Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 1, 2024

The metal-nucleic acid nanocomposites, first termed frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the efficiency stability of by increasing oligonucleotide folding entanglement probabilities during reaction. Besides, provide upgraded metal ions binding facilitating to load macromolecular protein drugs at room temperature. Furthermore, facilitate expansion nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, build an interferon regulatory factor-1(IRF-1) loaded Ca

Язык: Английский

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Functional Nucleic Acids-Engineered Bio-Barcode Nanoplatforms for Targeted Synergistic Therapy of Multidrug-Resistant Cancer

ACS Nano, Год журнала: 2023, Номер 17(14), С. 13533 - 13544

Опубликована: Июль 17, 2023

Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy cancers. Herein, we have constructed functional nucleic acids (FNAs)-engineered nanoplatforms based on concept a bio-barcode (BBC) for synergistic targeted therapy multidrug-resistant (MDR) cancer. In this study, platinum(IV) prodrug is synthesized to covalently link two kinds FNAs at rational ratio fabricate three-dimensional BBC-like DNA nanoscaffolds, accompanied by one-pot encapsulation ZnO nanoparticles (NPs) through electrostatic interaction. The multivalent AS1411 aptamers equipped in ZnO@BBCs facilitate specific and efficient endocytosis into MDR human lung adenocarcinoma cells (A549/DDP). response intracellular environment A549/DDP cells, such as lysosome-acidic pH overexpressed GSH, NPs are degraded Zn2+ ions generating reactive oxygen species (ROS), while Pt(IV) prodrugs reduced Pt(II) active glutathione (GSH), followed release DNAzymes chemotherapy gene therapy. particular, designed system plays an important role remodeling reverse cancer MDR. On one hand, depletion GSH promotes downregulation peroxidase 4 (GPX4) amplifying oxidative stress increasing lipid peroxidation (LPO), resulting activation ferroptosis. other silence early growth protein 1 (Egr-1) mRNA Zn2+-dependent directly inhibits proliferation migration which further suppresses P-glycoprotein (P-gp)-mediated drug efflux. Thus, proposed show great promise development versatile tools personalized

Язык: Английский

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Site-Specific Bioorthogonal Activation of DNAzymes for On-Demand Gene Therapy

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(32), С. 17926 - 17935

Опубликована: Авг. 3, 2023

RNA-cleaving DNAzymes hold great promise as gene silencers, and spatiotemporal control of their activity through site-specific reactions is crucial but challenging for on-demand therapy. We herein report a novel design bioorthogonally inducible DNAzyme that deactivated by installation bioorthogonal caging groups on the designated backbone sites restores via phosphine-triggered Staudinger reduction. perform systematical screening installing each site in catalytic core 10–23 identify an with very low leakage activity. This demonstrated to achieve controlled cleavage exogenous endogenous mRNA live cells. It further extended photoactivation stimuli activation or targeted silencing. The applied triple-negative breast cancer mouse model using lipid nanoparticle delivery system, demonstrating high efficiency knockdown Lcn2 oncogenes substantial suppression tumor growth, thus highlighting potential precisely controlling functions

Язык: Английский

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Software Infrastructure for Next-Generation QM/MM−ΔMLP Force Fields

The Journal of Physical Chemistry B, Год журнала: 2024, Номер 128(26), С. 6257 - 6271

Опубликована: Июнь 21, 2024

We present software infrastructure for the design and testing of new quantum mechanical/molecular mechanical machine-learning potential (QM/MM-ΔMLP) force fields a wide range applications. The integrates Amber's molecular dynamics simulation capabilities with fast, approximate models in xtb package corrections DeePMD-kit. implements recently developed density-functional tight-binding QM multipolar electrostatics density-dependent dispersion (GFN2-xTB), interface Amber enables their use periodic boundary QM/MM simulations linear-scaling particle-mesh Ewald electrostatics. accuracy semiempirical is enhanced by including correction potentials (ΔMLPs) enabled through an DeePMD-kit software. goal this paper to validate implementation free energy simulations. utility demonstrated proof-of-concept example elements presented here are open source freely available. Their provides powerful enabling technology QM/MM-ΔMLP studying problems, biomolecular reactivity protein-ligand binding.

Язык: Английский

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Strand-Cleaving Deoxyribozymes Enable the Mid-Down Sequencing of mRNA by Mass Spectrometry with No Front-End Separations

Analytical Chemistry, Год журнала: 2025, Номер 97(5), С. 2972 - 2980

Опубликована: Янв. 31, 2025

We evaluated the possible application of RNA-cleaving deoxyribozymes to control number and size cleavage products obtained during mid-down characterization larger nucleic acids by mass spectrometry (MS). assessed structural determinants substrate selectivity, as well effects cofactor, additives, environmental parameters on activity histidine-dependent deoxyribozyme 3 (HD3). designed dedicated sets HD3 variants capable cleaving RNA strands large 758 nt enhanced green fluorescent protein (eGFP) mRNA. This was dissected into only 10 oligonucleotides with lengths ranging from 46 120 nt, which compared favorably 87 unique 14 be expected instead putative RNase T1 digestion. The complexity such mixture sufficiently limited enable its comprehensive analysis direct infusion nanospray-MS without front-end separation. Their unambiguous assignment accomplished matching experimental predicted masses, revealed formation mis-cleaved enabled mapping 100% initial substrate. Product identity verified collision-induced dissociation (CID), provided individual sequence coverages 100%, lower figure a product. All information combined accounted for 95% coverage substrate, but all ambiguities engendered classic nucleotide-specific endonucleases. outcome demonstrated feasibility approaches based underscored their potential in RNAs.

