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1.
ACS Nano ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34766752

RESUMO

Surface modification of inorganic nanomaterials with biomolecules has enabled the development of composites integrated with extensive properties. Lanthanide ion-doped upconversion nanoparticles (UCNPs) are one class of inorganic nanomaterials showing optical properties that convert photons of lower energy into higher energy. Additionally, DNA oligonucleotides have exhibited powerful capabilities for organizing various nanomaterials with versatile topological configurations. Through rational design and nanotechnology, DNA-based UCNPs offer predesigned functionality and potential. To fully harness the capabilities of UCNPs integrated with DNA, various DNA-UCNP composites have been developed for diagnosis and therapeutics. In this review, beginning with the introduction of the UCNPs and the conjugation of DNA strands on the surface of UCNPs, we present an overview of the recent progress of DNA-UCNP composites while focusing on their applications for bioanalysis and therapeutics.

2.
Nat Commun ; 12(1): 6584, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34782610

RESUMO

Despite bacterial-mediated biotherapies have been widely explored for treating different types of cancer, their implementation has been restricted by low treatment efficacy, due largely to the absence of tumor-specific accumulation following administration. Here, the conjugation of aptamers to bacterial surface is described by a simple and cytocompatible amidation procedure, which can significantly promote the localization of bacteria in tumor site after systemic administration. The surface density of aptamers can be easily adjusted by varying feed ratio and the conjugation is able to increase the stability of anchored aptamers. Optimal bacteria conjugated with an average of 2.8 × 105 aptamers per cell present the highest specificity to tumor cells in vitro, separately generating near 2- and 4-times higher accumulation in tumor tissue at 12 and 60 hours compared to unmodified bacteria. In both 4T1 and H22 tumor-bearing mouse models, aptamer-conjugated attenuated Salmonella show enhanced antitumor efficacy, along with highly activated immune responses inside the tumor. This work demonstrates how bacterial behaviors can be tuned by surface conjugation and supports the potential of aptamer-conjugated bacteria for both targeted intratumoral localization and enhanced tumor biotherapy.

3.
Anal Chem ; 93(40): 13727-13733, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34596402

RESUMO

As an early-stage tumor biomarker, microRNA (miRNA) has clinical application potential and its sensitive and accurate detection is significant for early tumor diagnosis. In this study, a photoelectrochemical (PEC) biosensing platform was fabricated for ultrasensitive miRNA-141 detection, which is based on a photocurrent polarity-switchable system using CdS quantum dots (QDs) in the presence of a 5,10,15,20-tetrakis (4-aminophenyl)-21H,23H-porphine (Tph-2H)-coated glassy carbon electrode (GCE). As an excellent photoactive material, Tph-2H has a narrow band gap that effectively gathers photoelectrons under visible light irradiation and improves the transfer ability of photogenerated electrons. Further, the detection sensitivity of miRNA-141 could be significantly improved by combining an enzyme-assisted recycle amplification reaction and a magnetic bead-based separation strategy. The proposed photocurrent polarity-switchable PEC biosensor could efficiently eliminate the false-positive or false-negative signals and achieve a wide linear response range from 1 fM to 1 nM with a low detection limit of 0.33 fM for miRNA-141, providing a potentially alternative solution for detecting other biomarkers in bioanalysis and clinical diagnosis.


Assuntos
Biomarcadores Tumorais/análise , Técnicas Biossensoriais , MicroRNAs/análise , Pontos Quânticos , Técnicas Eletroquímicas , Humanos , Limite de Detecção
4.
Reprod Biol Endocrinol ; 19(1): 158, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641897

