A Versatile Nanozyme-Based NADH Circulating Oxidation Reactor for Tumor Therapy through Triple Cellular Metabolism Disruption.

Nanozyme-based metabolic regulation triggered by tumor-specific endogenous stimuli has emerged as a promising therapeutic strategy for tumors. The current efficacy, however, is constrained by the limited concentration of endogenous substrates and the metabolic plasticity of tumors. Consequently, the implementation of efficient metabolic regulation in tumor therapy is urgently needed. Herein, a versatile nanozyme-based nicotinamide adenine dinucleotide (NADH) circulating oxidation nanoreactor is reported. First, the synthesized cobalt-doped hollow carbon spheres (Co-HCS) possess NADH oxidase (NOX)-mimicking activity for the NADH oxidation to disrupt oxidative phosphorylation (OXPHOS) pathway of tumor cells. Second, the substrate-cycle manner of Co-HCS can be used for NADH circulating oxidation to overcome the limitation of substrate deficiency. Finally, 2-Deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) are introduced to block glycolysis and pentose phosphate pathway (PPP), thus creating a versatile nanozyme-based NADH circulating oxidation nanoreactor (Co-HCS/D/A) for tumor therapy through triple cellular metabolism disruption. In vitro and in vivo results demonstrate that the designed nanoreactor not only enhances the catalytic efficiency but also disrupts the tumor metabolic homeostasis, leading to efficient therapy outcome. This study develops a novel NADH circulating oxidation nanoreactor for tumor therapy through triple cellular metabolism disruption, which addresses the limitations of current nanozyme-based metabolism regulation for tumor therapy.

Biodegradable Metal Complex-Gated Organosilica for Dually Enhanced Chemodynamic Therapy through GSH Depletions and NIR Light-Triggered Photothermal Effects.

Hollow silica spheres have been widely studied for drug delivery because of their excellent biosecurity and high porosity. However, difficulties with degradation in the tumor microenvironment (TME) and premature leaking during drug delivery limit their clinical applications. To alleviate these problems, herein, hollow organosilica spheres (HOS) were initially prepared using a "selective etching strategy" and loaded with a photothermal drug: new indocyanine green (IR820). Then, the Cu2+-tannic acid complex (Cu-TA) was deposited on the surface of the HOS, and a new nanoplatform named HOS@IR820@Cu-TA (HICT) was finally obtained. The deposition of Cu-TA can gate the pores of HOS completely to prevent the leakage of IR820 and significantly enhance the loading capacity of HOS. Once in the mildly acidic TME, the HOS and outer Cu-TA decompose quickly in response, resulting in the release of Cu2+ and IR820. The released Cu2+ can react with the endogenous glutathione (GSH) to consume it and produce Cu+, leading to the enhanced production of highly toxic ·OH through a Fenton-like reaction due to the overexpressed H2O2 in the TME. Meanwhile, the ·OH generation was remarkably enhanced by the NIR light-responsive photothermal effect of IR820. These collective properties of HICT enable it to be a smart nanomedicine for dually enhanced chemodynamic therapy through GSH depletions and NIR light-triggered photothermal effects.

Coaxial Graphene/MXene Microfibers with Interfacial Buffer-Based Lightweight Distance Sensors Assisting Lossless Grasping of Fragile and Deformable Objects.

Lossless and efficient robotic grasping is becoming increasingly important with the widespread application of intelligent robotics in warehouse transportation, human healthcare, and domestic services. However, current sensors for feedback of grasping behavior are greatly restricted by high manufacturing cost, large volume and mass, complex circuit, and signal crosstalk. To solve these problems, here, we prepare lightweight distance sensor-based reduced graphene oxide (rGO)/MXene-rGO coaxial microfibers with interface buffer to assist lossless grasping of a robotic manipulator. The as-fabricated distance microsensor exhibits a high sensitivity of 91.2 m-1 in the distance range of 50-300 µm, a fast response time of 116 ms, a high resolution of 5 µm, and good stability in 500 cycles. Furthermore, the high-performance and lightweight microsensor is installed on the robotic manipulator to reflect the grasp state by the displacement imposed on the sensor. By establishing the correlation between the microsensing signal and the grasp state, the safe, non-destructive, and effective grasp and release of the target can be achieved. The lightweight and high-powered distance sensor displays great application prospects in intelligent fetching, medical surgery, multi-spindle automatic machines, and cultural relics excavation.

