Cold to Hot: Tumor Immunotherapy by Promoting Vascular Normalization Based on PDGFB Nanocomposites.

Immunotherapy is a promising cancer therapeutic strategy. However, the "cold" tumor immune microenvironment (TIME), characterized by insufficient immune cell infiltration and immunosuppressive status, limits the efficacy of immunotherapy. Tumor vascular abnormalities due to defective pericyte coverage are gradually recognized as a profound determinant in "cold" TIME establishment by hindering immune cell trafficking. Recently, several vascular normalization strategies by improving pericyte coverage have been reported, whereas have unsatisfactory efficacy and high rates of resistance. Herein, a combinatorial strategy to induce tumor vasculature-targeted pericyte recruitment and zinc ion-mediated immune activation with a platelet-derived growth factor B (PDGFB)-loaded, cyclo (Arg-Gly-Asp-D-Phe-Lys)-modified zeolitic imidazolate framework 8 (PDGFB@ZIF8-RGD) nanoplatform is proposed. PDGFB@ZIF8-RGD effectively induced tumor vascular normalization, which facilitated trafficking and infiltration of immune effector cells, including natural killer (NK) cells, M1-like macrophages and CD8+ T cells, into tumor microenvironment. Simultaneously, vascular normalization promoted the accumulation of zinc ions inside tumors to trigger effector cell immune activation and effector molecule production. The synergy between these two effects endowed PDGFB@ZIF8-RGD with superior capabilities in reprogramming the "cold" TIME to a "hot" TIME, thereby initiating robust antitumor immunity and suppressing tumor growth. This combinatorial strategy for improving immune effector cell infiltration and activation is a promising paradigm for solid tumor immunotherapy.

Bioinspired porous three-coordinated single-atom Fe nanozyme with oxidase-like activity for tumor visual identification via glutathione.

Inspired by structures of natural metalloenzymes, a biomimetic synthetic strategy is developed for scalable synthesis of porous Fe-N3 single atom nanozymes (pFeSAN) using hemoglobin as Fe-source and template. pFeSAN delivers 3.3- and 8791-fold higher oxidase-like activity than Fe-N4 and Fe3O4 nanozymes. The high catalytic performance is attributed to (1) the suppressed aggregation of atomically dispersed Fe; (2) facilitated mass transfer and maximized exposure of active sites for the created mesopores by thermal removal of hemoglobin (2 ~ 3 nm); and (3) unique electronic configuration of Fe-N3 for the oxygen-to-water oxidation pathway (analogy with natural cytochrome c oxidase). The pFeSAN is successfully demonstrated for the rapid colorimetric detection of glutathione with a low limit of detection (2.4 nM) and wide range (50 nM-1 mM), and further developed as a real-time, facile, rapid (~6 min) and precise visualization analysis methodology of tumors via glutathione level, showing its potentials for diagnostic and clinic applications.

Hyperbaric Oxygen Treatment for Long COVID: From Molecular Mechanism to Clinical Practice.

Long COVID symptoms typically occur within 3 months of an initial COVID-19 infection, last for more than 2 months, and cannot be explained by other diagnoses. The most common symptoms include fatigue, dyspnea, coughing, and cognitive impairment. The mechanisms of long COVID are not fully understood, but several hypotheses have been put forth. These include coagulation and fibrosis pathway activation, inflammatory and autoimmune manifestations, persistent virus presence, and Epstein-Barr virus reactivation. Hyperbaric oxygen therapy (HBOT) is a therapeutic method in which a person inhales 100% oxygen under pressure greater than that of the atmosphere. HBOT has some therapeutic effects, including improvement of microcirculation, inhibition of cytokine release leading to a reduction in inflammatory responses, inhibition of autoimmune responses, and promotion of neurological repair. Several clinical trials have been carried out using HBOT to treat long COVID. The results suggest that HBOT helps to improve symptom severity, reduce symptom duration, and enhance patients' quality of life. It is believed that HBOT is an effective option for patients with long COVID, which is worth actively promoting.

Reduction of Reactive Oxygen Species Accumulation Using Gadolinium-Doped Ceria for the Alleviation of Atherosclerosis.

