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Here, we provide an out-of-the-box G-quadruplex (G4) targeting-based strategy for rescuing mitochondrial dysfunction in Alzheimer's disease. We predict and verify the presence of G4s within the promoter of an ageing epigenetic regulator BAZ2B. G4-specific ligands targeting BAZ2B G4s could significantly down-regulate the BAZ2B expression and relieve mitochondrial dysfunction. Therefore, this work may provide a new way of rescuing mitochondrial dysfunction in AD by targeting G4s in a specific ageing epigenetic regulator promoter.

Chiral metallohelix ΛA inhibited amyloid-β aggregation with enantioselectivity in vivo. Beyond the intrinsic bioactivity, alkyne-bearing ΛA was employed as a building block for convenient visualization and versatile modification via click reaction.

COF-based artificial probiotics, functioning like natural probiotics, markedly relieve IBD by modulating the gut microbiota, suppressing intestinal inflammation, protecting the intestinal epithelial cells, and regulating immunity.

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been widely regarded as a promising avenue in bioorthogonal chemistry. The emerging heterogeneous copper catalysts have been developed with a series of exciting applications such as

The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.

Ferroptosis, resulting from the catastrophic accumulation of lipid reactive oxygen species (ROS) and the inactivation of glutathione (GSH)-dependent peroxidase 4 (GPX4), has emerged as a form of regulated cell death for cancer therapy. Despite progress made with current ferroptosis inducers, efficient systems to trigger ferroptosis remain challenging, owing largely to their low activity, uncontrollable behavior, and even nonselective interactions. Here, we report a self-adaptive ferroptosis platform by engineering a DNA modulator onto the surface of single-atom nanozymes (SAzymes). The modulator could not only specifically intensify the ROS-generating activity but also endow the SAzymes with on-demand GSH-consuming ability in tumor cells, accelerating selective and safe ferroptosis. The self-adaptive antitumor response has been demonstrated in colon cancer and breast cancer, promoting the development of selective cancer therapy.

Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a spatiotemporally controllable therapeutic modality in combating cancer because of its high tissue-penetration depth and minimal invasiveness. However, the elevated nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant program in cancer cells can serve as a chief reactive oxygen species (ROS) detoxification system to alleviate oxidative injury and promote tumorigenesis, and thus greatly antagonize the therapeutic efficacy of ROS-mediated anticancer therapies. Herein, we report that vanadium carbide MXene-derived carbon dots (PMQDs) can act as high-efficacy sonosensitizers to efficiently generate ROS upon US irradiation and simultaneously hinder the Nrf2 antioxidant program for enhanced sonodynamic therapy of cancer. These PMQDs show superior US-triggered ROS generating ability because of their efficient migration/separation of electron-hole pairs and narrow bandgap. Importantly, these PMQDs can serve as efficient redox homeostasis regulators to perturb the Nrf2 antioxidant mechanism and thus reduce its effects on ROS neutralization for enhanced SDT efficacy. Overall, the present study will not only provide a new paradigm to augment SDT by perturbing the Nrf2 antioxidant program, but also give valuable insights into developing high-efficacy MXene-derived nanoagents for cancer therapy.

A magnetoelectrically ignited nanozyme-eel was developed, which could generate abundant surface charges upon the ignition of an alternating magnetic field, leading to a controllable electron transport burst between the nanozyme-eel and bacteria for the eradication of bacterial biofilms.

Tumor-associated macrophages (TAMs) that infiltrate in most tumor tissues are closely correlated with proliferation and metastasis of tumor cells. Immunomodulation of TAMs from pro-tumorigenic M2 phenotype to anti-tumorigenic M1 phenotype is crucial for oncotherapy. Herein, an iron nanotrap was utilized to remodel TAMs for tumor growth inhibition. In the formulation, the ultrasmall nanotrap could capture and targetedly transport endogenous iron into TAMs even inside the tumor. Upon exposing to the lysosomal acidic conditions and intracellular H

Off-target toxicity and insufficient hydroxyl radicals (. OH) generation limit the further clinical application of nanozymes in chemodynamic therapy (CDT). Herein, we designed and constructed a microRNA-triggered nanozyme cascade platform for enhanced tumor-specific chemodynamic therapy. The nanozyme-based cascade reaction could be triggered successfully by the high expression of microRNA in cancer cells to generate more . OH, thus exhibiting excellent tumor-specific therapeutic performance. Our work provides a new dimension for tumor-specific chemodynamic therapy.

