Engineering Single-Atom Iron Nanozymes with Radiation-Enhanced Self-Cascade Catalysis and Self-Supplied H2O2 for Radio-enzymatic Therapy.

Single-atom nanozymes (SAzymes), with individually isolated metal atom as active sites, have shown tremendous potential as enzyme-based drugs for enzymatic therapy. However, using SAzymes in tumor theranostics remains challenging because of deficient enzymatic activity and insufficient endogenous H2O2. We develop an external-field-enhanced catalysis by an atom-level engineered FeN4-centered nanozyme (FeN4-SAzyme) for radio-enzymatic therapy. This FeN4-SAzyme exhibits peroxidase-like activity capable of catalyzing H2O2 into hydroxyl radicals and converting single-site FeII species to FeIII for subsequent glutathione oxidase-like activity. Density functional theory calculations are used to rationalize the origin of the single-site self-cascade enzymatic activity. Importantly, using X-rays can improve the overall single-site cascade enzymatic reaction process via promoting the conversion frequency of FeII/FeIII. As a H2O2 producer, natural glucose oxidase is further decorated onto the surface of FeN4-SAzyme to yield the final construct GOD@FeN4-SAzyme. The resulting GOD@FeN4-SAzyme not only supplies in situ H2O2 to continuously produce highly toxic hydroxyl radicals but also induces the localized deposition of radiation dose, subsequently inducing intensive apoptosis and ferroptosis in vitro. Such a synergistic effect of radiotherapy and self-cascade enzymatic therapy allows for improved tumor growth inhibition with minimal side effects in vivo. Collectively, this work demonstrates the introduction of external fields to enhance enzyme-like performance of nanozymes without changing their properties and highlights a robust therapeutic capable of self-supplying H2O2 and amplifying self-cascade reactions to address the limitations of enzymatic treatment.

Effects of Titanium Dioxide Nanoparticles on Cell Growth and Migration of A549 Cells under Simulated Microgravity.

With the increasing application of nanomaterials in aerospace technology, the long-term space exposure to nanomaterials especially in the space full of radiation coupled with microgravity condition has aroused great health concerns of the astronauts. However, few studies have been conducted to assess these effects, which are crucial for seeking the possible intervention strategy. Herein, using a random positioning machine (RPM) to simulate microgravity, we investigated the behaviors of cells under simulated microgravity and also evaluated the possible toxicity of titanium dioxide nanoparticles (TiO2 NPs), a multifunctional nanomaterial with potential application in aerospace. Pulmonary epithelial cells A549 were exposed to normal gravity (1 g) and simulated gravity (~10-3 g), respectively. The results showed that simulated microgravity had no significant effect on the viability of A549 cells as compared with normal gravity within 48 h. The effects of TiO2 NPs exposure on cell viability and apoptosis were marginal with only a slightly decrease in cell viability and a subtle increase in apoptosis rate observed at a high concentration of TiO2 NPs (100 µg/mL). However, it was observed that the exposure to simulated microgravity could obviously reduce A549 cell migration compared with normal gravity. The disruption of F-actin network and the deactivation of FAK (Tyr397) might be responsible for the impaired mobility of simulated microgravity-exposed A549 cells. TiO2 NPs exposure inhibited cell migration under two different gravity conditions, but to different degrees, with a milder inhibition under simulated microgravity. Meanwhile, it was found that A549 cells internalized more TiO2 NPs under normal gravity than simulated microgravity, which may account for the lower cytotoxicity and the lighter inhibition of cell migration induced by the same exposure concentration of TiO2 NPs under simulated microgravity at least partially. Our study has provided some tentative information on the effects of TiO2 NPs exposure on cell behaviors under simulated microgravity.

Plasmonic AuPt@CuS Heterostructure with Enhanced Synergistic Efficacy for Radiophotothermal Therapy.