Atherosclerosis is a common cardiovascular disease with increasing morbidity and mortality. The pathogenesis of atherosclerosis is strongly related to endothelial dysfunction, which is induced by severe oxidative stress damage derived from reactive oxygen species (ROS). Thus, ROS plays a critical role in the pathogenesis and progression of atherosclerosis. In this work, we demonstrated that the gadolinium doping of CeO2 (Gd/CeO2) nanozymes as effective ROS scavengers delivered high performance for antiatherosclerosis. It was found that the chemical doping of Gd promoted the surface proportion of Ce3+ in the nanozymes and thereby enhanced the overall ROS scavenging ability. In vitro and in vivo experiments unambiguously showed that the Gd/CeO2 nanozymes efficiently scavenged harmful ROS at the cellular and histological levels. Further, Gd/CeO2 nanozymes were demonstrated to significantly reduce vascular lesions by reducing lipid accumulation in macrophage and decreasing inflammatory factor levels, thereby inhibiting the exacerbation of atherosclerosis. Moreover, Gd/CeO2 can serve as T1-weighted magnetic resonance imaging contrast agents, which can generate sufficient contrast to distinguish the location of plaque during living imaging. Through those efforts, Gd/CeO2 may serve as a potential diagnostic and treatment nanomedicine for the ROS-induced atherosclerosis.

Reductive damage induced autophagy inhibition for tumor therapy.

Numerous therapeutic anti-tumor strategies have been developed in recent decades. However, their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors. Autophagy plays a key role in tumorigenesis and tumor treatment, in which the overproduction of reactive oxygen species (ROS) is recognized as the direct cause of protective autophagy. Only a few molecules have been employed as autophagy inhibitors in tumor therapy to reduce protective autophagy. Among them, hydroxychloroquine is the most commonly used autophagy inhibitor in clinics, but it is severely limited by its high therapeutic dose, significant toxicity, poor reversal efficacy, and nonspecific action. Herein, we demonstrate a reductive-damage strategy to enable tumor therapy by the inhibition of protective autophagy via the catalytic scavenging of ROS using porous nanorods of ceria (PN-CeO2) nanozymes as autophagy inhibitor. The antineoplastic effects of PN-CeO2 were mediated by its high reductive activity for intratumoral ROS degradation, thereby inhibiting protective autophagy and activating apoptosis by suppressing the activities of phosphatidylinositide 3-kinase/protein kinase B and p38 mitogen-activated protein kinase pathways in human cutaneous squamous cell carcinoma. Further investigation highlighted PN-CeO2 as a safe and efficient anti-tumor autophagy inhibitor. Overall, this study presents a reductive-damage strategy as a promising anti-tumor approach that catalytically inhibits autophagy and activates the intrinsic antioxidant pathways of tumor cells and also shows its potential for the therapy of other autophagy-related diseases. Electronic Supplementary Material: Supplementary material (cellular uptake of PN-CeO2, effects of PN-CeO2 on several common malignant tumor models, viability of HaCaT cells treated with PN-CeO2 at different concentrations, time-dependent body-weight curves of SCL-1 tumor-bearing nude mice, the biodistribution of Ce element in main tissues and tumors after injection of PN-CeO2, measurement of Ce element concentration in urine and feces samples, H&E-stained images of main organs, and measurement of liver and kidney function in mice after different treatment) is available in the online version of this article at 10.1007/s12274-022-5139-z.

Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.

Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

Insights on catalytic mechanism of CeO2 as multiple nanozymes.

CeO2 with the reversible Ce3+/Ce4+ redox pair exhibits multiple enzyme-like catalytic performance, which has been recognized as a promising nanozyme with potentials for disease diagnosis and treatments. Tailorable surface physicochemical properties of various CeO2 catalysts with controllable sizes, morphologies, and surface states enable a rich surface chemistry for their interactions with various molecules and species, thus delivering a wide variety of catalytic behaviors under different conditions. Despite the significant progress made in developing CeO2-based nanozymes and their explorations for practical applications, their catalytic activity and specificity are still uncompetitive to their counterparts of natural enzymes under physiological environments. With the attempt to provide the insights on the rational design of highly performed CeO2 nanozymes, this review focuses on the recent explorations on the catalytic mechanisms of CeO2 with multiple enzyme-like performance. Given the detailed discussion and proposed perspectives, we hope this review can raise more interest and stimulate more efforts on this multi-disciplinary field.