Bioorthogonal catalysis mediated by Pd-based transition metal catalysts has sparked increasing interest in combating diseases. However, the catalytic and therapeutic efficiency of current Pd0 catalysts is unsatisfactory. Herein, inspired by the concept that ligands around metal sites could enable enzymes to catalyze astonishing reactions by changing their electronic environment, LM-Pd catalyst with liquid metal (LM) as an unusual modulator has been designed to realize efficient bioorthogonal catalysis for tumor inhibition. LM matrix can serve as a "ligand" to afford an electron-rich environment to stabilize the active Pd0 and promote nucleophilic turnover of the p-allylpalladium species to accelerate the uncaging process. Besides, the photothermal properties of LM can lead to the enhanced removal of tumor cells by photo-enhanced catalysis and photothermal effect. We believe that our work will broaden the application of LM and motivate the design of bioinspired bioorthogonal catalysts.

Multi-nanozymes are widely applied in disease treatment, biosensing, and other fields. However, most current multi-nanozyme systems exhibit only moderate activity since reaction microenvironments of different nanozyme are often distinct or even incompatible. Conventional assemble strategies are inapplicable for designing multi-nanozymes consisting of incompatible nanozymes. Herein, a versatile fiber-based compartmentalization strategy is developed to construct multi-nanozyme system capable of simultaneously performing incompatible reactions. In this system, the incompatible nanozymes are spatially distributed in distinct compartmentalized fibers, where different microenvironments can be tailored by controlling the doping reagent, endowing each nanozymes with the preferential microenvironments to exhibit their highest activity. As a proof of concept, pH-incompatible peroxidase-like and catalase-like catalytic reactions are tested to verify the feasibility of this strategy. By doping with benzoic acid in the desired location, the two pH-incompatible nanozymes can work simultaneously without interference. Further, it is demonstrated that the oxygen supply and antimicrobial power of the integrated platform can be applied for accelerating diabetic wound healing. It is hoped that this work provides a way to integrate incompatible nanozyme and broadens the application potential of multi-nanozymes.

As a burgeoning bioorthogonal reaction, the fluoride-mediated desilylation is capable of prodrug activation. However, due to the reactions lack of cell selectivity and unitary therapy modality, this strongly impedes their biomedical applications. Herein, we construct a cancer cell-selective biomimetic metal-organic framework (MOF)-F platform for prodrug activation and enhanced synergistic chemodynamic therapy (CDT). With cancer cell membranes camouflage, the designed biomimetic nanocatalyst displays preferential accumulation to homotypic cancer cells. Then, pH-responsive nanocatalyst releases fluoride ions and ferric ions. For activation of our designed prodrug

As a neat combination of the characteristics of enzymatic activity and nanomaterials, nanozymes have attracted much attention. Although tremendous effort has been devoted to developing nanozymes with high catalytic activity, substrate selectivity is often overlooked in the construction of nanozymes. With their subtly evolving structures, natural enzymes generally possess high selectivity for chiral substrates which play important roles in biosynthesis and biomedical applications. However, the rational construction of nanozymes with high enantioselectivity remains a significant challenge. In this Minireview, we provide an overview of recent advances in strategies for the synthesis of chiral nanozymes and their enantioselective biological catalysis. We further focus on current challenges, potential solutions, and future developing trends of chiral nanozyme-based enantioselective biological catalysis. There is plenty of room to explore. This Minireview will provide new insights into the development of chiral nanozymes and their applications.

The intelligent nanomachine usually has a control center to carry out self-regulation. Unfortunately, most of the nanomaterials for chemodynamic therapy (CDT) do not have such a control center to sense and process the chemical or biological signals, which greatly weakens the selectivity and efficiency of CDT. To address this problem, here an intelligent nanomachine was constructed with a DNAzyme logic gate as the control center, and metal organic framework as the actuator. The well-designed nanomachine showed an enhanced killing effect on cancer cells but posed no harm to normal cells, acquiring better selectivity than clinical chemotherapy drugs (doxorubicin and cisplatin). To the best of our knowledge, this is the first reported cell-specific CDT by the guidance of DNAzyme logic gate. Our work highlights the great potential of DNAzymes in intelligent response networks, and extends the implementation of nanomachines in precision medicine.