Язык: Английский

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DNA Nanoflower Eye Drops with Antibiotic‐Resistant Gene Regulation Ability for MRSA Keratitis Target Treatment

Small, Год журнала: 2023, Номер 19(47)

Опубликована: Июль 25, 2023

Methicillin-resistant Staphylococcus aureus (MRSA) biofilm-associated bacterial keratitis is highly intractable, with strong resistance to β-lactam antibiotics. Inhibiting the MRSA gene mecR1 downregulate penicillin-binding protein PBP2a has been implicated in sensitization of antibiotics MRSA. However, oligonucleotide regulators struggle penetrate dense biofilms, let alone achieve efficient regulation inside bacteria cells. Herein, an eye-drop system capable penetrating biofilms and targeting for chemo-gene therapy MRSA-caused developed. This employed rolling circle amplification prepare DNA nanoflowers (DNFs) encoding MRSA-specific aptamers deoxyribozymes (DNAzymes). Subsequently, antibiotic ampicillin (Amp) zinc oxide (ZnO) nanoparticles are sequentially loaded into DNFs (ZnO/Amp@DNFs). Upon application, ZnO on surface nanosystem disrupts structure biofilm fully exposes free bacteria. Later, bearing encoded aptamer, nanoflower intensively endocytosed by bacteria, releases DNAzyme under acidic conditions cleave down-regulation, elimination. In vivo tests showed that effectively cleared cornea, suppressed proinflammatory cytokines interleukin 1β （IL-1β） tumor neocrosis factor-alpha （TNF-α）, safe corneal epithelial Overall, this design offers a promising approach treating MRSA-induced keratitis.

Язык: Английский

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Bioorthogonal Activation of RCA-Based Amplifiable DNAzymes in Bimetallic NMOF for Precise Gene/Chemo-Dynamic Combination Therapy

ACS Materials Letters, Год журнала: 2024, Номер 6(2), С. 498 - 507

Опубликована: Янв. 3, 2024

Controllable and sufficient concentrations of therapeutic agents in gene therapy are critical to achieve satisfactory outcomes. Herein, a Zn2+/Cu2+ bimetallic nano metal–organic framework loaded with rolling circle amplification (RCA) substrates (termed PZCT) was established for precise efficient DNAzyme-based chemo-dynamic combined therapy. The activation PZCT is bioorthogonally controlled by tumor-specific miR-21, which generates numerous DNAzyme silencing EGR-1 mRNA the assistance Zn2+ from PZCT. Simultaneously, doped copper ions on exert (CDT) reducing glutathione (GSH) converting endogenous hydrogen peroxide (H2O2) into hydroxyl radical (·OH). These combination therapies exhibited remarkable tumor elimination effects vivo promised excellent specificity via bioorthogonal strategy. proposed nanoplatform offers new prospects cancer therapeutics overcoming low transfection efficiency off-target toxicity approaches.

Язык: Английский

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Engineered Microorganisms for Advancing Tumor Therapy

Advanced Materials, Год журнала: 2024, Номер 36(24)

Опубликована: Март 15, 2024

Engineered microorganisms have attracted significant interest as a unique therapeutic platform in tumor treatment. Compared with conventional cancer treatment strategies, engineering microorganism-based systems provide various distinct advantages, such the intrinsic capability targeting tumors, their inherent immunogenicity, situ production of antitumor agents, and multiple synergistic functions to fight against tumors. Herein, design, preparation, application engineered for advanced therapy are thoroughly reviewed. This review presents comprehensive survey innovative strategies based on series representative microorganisms, including bacteria, viruses, microalgae, fungi. Specifically, it offers extensive analyses design principles, mechanisms, well advantages limitations different systems. Finally, current challenges future research prospects this field, which can inspire new ideas creative paradigms utilizing facilitate clinical applications, discussed.

Язык: Английский

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Research Progress of Metal–Organic Frameworks as Drug Delivery Systems

ACS Applied Materials & Interfaces, Год журнала: 2024, Номер 16(33), С. 43156 - 43170

Опубликована: Авг. 12, 2024

Metal-organic frameworks (MOFs) are composite crystalline materials created through the coordination of metal ions and organic ligands. MOFs have attracted extensive attention in biomedical field based on advantages internal porosity, customizable facile surface modification. This review examines utilization drug delivery systems, focusing research progress from aspects coloading intelligent responsive carriers, biological macromolecule stabilizers, self-driving micro/nanomotors, multifunctional living carriers. In addition, current challenges faces also discussed. The aims to provide a reference for further application as advanced systems.

Язык: Английский

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Advancing cancer treatments: The role of oligonucleotide-based therapies in driving progress

Molecular Therapy — Nucleic Acids, Год журнала: 2024, Номер 35(3), С. 102256 - 102256

Опубликована: Июнь 17, 2024

Although recent advancements in cancer immunology have resulted the approval of numerous immunotherapies, minimal progress has been observed addressing hard-to-treat cancers. In this context, therapeutic oligonucleotides, including interfering RNAs, antisense aptamers, and DNAzymes, gained a central role approaches due to their capacity regulate gene expression protein function with reduced toxicity compared conventional chemotherapeutics. Nevertheless, systemic administration naked oligonucleotides faces many extra- intracellular challenges that can be overcome by using effective delivery systems. Thus, viral non-viral carriers improve oligonucleotide stability uptake, enhance tumor accumulation, increase probability endosomal escape while minimizing other adverse effects. Therefore, gaining more insight into fundamental mechanisms actions various posed administration, article provides comprehensive review on systems an overview completed ongoing clinical trials shape future oncological treatments.

Язык: Английский

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