An Ultrastable Virus-Like Particle with a Carbon Dot Core and Expanded Sequence Plasticity.

Ordered bio-inorganic hybridization has evolved for the generation of high-performance materials in living organisms and inspires novel strategies to design artificial hybrid materials. Virus-like particles (VLPs) are attracting extensive interest as self-assembling systems and platforms in the fields of biotechnology and nanotechnology. However, as soft nanomaterials, their structural stability remains a general and fundamental problem in various applications. Here, an ultrastable VLP assembled from the major capsid protein (VP1) of simian virus 40 is reported, which contains a carbon dot (C-dot) core. Co-assembly of VP1 with C-dots led to homogeneous T = 1 VLPs with a fourfold increase in VLP yields. The resultant hybrid VLPs showed markedly enhanced structural stability and sequence plasticity. C-dots and a polyhistidine tag fused to the inner-protruding N-terminus of VP1 contributed synergistically to these enhancements, where extensive and strong noncovalent interactions on the C-dot/VP1 interfaces are responsible according to cryo-EM 3D reconstruction, molecular simulation, and affinity measurements. C-dot-enhanced ultrastable VLPs can serve as a new platform, enabling the fabrication of new architectures for bioimaging, theranostics, nanovaccines, etc. The hybridization strategy is simple and can easily be extended to other VLPs and protein nanoparticle systems.

Photoluminescence Enhancement of Carbon Dots by Surfactants at Room Temperature.

During the past decade, increasing attention has been paid to fluorescent carbon dots (CDs) due to their unique photoluminescence (PL) properties. As synthetic methods gradually develop, many post-functionalization strategies have been developed to enhance the PL of CDs. However, in most cases, the PL enhancement was less than 10-fold with multistep modification processes. In this work, a facile and efficient post-functionalization strategy was successfully applied to enhance the PL intensity of CDs dramatically up to 69 times by surfactants at room temperature for the first time. Furthermore, the mechanism of surfactant-induced PL enhancement of CDs was investigated and in vivo bioimaging was performed. The results demonstrated that electrostatic/non-electrostatic interactions between CDs and surfactants could effectively lower the vibration and rotation of CDs, increase radiative decay processes and, thus, enhance the PL of CDs. This finding may provide new insights into the strategies for enhancing the PL of CDs, further broadening their potential applications.

Coumarin-Based Boron Complexes with Aggregation-Induced Emission.

Two coumarin-based boron complexes (HBN and MBN) with aggregation-induced emission were designed and synthesized. The photophysical properties of the complexes were investigated in different solvents and in the solid state. Results showed that the inhibited C═N isomerization by N,O-chelated BF2 caused the significant enhancement of fluorescence in THF. In particular, the complexes displayed red-shifted emissions (>60 nm) in mixed solvents of CH3CN and water because of the aggregation-induced charge-transfer enhancement. In the solid state, the bright red emission appeared at 650 nm (620 nm), with a Stokes shift of 170 nm. Cell-imaging experiments indicated that the complexes have good membrane permeability and can be used as lysosome trackers.

Deep-Red and Near-Infrared Xanthene Dyes for Rapid Live Cell Imaging.

In this work, two xanthene dyes (H-hNR and TF-hNR) have been synthesized by a convenient and efficient method. These two dyes exhibited deep-red and near-infrared emissions, high fluorescence quantum yields, and good photostability. Their structure-optical properties were investigated by X-ray crystal structure analysis and density functional theory calculations. Live cell imaging data revealed that H-hNR and TF-hNR could rapidly stain both A549 and HeLa cells with low concentrations. The excellent photophysical and imaging properties render them as promising candidates for use in live cell imaging.