Although chemotherapy is one of the most widely used cancer treatments, there are serious side effects, drug resistance, and secondary metastasis. To address these problems, herein we designed a bimetallic metal-organic framework (MOF) encapsulated with DNAzyme for co-triggered in situ cancer drug synthesis and DNAzyme-based gene therapy. Once in cancer cells, MOFs would disassemble and liberate copper ions, zinc ions, and DNAzyme under the acidic environment of lysosomes. Copper ions can catalyze the synthesis of the chemotherapeutic drug through copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction after being reduced to CuI ; zinc ions act as the cofactor to activate the cleavage activity of DNAzyme. The anticancer drug is synthesized intracellularly and can kill cancer cells on site to minimize side effects to normal organisms. The activated DNAzyme starts gene therapy to inhibit tumor proliferation and metastasis by targeting and cleaving oncogene substrates.

Alzheimer's disease (AD), as the primary cause of dementia, has seriously affected millions of people worldwide and brought a very heavy financial and social burden. With the growth of population and aging, the situation will worsen unless efficacious drugs are found to reverse, stop, or even slow down disease progression. More and more evidence has demonstrated that amyloid-β (Aβ) aggregation is an upstream causative factor in AD pathogenesis and then triggers a slew of pathological events. Furthermore, the concentrated redox metal ions in the AD brain, especially Cu(II), can significantly exacerbate Aβ aggregation and contribute to the formation of neurotoxic reactive oxygen species (ROS). Therefore, the inhibition of Aβ aggregation and relief of amyloidosis-initiated neurotoxicity play a critical role in AD treatment. Until now, several methods have been proposed to modulate Aβ aggregation, such as developing aggregation inhibitors to interfere with Aβ assembly via noncovalent interactions, copper chelators to cut off metal-accelerated Aβ aggregation and concomitant cytotoxicity, photooxidation to reduce the hydrophobicity and aggregation tendency of Aβ, thermal dissociation to disrupt amyloid aggregates susceptible to temperature, degradation with artificial protease to fracture the Aβ peptide into small fragments, and the clearance of peripheral Aβ to bypass the obstruction of the BBB and reduce the Aβ burden.In this Account, we focus on our contributions to the development of Aβ-targeted multifunctional molecules and nanoparticles, emphasizing the diversified strategies and synergistic therapeutic effects. These therapeutic agents possess the following multifunctionalities: (1) compared with frequently used aggregation inhibitors restricted by intrinsically feeble and sensitive noncovalent interactions, multifunctional agents can efficiently block Aβ aggregation by exploiting two or more Aβ-specific inhibition strategies simultaneously; (2) apart from regulating Aβ aggregation, multipronged agents can also target and modulate other pathological factors in AD pathogenesis, such as increased oxidative stress, abnormal copper accumulation, and irreversible neuron loss; (3) multifunctional platforms with both diagnostic and therapeutic modalities through integrating in situ imaging, real-time diagnostics, a multitarget direction, stimuli-responsive drug release, and the blood-brain barrier (BBB) translocation features are instrumental in improving drug levels at trouble sites, diminishing off-target adverse reactions, evaluating therapeutic effects, and averting overtreatment.Given the fact that amyloid aggregation, local inflammation, and metal dyshomeostasis are universal biomarkers shared by various neurodegenerative disorders, this Account provides a perspective for the evolution of customized therapeutic agents with multiple reactivities for other neurodegenerative diseases. In addition, recent studies have indicated that Aβ aggregates can enter the nucleus and induce DNA damage and anomalous conformational transition. We also explore the influences of DNA on the biological effects of Aβ aggregates.

Herein, an environmentally friendly biomimetic strategy was proposed and validated for the catalytic hydrogenation reaction in live bacteria. First, we used a thermophilic hydrogen-producing bacterial strain to in situ prepare ultrafine gold nanoparticles (AuNPs) and palladium nanoparticles (PdNPs). Then, by utilizing AuNPs or PdNPs as catalysts and on-site hydrogen gas generated directly through living thermophilic hydrogen-producing bacteria, we realized highly efficient asymmetric hydrogenation reactions.

An amphiphilic taurocholic acid (TCA) doped polypyrrole (PPy) film (PPy/TCA) was used as a dynamic mimic membrane model to explore how switchable surface wettability influences amyloid aggregation. Our results indicate that the hydrophobic surface, not the hydrophilic surface, plays important roles in Aβ40 adsorption and aggregation.