Photoinduced Phase Transition of Ce-UiO-66 to Ce-BDC-OH.

External stimuli-responsive phase transition of metal-organic frameworks (MOFs) introduces intriguing functions for diverse applications under practical settings. Herein, we reported a phase transition from cubic Ce-UiO-66 to triclinic Ce-BDC-OH under light irradiation. Such a phase transition underwent a ligand-to-metal charge transfer process, which was unambiguously revealed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, electron paramagnetic resonance, etc. We proposed a phase transition mechanism through (1) the photoreduction of the metal core from Ce4+ into Ce3+; (2) the photogeneration of •OH and hydroxylation of BDC into BDC-OH; and (3) the carboxylate migration and lattice rearrangement for transitions. The phenomenon of the Ce4+-to-Ce3+ reduction also enables a diamagnetism-to-paramagnetism transition, suggesting its potential as a photostimulus-responsive magnetic switch.

Phytic acid-modified CeO2 as Ca2+ inhibitor for a security reversal of tumor drug resistance.

Ca2+ plays critical roles in the development of diseases, whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency. To solve this issue, with the help of Ca overexpressed tumor drug resistance model, the phytic acid (PA)-modified CeO2 nano-inhibitors have been rationally designed as an unprecedentedly safe and efficient Ca2+ inhibitor to successfully reverse tumor drug resistance through Ca2+ negative regulation strategy. Using doxorubicin (Dox) as a model chemotherapeutic drug, the Ca2+ nano-inhibitors efficiently deprived intracellular excessive free Ca2+, suppressed P-glycoprotein (P-gp) expression and significantly enhanced intracellular drug accumulation in Dox-resistant tumor cells. This Ca2+ negative regulation strategy improved the intratumoral Dox concentration by a factor of 12.4 and nearly eradicated tumors without obvious adverse effects. Besides, nanocerias as pH-regulated nanozyme greatly alleviated the adverse effects of chemotherapeutic drug on normal cells/organs and substantially improved survivals of mice. We anticipate that this safe and effective Ca2+ negative regulation strategy has potentials to conquer the pitfalls of traditional Ca inhibitors, improve therapeutic efficacy of common chemotherapeutic drugs and serves as a facile and effective treatment platform of other Ca2+ associated diseases. Electronic Supplementary Material: Supplementary material (further details of the XRD pattern of CeO2, TEM images, XPS spectra, cellular uptake study, cytotoxicity data, apoptosis study, biodistribution, and biosecurity of nanocerias in vivo, etc.) is available in the online version of this article at 10.1007/s12274-022-4069-0.

A pH-Responsive Polymer-CeO2 Hybrid to Catalytically Generate Oxidative Stress for Tumor Therapy.

Catalytic generation of reactive oxygen species has been developed as a promising methodology for tumor therapy. Direct O2•- production from intratumor oxygen exhibits exceptional tumor therapeutic efficacy. Herein, this therapy strategy is demonstrated by a pH-responsive hybrid of porous CeO2 nanorods and sodium polystyrene sulfonate that delivers high oxidative activity for O2•- generation within acidic tumor microenvironments for chemodynamic therapy and only limited oxidative activity in neutral media to limit damage to healthy organs. The hydrated polymer-nanorod hybrids with large hydrodynamic diameters form nanoreactors that locally trap oxygen and biological substrates inside and improve the charge transfer between the catalysts and substrates in the tumor microenvironment, leading to enhanced catalytic O2•- production and consequent oxidation. Together with successful in vitro and in vivo experiments, these data show that the use of hybrids provides a compelling opportunity for the delivery selective chemodynamic tumor therapy.

Circular RNA hsa_circ_0004277 contributes to malignant phenotype of colorectal cancer by sponging miR-512-5p to upregulate the expression of PTMA.