Aminobenzofuran-fused rhodamine dyes with deep-red to near-infrared emission for biological applications.

Aminobenzofuran-fused rhodamine dyes (AFR dyes) containing an amino group were constructed by an efficient condensation based on 3-coumaranone derivatives. AFR dyes exhibited significantly improved properties, including deep-red and near-infrared emissions, a large Stokes shift, good photostability, and wide pH stability. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium assay experiments show that these AFR dyes are biocompatible for their low cytotoxicity to both A549 and HeLa cells. Cell imaging data reveal that AFR1, AFR1E, and AFR2 are mainly located in the mitochondria, while AFR3 is a lysosome tracker. As far as we know, NIR AFR3 is the longest fluorescent rhodamine derivative containing the amino group. These amino group-containing AFR dyes hold great potential in fluorogenic detection, biomolecule labeling, and cell imaging.

G-quadruplex DNAzymes-induced highly selective and sensitive colorimetric sensing of free heme in rat brain.

Direct selective determination of free heme in the cerebral system is of great significance due to the crucial roles of free heme in physiological and pathological processes. In this work, a G-quadruplex DNAzymes-induced highly sensitive and selective colorimetric sensing of free heme in rat brain is established. Initially, the conformation of an 18-base G-rich DNA sequence, PS2.M (5'-GTGGGTAGGGCGGGTTGG-3'), in the presence of K(+), changes from a random coil to a "parallel" G-quadruplex structure, which can bind free heme in the cerebral system with high affinity through π-π stacking. The resulted heme/G-quadruplex complex exhibits high peroxidase-like activity, which can be used to catalyze the oxidation of colorless ABTS(2-) to green ABTS˙(-) by H2O2. The concentration of heme can be evaluated by the naked eye and determined by UV-vis spectroscopy. The signal output showed a linear relationship for heme within the concentration range from 1 to 120 nM with a detection limit of 0.637 nM. The assay demonstrated here was highly selective and free from the interference of physiologically important species such as dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbate acid (AA), cysteine, uric acid (UA), glucose and lactate in the cerebral system. The basal dialysate level of free heme in the microdialysate from the striatum of adult male Sprague-Dawley rats was determined to be 32.8 ± 19.5 nM (n = 3). The analytic protocol possesses many advantages, including theoretical simplicity, low-cost technical and instrumental demands, and responsible detection of heme in rat brain microdialysate.

Metal-Organic Frameworks@Au Nanoreactor as an Oxidative Stress Amplifier for Enhanced Tumor Photodynamic Therapy through the Alleviation of Hypoxemia and the Depletion of Glutathione.

Recently, photodynamic therapy (PDT) based on the generation of cytotoxic reactive oxygen species (ROS) has drawn great attention in tumor treatment. However, the hypoxia tumor microenvironment (TME) inhibits the generation efficacy of ROS, and the high glutathione (GSH) level in TME could neutralize the generated ROS, both of which strongly reduce the therapeutic efficiency of PDT. In this work, we first constructed the porphyrinic metal-organic framework PCN-224. Then Au nanoparticles were decorated on the PCN-224 to obtain the PCN-224@Au. The decorated Au nanoparticles could not only produce O2 through the decomposition of H2O2 in tumor sites for enhancing the generation of 1O2 in PDT but also deplete glutathione through the strong interactions between Au and sulfhydryl groups on glutathione to weaken the antioxidant ability of tumor cells, thus amplifying the 1O2 damage to cancer cells. The in vitro and in vivo experiments totally exhibited that the as-prepared PCN-224@Au nanoreactor can be used as an oxidative stress amplifier for enhanced PDT, which provides a promising candidate to conquer the limitation of intratumor hypoxia and high GSH level on PDT of cancer.

Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy.