RESUMO

BACKGROUND: Synchronization of follicles is key to improving ovulation stimulation with the gonadotropin-releasing hormone (GnRH) antagonist protocol. GnRH antagonist administration in the early follicular phase can quickly decrease gonadotrophin (Gn) levels and achieve downregulation before stimulation, which may improves synchronization. A previous small randomized controlled study (RCT) showed that pretreatment with a GnRH antagonist for 3 days before stimulation may increase oocyte retrieval but cannot increase the pregnancy rate. This study investigated whether the GnRH antagonist pretreatment protocol in ovulatory women can increase the synchronization of follicles and pregnancy outcomes compared with the conventional GnRH antagonist protocol. METHODS: This RCT included 136 normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Both groups were treated with recombinant follicle-stimulating hormone (r-FSH) and a flexible GnRH antagonist protocol. The women were randomized into two equal groups with or without GnRH antagonist administration from day 2 of the menstrual cycle for 3 days before stimulation. Our primary outcome was the number of retrieved oocytes. Secondary outcomes included the pregnancy rate and live birth rate. RESULTS: Both groups had similar baseline characteristics. The number of retrieved oocytes in the study group was comparable to that in the control group (9.5 [8.0-13.0] vs. 11.0 [7.0-14.8], P = 0.469). There was no significant difference in the follicle size. The fertilization rate, number of good-quality embryos, implantation rate, pregnancy rate, ongoing pregnancy rate, live birth rate per embryonic transfer cycle, and miscarriage rate were similar between the two groups. CONCLUSION: This large RCT analysed GnRH antagonist pretreatment with the GnRH antagonist protocol applied to normal ovulatory women undergoing IVF/ICSI. The number of retrieved oocytes and pregnancy outcomes did not significantly vary. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800019730 . Registered 26 November 2018.

5.
Nano Lett ; 21(21): 9030-9037, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34699244

RESUMO

Low-cost and flexible biofilm humidity sensors with good wet strength are crucial for humidity detection. However, it remains a great challenge to integrate good reversibility, rapid humidity response, and robust humid mechanical strength in one sensor. In this respect, we report a facile method to prepare a sustainable biofilm (named MC film) from sisal cellulose microcrystals (MSF-g-COOH) and citric acid (CA). After cross-linking with CA, the MC film exhibits excellent wet strength and rapid humidity response. More importantly, MC film can be used over a wide temperature range with excellent durability and reversibility for humidity detection. A highly sensitive humidity sensor fabricated from the MC film exhibits high reversibility and excellent water resistance and can be applied in humidity and personalized breath health monitoring. Our work fills the gap between biomaterial design and high-performance sensing devices.

6.
Chem Soc Rev ; 50(22): 12551-12575, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34604889

RESUMO

Nucleic acids, with the advantages of programmability and biocompatibility, have been widely used to design different kinds of novel biocomputing devices. Recently, nucleic acid-based molecular computing has shown promise in making the leap from the test tube to the cell. Such molecular computing can perform logic analysis within the confines of the cellular milieu with programmable modulation of biological functions at the molecular level. In this review, we summarize the development of nucleic acid-based biocomputing devices that are rationally designed and chemically synthesized, highlighting the ability of nucleic acid-based molecular computing to achieve cellular applications in sensing, imaging, biomedicine, and bioengineering. Then we discuss the future challenges and opportunities for cellular and in vivo applications. We expect this review to inspire innovative work on constructing nucleic acid-based biocomputing to achieve the goal of precisely rewiring, even reconstructing cellular signal networks in a prescribed way.


Assuntos
Computadores Moleculares , Ácidos Nucleicos , Bioengenharia , DNA , Lógica
7.
Artigo em Inglês | MEDLINE | ID: mdl-34676964

RESUMO

Currently, the broad use of monovalent aptamers in oncology faces challenges, including insufficient recognition and internalization caused by finite unitary receptors, as well as confined recognition spectrum. Herein, we describe the development of a dual-targeting circular aptamer (DTCA) that can recognize two different biomarkers on living cells to augment aptamer-receptor interactions, thus allowing the enhanced recognition event to occur. This improvement not only boosts binding and internalization abilities, but also expands the recognition spectrum for different leukemia cells. Moreover, the stability of DTCA in serum can be significantly improved by an enzyme-promoted terminal ligation strategy. The chemical incorporation of 5-fluorodeoxyuridine into DTCA resulted in a pharmaceutically functional aptamer that exhibited excellent selectivity, as demonstrated by its high cytotoxicity against target cancer cells, but not to normal cells. The superiority of our newly developed strategy was further highlighted by its precise tumor imaging capability.

9.
J Am Chem Soc ; 143(39): 16113-16127, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34582167

RESUMO

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.