In recent years, extensive reports have been published concerning the molecular mechanism underlying the occurrence and progression of colorectal cancer. Circular RNAs (circRNAs) have been identified as important modulators in the biological processes of colorectal cancer. Microarray analysis unveiled that differential circ-0004277 expression was identified in tissue samples of colorectal cancer. High circ-0004277 expression was then verified in tissue samples and cell lines of colorectal cancer via qRT-PCR. Kaplan-Meier analysis was used for identifying the association between circ-0004277 expression and the overall survival rate of colorectal cancer patients. A relationship existed between higher circ-0004277 expression and decreased overall survival rate of colorectal cancer patients. From a functional perspective, circ-0004277 knockdown accelerated cell apoptosis and restrained cell proliferation of colorectal cancer. From mechanistic perspective, circ-0004277 upregulated PTMA by sponging miR-512-5p. Rescue assay was used for verifying the roles of the circ-0004277-miR-512-5p-PTMA axis. Both miR-512-5p and PTMA participated in circ-0004277-mediated colorectal cancer cell proliferation based on experiments. In summary, our study showed that circ-0004277 promoted the proliferation of colorectal cancer cells as a miR-512-5p sponge to upregulate the PTMA expression.

Photolyase-Like Catalytic Behavior of CeO2.

Nanomaterials with intrinsic enzyme-like characteristics exhibit their great potentials as alternatives to natural enzymes. Among various enzymes, the finding of substitutes of DNA photolyases, a family of photoenzymes for repairing the ultraviolet (UV)-induced DNA damage by forming cyclobutane pyrimidine dimers (CPDs) between two adjacent thymines in a DNA strand, is still unsuccessful. CPDs raise significant health concerns in various skin diseases. Essentially, DNA photolyases selectively split dimers into monomers by photoelectrons under visible-light irradiation, and this is a photocatalytic process. However, the majority of semiconductors are unprosperous due to the accompanied photogenerated reactive oxygen species (ROS), which decompose CPDs into fragments and thereby lead to a nonselective photocatalysis. Fortunately, CeO2 as a semiconductor might deliver the selectively photocatalytic repair of UV-induced DNA damages, where the photoelectrons are used for the CPD cleavage, and the photogenerated ROS are locally suppressed for its antioxidant nature. Herein, we reported the defective porous CeO2 delivered the photolyase-like activity by enhancing visible-light absorption, enabling the effective interaction between CPDs and catalysts, and subsequently triggering the selective photocleavage of CPDs into monomers. Further, in vitro cellular and in vivo animal evaluations illustrated its high potentials as alternatives to DNA photolyases.

Catalytically Selective Chemotherapy from Tumor-Metabolic Generated Lactic Acid.

Lactic acid (LA) is a powerful molecule as the metabolic driver in tumor microenvironments (TMEs). Inspired by its high intratumoral level (5-20 µmol g-1 ), a novel treatment paradigm via the cascade release of H2 O2 and ·OH from the LA generated by tumor metabolism is developed for catalytic and pH-dependent selective tumor chemotherapy. By utilizing the acidity and overexpression of LA within the TME, the constructed lactate oxidase (LOD)-immobilized Ce-benzenetricarboxylic acid (Ce-BTC) metal organic framework enables the intratumoral generation of ·OH via a cascade reaction: 1) the in situ catalytic release of H2 O2 from LA by LOD, and 2) the catalytic production of ·OH from H2 O2 by Ce-BTC with peroxidase-like activity. Highly toxic ·OH effectively induces tumor apoptosis/death. A new strategy for selective tumor chemotherapy is provided herein.

Phosphatase-like Activity of Porous Nanorods of CeO2 for the Highly Stabilized Dephosphorylation under Interferences.

Nanoceria with phosphatase-like behavior shows its great potential for many important biological applications through a catalytic dephosphorylation process. Herein, we synthesize a series of porous nanorods of ceria (PN-CeO2) with the controllable surface Ce3+ fractions modulated by thermal annealing, understanding the correlations between their surface properties and reactivity for the dephosphorylation of p-nitrophenyl phosphate ( p-NPP) and investigating their catalytic performance under various interferences. Our results suggest that PN-CeO2 with abundant surface defects deliver higher catalytic activity to break down p-NPP. Most importantly, PN-CeO2 exhibited a better adaptability over a wide pH range and preserved the catalytic activity over a wide temperature range from 20 to 80 °C, if compared with natural enzymes. Moreover, PN-CeO2 delivered the high catalytic stability against various interference ions. Their great prospects for practical applications were further demonstrated by dephosphorylation of DNA.

Dual-responsive dithio-polydopamine coated porous CeO2 nanorods for targeted and synergistic drug delivery.