Carbon dots (CDs) have emerged as promising nanomaterials for bioimaging-guided photodynamic therapy (PDT). However, designing red-emissive CDs (RCDs) with tunable type I and type II reactive oxygen species (ROS) generation to simultaneously meet PDT applications in aerobic and hypoxic scenarios still remain major challenges. Herein, three types of RCDs with maximum emission at approximately 680 nm are successfully prepared. It is noteworthy that they exhibit the adjustable ROS production with equal superoxide anion (via type I PDT) and incremental singlet oxygen (via type II PDT). Detailed structural and optical characterizations along with theoretical calculation reveal that the unique type I/II ROS formation mainly depends on the core sizes and surface states of RCDs, which determine their identical redox potentials and tapering energy gaps between singlet- and triplet states, respectively. Additionally, due to the inherent mitochondria targeting capability, RCDs enable themselves to induce cell programmed death via activating mitochondrion-mediated apoptotic pathways. This work exploits the unprecedented RCDs with tunable type I and type II ROS generation that could ensure highly efficient tumor eradication both in vitro and in vivo, even under the harsh tumor microenvironment, providing a new prospect for CDs as nanophotosensitizers to conquer the limitations of single type PDT.

Lysosome-targeted silicon quantum dots theranostics for simultaneous fluorescent imaging and photodynamic therapy.

As an emerging treatment method, photodynamic therapy (PDT) has attracted considerable interest due to the characteristics of non-invasiveness, repeatable treatment, high spatiotemporal resolution and few side effects. However, the life span (<40 ns) and diffusion distance (<20 nm) of reactive oxygen species such as singlet oxygen (1O2) in tumor cells are extremely short, which has seriously limited therapeutic efficacy of PDT. The enrichment site of photosensitizers in cancer cells is usually the first site of PDT action, which will not only affect the biological signaling pathway of cancer cell death, but also is closely related to the final therapeutic effect. Therefore, the design and preparation of photosensitizers targeting specific subcellular organelles can directly break the biological function of the organelle and trigger the corresponding cell death signaling pathway, which can significantly improve the efficacy of PDT. Herein, a lysosome-targeted silicon quantum dots (L-Si QDs) was first made by diethylene glycol-mediated synthetic route as a multicolor fluorescent imaging reagents and a new photosensitizer. The as-prepared L-Si QDs exhibit bright fluorescence with excellent pH stability and time stability, excitation-dependent emission, and good biocompatibility. Furthermore, the results of cell experiments showed that L-Si QDs was accumulated in lysosomes after being taken up by cancer cells, and can efficiently produce1O2upon 635 nm laser irradiation, which can damage lysosomes, up-regulate cleavage caspase-3, increase Bax release, down-regulate Bcl-2 and induce cell apoptosis finally. This study significantly broadens the biomedical applications of silicon quantum dots and provides excellent nanomaterials candidates for tumor phototherapy.

Copper-Bacteriochlorin Nanosheet as a Specific Pyroptosis Inducer for Robust Tumor Immunotherapy.

Pyroptosis is increasingly considered a new weathervane in cancer immune therapy. However, triggering specific pyroptotic tumor cell death while preserving normal cells still remains a major challenge. Herein, a brand-new pyroptosis inducer, copper-bacteriochlorin nanosheet (Cu-TBB), is designed. The synthesized Cu-TBB can be activated to an "on" state in the tumor microenvironment with glutathione (GSH) overexpression, leading to the release of Cu+ and TBB, respectively. Intriguingly, the released Cu+ can drive cascade reactions to produce O2 -• and highly toxic ·OH in cells. Additionally, the released TBB can also generate O2 -• and 1 O2 upon 750 nm laser irradiation. Encouragingly, both Cu+ -driven cascade reactions and photodynamic therapy pathways result in potent pyroptosis along with dendritic cell maturation and T cell priming, thus simultaneously eliminating the primary tumors and inhibiting the distant tumor growth and metastases. Conclusively, the well-designed Cu-TBB nanosheet is shown to trigger specific pyroptosis in vitro and in vivo, leading to enhanced tumor immunogenicity and antitumor efficacy while minimizing systemic side effects.

Copolythiophene-derived colorimetric and fluorometric sensor for visually supersensitive determination of lipopolysaccharide.