Integrating multifunctional nanostructures capable of radiotherapy and photothermal ablation is an emerging alternative in killing cancer cells. In this work, we report a novel plasmonic heterostructure formed by decorating AuPt nanoparticles (NPs) onto the surfaces of CuS nanosheets (AuPt@CuS NSs) as a highly effective nanotheranostic toward dual-modal photoacoustic/computed tomography imaging and enhanced synergistic radiophotothermal therapy. These heterostructures can confer higher photothermal conversion efficiency via the local electromagnetic enhancement as well as a greater radiation dose deposition in the form of glutathione depletion and reactive oxygen species generation. As a result, the depth of tissue penetration is improved, and hypoxia of the tumor microenvironment is alleviated. With synergistic enhancement in the efficacy of photothermal ablation and radiotherapy, the tumor can be eliminated without later recurrence. It is believed that these multifunctional heterostructures will play a vital role in future oncotherapy with the enhanced synergistic effects of radiotherapy and photothermal ablation under the guided imaging of a potential dual-modality system.

Highly Stable Silica-Coated Bismuth Nanoparticles Deliver Tumor Microenvironment-Responsive Prodrugs to Enhance Tumor-Specific Photoradiotherapy.

Radiosensitizers are agents capable of amplifying injury to tumor tissues by enhancing DNA damage and fortifying production of radical oxygen species (ROS). The use of such radiosensitizers in the clinic, however, remains limited by an insufficient ability to differentiate between cancer and normal cells and by the presence of a reversible glutathione system that can diminish the amount of ROS generated. Here, to address these limitations, we design an H2O2-responsive prodrug which can be premixed with lauric acid (melting point ∼43 °C) and loaded around the surface of silica-coated bismuth nanoparticles (BSNPs) for cancer-specific photoradiotherapy. Particularly, silica coating confers BSNPs with improved chemical stability against both near-infrared light and X-rays. Upon photothermal heating, lauric acid is melted to trigger prodrug release, followed by its transformation into p-quinone methide via H2O2 stimulation to irreversibly alkylate glutathione. Concurrently, this heat boosts tumor oxygenation and helps relieve the hypoxic microenvironment. Following sequential irradiation by X-rays, BSNPs generate plentiful ROS, which act in combination with these events to synergistically induce cell death via DNA breakage and mitochondria-mediated apoptosis pathways, ultimately enabling effective inhibition of tumor growth in vivo with high tumor specificity and reduced side effects. Collectively, this work presents a promising approach for the improvement of other ROS-responsive proalkylating agents, while simultaneously highlighting a robust nanosystem for combining these prodrugs with photoradiosensitizers to realize precision photoradiotherapy.

Suppressing the Radiation-Induced Corrosion of Bismuth Nanoparticles for Enhanced Synergistic Cancer Radiophototherapy.

The level of tumor killing by bismuth nanoparticles (BiNPs) as radiosensitizers depends strongly on the powerful particle-matter interaction. However, this same radiation leads to the structural damage in BiNPs, consequently weakening their specific physicochemical properties for radiosensitization. Herein, we studied the radiation-induced corrosion behavior of BiNPs and demonstrated that these damages were manifested by the change in their morphology and crystal structure as well as self-oxidation at their surface. Furthermore, artificial heterostructures were created with graphene nanosheets to greatly suppress the radiation-induced corrosion in BiNPs and enhance their radiocatalytic activity for radiotherapy enhancement. Such a nanocomposite allows the accumulation of overexpressed glutathione, a natural hole scavenger, at the reaction interfaces. This enables the rapid removal of radiogenerated holes from the surface of BiNPs and minimizes the self-radiooxidation, therefore resulting in an efficient suppression of radiation corrosion and a decrease of the depletion of reactive oxygen species (ROS). Meanwhile, the radioexcited conduction band electrons react with the high-level H2O2 within cancer cells to yield more ROS, and the secondary electrons are trapped by H2O molecules to produce hydrated electrons capable of reducing a highly oxidized species such as cytochrome c. These radiochemical reactions together with hyperthermia can regulate the tumor microenvironment and accelerate the onset of cellular redox disequilibrium, mitochondrial dysfunction, and DNA damage, finally triggering tumor apoptosis and death. The current work will shed light on radiosensitizers with an enhanced corrosion resistance for controllable and synergistic radio-phototherapeutics.