OBJECTIVE: The aim was to produce the first report of assembling degradable stimuli-responsive dithio-polydopamine coating with a cancer target unit for synergistic and targeted drug delivery. METHODS: A multifunctional drug delivery system was constructed by coating a dual-responsive dithio-polydopamine (PDS) on porous CeO2 nanorods and subsequent conjugation of lactose derivative, where the PDS was formed by self-polymerization of dithio-dopamine (DOPASS). RESULTS: The multifunctional drug delivery system displayed excellent cancer targeted ability resulting from the conjugation of lactose derivative, which could specifically recognize the overexpressed asialoglycoprotein receptors on the surface of HepG2 cells. It also showed a dual-responsive property of glutathione and pH, achieving controllable drug release from the cleavage of disulfide bond and subsequent degradation of PDS in cancer cells. Moreover, the degradation of PDS led to the exposure of CeO2 nanorods, which has a synergistic anticancer effect due to its cytotoxicity to cancer cells. CONCLUSION: This work presents a good example of a rational design towards synergistic and targeted DDS for cancer chemotherapies.

Quantitatively Intrinsic Biomimetic Catalytic Activity of Nanocerias as Radical Scavengers and Their Ability against H2O2 and Doxorubicin-Induced Oxidative Stress.

Artificial enzymes as radical scavengers show great potentials in treatments of various diseases induced by oxidative stress. Herein, the quantitative analysis indicates that the intrinsic activity of nanocerias for the degradation of radicals is determined by the concentration of surface defects as well as their morphological features. The surface Ce3+ fraction of the CeO2 nanozymes with a similar morphology can be used as a descriptor to index their catalytic activity as radical scavengers. Defect-abundant porous nanorods of ceria (PN-CeO2) with a large surface area (141 m2/g) and high surface Ce3+ fraction (32.8%) deliver an excellent catalytic capability for the degradation of radicals, which is 15.5 times higher than that of Trolox. Results indicate that PN-CeO2 not only provides more surface catalytic centers but also supplies the active site with higher activity. Oxidative stress induced by doxorubicin (Dox), an essential medicine for a wide range of tumors, was used as the model system to evaluate the radical degradation ability of PN-CeO2. Both in vitro cellar (H9c2 cells) and in vivo animal models revealed that PN-CeO2 did not affect the cell and rat growth and was able to alleviate the Dox-induced oxidative stress. Results suggest that the artificial PN-CeO2 nanozymes have potentials to function as an adjuvant medicine during tumor chemotherapy.

Correction: Synergistic and targeted drug delivery based on nano-CeO2 capped with galactose functionalized pillar[5]arene via host-guest interactions.

Correction for 'Synergistic and targeted drug delivery based on nano-CeO2 capped with galactose functionalized pillar[5]arene via host-guest interactions' by Xiaowen Wu et al., J. Mater. Chem. B, 2017, 5, 3483-3487.

Synergistic and targeted drug delivery based on nano-CeO2 capped with galactose functionalized pillar[5]arene via host-guest interactions.

A smart drug delivery system based on porous CeO2 nano-rods (CeONRs) capped with galactose functionalized pillar[5]arene via host-guest interactions has been constructed, which showed GSH-responsiveness, synergism with anticancer drugs and cancer targeting ability resulting from its disulphide unit, ceria properties and galactose units, respectively.

Highly sensitive and robust peroxidase-like activity of porous nanorods of ceria and their application for breast cancer detection.

Porous nanorods of ceria (PN-Ceria), a novel ceria nanostructure with a large surface area and a high surface Ce(3+) fraction, exhibited strong intrinsic peroxidase activity toward a classical peroxidase substrate in the presence of H2O2. Peroxidase-like activity of ceria originated from surface Ce(3+) species as the catalytic center, thereby explaining the high performance of PN-Ceria as an artificial enzyme mimicking peroxidase. Compared with the natural enzyme horseradish peroxidase (HRP), PN-Ceria showed several advantages such as low cost, easy storage, high sensitivity, and, prominently, chemical and catalytic stability under harsh conditions. Importantly, the enzymatic activity of PN-Ceria remained nearly constant and stable over a wide range of temperature and pH values, ensuring the accuracy and reliability of measurements of its peroxidase-like activity. A PN-Ceria based novel diagnostic system was developed for breast cancer detection with a higher sensitivity than the standard HRP detection system. Our work has laid a solid foundation for the development of PN-Ceria as a novel diagnostic tool for clinical use.