3-Phenylthiophene-based water-soluble copolythiophenes (CPT1) were designed for colorimetric and fluorometric detection of lipopolysaccharide (LPS). The sensor (CPT1-C) shows a high selectivity to LPS in the presence of other negatively charged bioanalytes as well an extreme sensitivity with the detection limit at picomolar level, which is the lowest ever achieved among all synthetic LPS sensors available thus far. Significantly, the sensing interaction can be apparently observed by the naked eyes, which presents a great advantage for its practical applications. The appealing performance of sensor was demonstrated to originate from the multiple electrostatic and hydrophobic cooperative interactions, synergetic with signal amplification via the conformational change of the 3-phenylthiophene-based copolymer main chain. As a straightforward application, CPT1-C is capable of rapidly discriminating the Gram-negative bacteria (with LPS in the membrane) from Gram-positive bacteria (without LPS).

Nanoscale fullerene compression of an yttrium carbide cluster.

The nanoscale parameters of metal clusters and lattices have a crucial influence on the macroscopic properties of materials. Herein, we provide a detailed study on the size and shape of isolated yttrium carbide clusters in different fullerene cages. A family of diyttrium endohedral metallofullerenes with the general formula of Y(2)C(2n) (n = 40-59) are reported. The high field (13)C nuclear magnetic resonance (NMR) and density functional theory (DFT) methods are employed to examine this yttrium carbide cluster in certain family members, Y(2)C(2)@D(5)(450)-C(100), Y(2)C(2)@D(3)(85)-C(92), Y(2)C(2)@C(84), Y(2)C(2)@C(3v)(8)-C(82), and Y(2)C(2)@C(s)(6)-C(82). The results of this study suggest that decreasing the size of a fullerene cage with the same (Y(2)C(2))(4+) cluster results in nanoscale fullerene compression (NFC) from a nearly linear stretched geometry to a constrained "butterfly" structure. The (13)C NMR chemical shift and scalar (1)J(YC) coupling parameters provide a very sensitive measure of this NFC effect for the (Y(2)C(2))(4+) cluster. The crystal structural parameters of a previously reported metal carbide, Y(2)C(3) are directly compared to the (Y(2)C(2))(4+) cluster in the current metallofullerene study.

New sensing mechanisms for design of fluorescent chemosensors emerging in recent years.

During the past decade, fluorescent chemosensors have become an important research field of supramolecular chemistry and have attracted great attention because of their simplicity, high selectivity and sensitivity in fluorescent assays. In the design of new fluorescent chemosensors, exploration of new sensing mechanisms between recognition and signal reporting units is of continuing interest. Based on different photophysical processes, conventional sensing mechanisms including photo-induced electron transfer (PET), intramolecular charge transfer (ICT), metal-ligand charge transfer (MLCT), twisted intramolecular charge transfer (TICT), electronic energy transfer (EET), fluorescence resonance energy transfer (FRET), and excimer/exciplex formation have been investigated and reviewed extensively in the literature. This tutorial review will mainly focus on new fluorescent sensing mechanisms that have emerged in the past five years, such as aggregation-induced emission (AIE) and C=N isomerization, which can be ascribed to fluorescence changes via conformational restriction. In addition, excited-state intramolecular proton transfer (ESIPT) has not been well reviewed yet, although a number of chemosensors based on the ESIPT mechanism have been reported. Thus, ESIPT-based chemosensors have been also summarized in this review.

Emerging metal doped carbon dots for promising theranostic applications.

As a bridge between organic fluorophores and inorganic quantum dots, carbon dots (CDs) have been recognized as emerging nanotheranostics for biomedical applications owing to their distinctive merits such as superior optical properties, flexible modification, adjustable functionalities, and remarkable photoactive therapeutic outcome, etc. Compared to metal free CDs, the introduction of metal ion in CDs endowed metal-doped CDs (MCDs) with tunable optical properties and new intrinsic properties, thereby illustrating its different capabilities from metal-free CDs for bioimaging and therapy. This review aims to summarize the recent progress of photonic MCDs as emerging nanoagent for theranostic application such as disease-related diagnostic (involving biosensing and bioimaging) and cancer therapy. The challenges and potential development of MCDs in nanotheranostic fields are also discussed.

