+) pair for a promoted US-triggered singlet oxygen (1O2) generation, in the presence of Au as electron scavenger. Moreover, Cu2-xS is devote to Fenton-like reaction to catalyze H2O2 into ·OH under mild acidity and simultaneously deplete glutathione to aggravate intracellular oxidative stress. In another aspect, Au nanoparticles with glucose oxidase-mimic activity consumes intrinsic glucose, which contributes to a higher degree of oxidative damage and energy exhaustion of cancer cells. Importantly, such tumor starvation and 1O2 yield can be enhanced by Cu2-xS-catalyzed O2 self-replenishment in H2O2-rich TME. ASC-initiated M1 macrophage activation and therapy-triggered immunogenetic cell death (ICD) favors the systematic tumor elimination by eliciting antitumor immunity. This study undoubtedly enriches the rational design of SF-based nanocatalysts for medical utilizations.

A hollow Co3-xCuxS4 with glutathione depleting and photothermal properties for synergistic dual-enhanced chemodynamic/photothermal cancer therapy.

Chemodynamic therapy has become an emerging cancer treatment strategy, in which tumor cells are killed through toxic reactive oxygen species (ROS), especially hydroxyl radicals (˙OH) produced by the Fenton reaction. Nevertheless, low ROS generation efficiency and ROS depletion by cellular antioxidant systems are still the main obstacles in chemodynamic therapy. In the present work, we propose a dually enhanced chemodynamic therapy obtained by inhibiting ˙OH consumption and promoting ˙OH production based on the administration of bimetallic sulfide Co3-xCuxS4 nanoparticles functionalized by polyethylene glycol. These bimetallic nanoparticles display glutathione depleting and photothermal properties. The nanoparticles are gradually degraded in a tumor microenvironment, resulting in Co2+ and Cu2+ release. The released Co2+ triggers a Fenton-like reaction that turns endogenous hydrogen peroxide into highly toxic ˙OH. In the cellular environment, Cu2+ ions are reduced to Cu+ by endogenous GSH, which decreases the intracellular antioxidant capacity and additionally up-regulates ˙OH production via the Cu+-induced Fenton-like reaction. Moreover, under near-infrared light irradiation, the bimetallic nanoparticles display a photothermal conversion efficacy of 46.7%, which not only improves chemodynamic therapy via boosting a Fenton-like reaction but results in photothermal therapy through hyperthermia. Both in vitro cancer cell killing and in vivo tumor ablation experiments show that the bimetallic nanoparticles display outstanding therapeutic efficacy and negligible systemic toxicity, indicating their anticancer potential.

Zirconia-Platinum Nanohybrids for Ultrasound-Activated Sonodynamic-Thermodynamic Bimodal Therapy by Inducing Intense Intracellular Oxidative Stress.

The therapeutic exploration of nano-zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano-sonosensitizer of ZrO2- x @Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen-deficient ZrO2- x . Compared to 3.09 eV of nano-ZrO2- x , the bandgap of ZrO2- x @Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e- /h+ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase-mimic activity can promote 1 O2  generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), US-stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (• R). US-triggered reactive oxygen species generation and hyperthermia-induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic-thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof-of-concept paradigm expands the medical use of nano-zirconia and provides useful insights for its therapeutic perspectives.

A platinum nanourchin-based multi-enzymatic platform to disrupt mitochondrial function assisted by modulating the intracellular H2O2 homeostasis.

Endogenous H2O2 sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H2O2 supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and H2O2-rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn2+/3+. The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O2 replenishment through Pt-catalyzed decomposition of H2O2. Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn2+/3+ couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular H2O2 level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H2O2 balance during H2O2-depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction.

Silk fibroin-capped metal-organic framework for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy.

Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.

Acidic TME-Responsive Nano-Bi2 Se3 @MnCaP as a NIR-II-Triggered Free Radical Generator for Hypoxia-Irrelevant Phototherapy with High Specificity and Immunogenicity.

Here, acidic tumor microenvironment (TME)-responsive nano-Bi2 Se3 @MnCaP, as a near-infrared-II (NIR-II) biowindow-triggered free radical generator for hypoxia-irrelevant phototherapy, is elaborately developed by biomimetic mineralization of MnCaP onto 2, 2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH)-loaded mesoporous nano-Bi2 Se3 to form Bi2 Se3 /AIPH@MnCaP (BAM). Surface mineral of MnCaP can be degraded under mild acidity, leading to the release of both Mn2+ and AIPH. The leached Mn2+ not only facilitates chemodynamic therapy (CDT) via hydroxyl radicals (• OH) from Mn2+ -mediated Fenton-like reaction but also acts as contrast agent for magnetic resonance imaging. In another aspect, the splendid photothermal conversion capacity of BAM enables a rapid hyperthermia generation under NIR-II laser irradiation for photothermal therapy (PTT). Simultaneously, the local thermal shock can induce the disintegration of AIPH to generate alkyl radicals (• R) for thermodynamic therapy (TDT) and accelerate Fenton-like reaction rate to augment CDT efficacy. The strong synergistic effects from cooperative CDT/PTT/TDT are applied to 4T1 tumor suppression with minimal side effects. Importantly, the combination therapy can effectively trigger immunogenetic cell death and enhance antitumor immunity for systemic tumor eradication. Collectively, this proof-of-concept study demonstrates a more efficacious and safer strategy for oxygenation-independent phototherapy, which holds a good potential for clinical translation in cancer management.

Proteomic profiling of the acid tolerance response (ATR) during the enhanced biomethanation process from Taihu Blue Algae with butyrate stress on anaerobic sludge.

Enhanced biomethanation with acid stress on anaerobic sludge, dehydrogenase activity, protein expression, and the primary proteomic profiling of microbial communities during the enhanced anaerobic digestion process from Taihu Blue Algae were investigated. It was found that the accumulation of organic acids and the specific biogas accumulation rate were 1.8 and 1.3 times of the control, when 10 g/L and 7.5 g/L of butyrate were selected for acid stress, respectively. Meanwhile, dehydrogenase activity of the 7.5 g/L acid stress group exhibited an increase of 1.6 times of the control, and protein expression was also found to be enhanced sharply as revealed by 1D-PAGE. Finally, twenty of the matched protein spots through 2D-PAGE from both the control and the 7.5 g/L stress groups were identified by MALDI-TOF MS, and five of which were proved to be involved in bioenergy metabolism. Significantly, ATR related proteins might be induced as the pIs of which were acidic as 5.92, 5.51 and 5.54, respectively.