Iron phthalocyanine-derived nanozyme as dual reactive oxygen species generation accelerator for photothermally enhanced tumor catalytic therapy.

Nanozymes are artificial enzymes that mimic natural enzyme-like activities and show great promise for tumor catalytic therapy. However, new nanozymes with multiple catalytic activities for multifunctional nanotheranostic use remain challenging to design. Herein, for the first time, iron phthalocyanine (Fe(II)Pc) was assembled with poly(l-lactide-co-glycolide)-block-poly(ethylene glycol) to prepare an Fe(II)Pc assembly (denoted as Fe(II)Pc-A). The obtained Fe(II)Pc-A could be applied as a smart near-infrared (NIR) light-responsive nanotheranostic for simultaneous photoacoustic imaging-guided photothermal therapy. Notably, Fe(II)Pc-A possessed peroxidase, catalase, and oxidase mimicking activities, which could not only catalyze the conversion of intratumoral H2O2 to •OH, but also degrade H2O2 to generate O2 and continuously catalyze the conversion of O2 to cytotoxic O2•-. Impressively, the dual reactive oxygen species (ROS) generation of Fe(II)Pc-A was further remarkably enhanced by the endogenous acidity of the tumor microenvironment and the exogenous NIR light-responsive photothermal effect. Moreover, the O2 self-supplying ability of Fe(II)Pc-A led to increased generation of O2•- for enhancing catalytic therapy in hypoxic tumor. These collective properties of Fe(II)Pc-A nanozyme enabled it to be a dual ROS generation accelerator for photothermally enhanced tumor catalytic therapy. Thus, a new type of high-performance nanozyme for multifunctional nanotheranostic use toward cancer was presented.

Gd2@C79N: isolation, characterization, and monoadduct formation of a very stable heterofullerene with a magnetic spin state of S = 15/2.

The dimetallic endohedral heterofullerene (EHF), Gd(2)@C(79)N, was prepared and isolated in a relatively high yield when compared with the earlier reported heterofullerene, Y(2)@C(79)N. Computational (DFT), chemical reactivity, Raman, and electrochemical studies all suggest that the purified Gd(2)@C(79)N, with the heterofullerene cage, (C(79)N)(5-) has comparable stability with other better known isoelectronic metallofullerene (C(80))(6-) cage species (e.g., Gd(3)N@C(80)). These results describe an exceptionally stable paramagnetic molecule with low chemical reactivity with the unpaired electron spin density localized on the internal diatomic gadolinium cluster and not on the heterofullerene cage. EPR studies confirm that the spin state of Gd(2)@C(79)N is characterized by a half-integer spin quantum number of S = 15/2. The spin (S = ½) on the N atom of the fullerene cage and two octet spins (S = 7/2) of two encapsulated gadoliniums are coupled with each other in a ferromagnetic manner with a small zero-field splitting parameter D. Because the central line of Gd(2)@C(79)N is due to the Kramer's doublet with a half-integer spin quantum number of S = 15/2, this relatively sharp line is prominent and the anisotropic nature of the line is weak. Interestingly, in contrast with most Gd(3+) ion environments, the central EPR line (g = 1.978) is observable even at room temperature in a toluene solution. Finally, we report the first EHF derivative, a diethyl bromomalonate monoadduct of Gd(2)@C(79)N, which was prepared and isolated via a modified Bingel-Hirsch reaction.

Hierarchically nanoporous ceria nanoparticles with a high-surface area: synthesis, characterization, and their catalytic activity.

A redox route based on ethylene glycol mediated process was developed to synthesize hierarchically nanoporpous ceria nanoparticles (ceria HNPNPs). The synthesized ceria HNPNPs are composed of building blocks fabricated with cubic ceria nanocrystals of several nanometers in diameter. Scanning electron microscopy was performed to investigate the evolution process of ceria precursor, and a two-step growth process was suggested for the morphology evolution. The synthesized ceria HNPNPs exhibit high surface area, which lead to high catalytic activity for CO oxidation.