10.
Adv Mater ; 33(45): e2102271, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34554618

RESUMO

Long-term accumulation of adenosine (Ado) in tumor tissues helps to establish the immunosuppressive tumor microenvironment and to promote tumor development. Regulation of Ado metabolism is particularly pivotal for blocking Ado-mediated immunosuppression. The activity of adenosine kinase (ADK) for catalyzing the phosphorylation of Ado plays an essential role in regulating Ado metabolism. Specifically, accumulated Ado in the tumor microenvironment occupies the active site of ADK, inhibiting the phosphorylation of Ado. Phosphate can protect ADK from inactivation and restore the activity of ADK. Herein, calcium phosphate-reinforced iron-based metal-organic frameworks (CaP@Fe-MOFs) are designed to reduce Ado accumulation and to inhibit Ado-mediated immunosuppressive response in the tumor microenvironment. CaP@Fe-MOFs are found to regulate the Ado metabolism by promoting ADK-mediated phosphorylation and relieving the hypoxic tumor microenvironment. Moreover, CaP@Fe-MOFs can enhance the antitumor immune response via Ado regulation, including the increase of T lymphocytes and dendritic cells and the decrease of regulatory T lymphocytes. Finally, CaP@Fe-MOFs are used for cancer treatment in mice, alleviating the Ado-mediated immunosuppressive response and achieving tumor suppression. This study may offer a general strategy for blocking the Ado-mediated immunosuppression in the tumor microenvironment and further for enhancing the immunotherapy efficacy in vivo.

11.
Nano Lett ; 21(16): 6946-6951, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34396773

RESUMO

Despite its polyanionic nature, DNA can cross the negatively charged membrane to enter living cells by assembling into specific nanostructures, establishing various opportunities for biomedical applications. Mechanistic studies to explain how the geometrical parameters of DNA nanostructures impact the cell entry are critical but elusive. Here, we use experimentation and simulation to study the interaction between cells and three typical framework nucleic acids (FNAs), including tetrahedron, triangular prism, and cube. Different cellular uptake efficiency was observed among these FNAs, and similar distinction consistently existed in multiple cell lines. Scavenger receptors (SRs) were demonstrated to be essential in mediating the uptake process. Molecular docking simulations revealed that the SR binding predominantly depended on the corner angle of FNAs, determining cellular internalization frequency. This study clearly explains how FNAs interact with the membrane to initiate cell entry, offering new clues for the design of theranostic nanocarriers and the study of virus invasion.


Assuntos
Nanoestruturas , Ácidos Nucleicos , DNA , Simulação de Acoplamento Molecular , Internalização do Vírus
12.
J Am Chem Soc ; 143(36): 14573-14580, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34464111

RESUMO

Quantum-size metal clusters with multiple delocalized electrons could support collective plasmon excitation, and thus, theoretically, coupling of plasmons in the few-atom limit might exist between assembled metal clusters, while currently few experimental observations about this phenomenon have been reported. Here we examined the optical absorption of DNA-templated Ag nanoclusters (DNA-AgNCs) assembled through DNA hybridization and found their absorption peaks were sensitive to the assembled distances, which share common characteristics with classical plasmon coupling. Dipolar charge distribution, multiple transition contributed optical absorption, and strongly enhanced electric field simulated by time-dependent density functional theory (TDDFT) indicated the origin of the absorption of individual DNA-AgNCs is a plasmon. The consistency of the peak-shifting trend between experimental and simulation results for assembled DNA-AgNCs suggested the possible presence of plasmon coupling. Our data imply the possibility for quantum-size structures to support plasmon coupling and also show that DNA-AgNCs possess the potential to be promising materials for construction of plasmon-coupling devices with ultrasmall size, site-specific and stoichiometric binding abilities, and biocompatibility.

13.
Chem Commun (Camb) ; 57(62): 7669-7672, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34254065

RESUMO

A novel nanozyme comprised of graphene encapsuled Ru nanocrystals (Ru@G) with effective and stable peroxidase-like activity prepared using a chemical vapor deposition (CVD) method was used for the detection of glutathione at near-physiological pH.


Assuntos
Materiais Biomiméticos/química , Glutationa/análise , Grafite/química , Nanopartículas Metálicas/química , Peroxidase/metabolismo , Rutênio/química , Concentração de Íons de Hidrogênio
14.
J Am Chem Soc ; 143(29): 11036-11043, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34270902

RESUMO

Biomolecular condensates comprised of specific proteins and nucleic acids are now recognized as one of the key organizing mechanisms in eukaryotic cells. However, the specific roles played by the nucleic acid secondary structure and sequence in biomolecular phase separation are still not clear. Here, utilizing giant membrane vesicles (GMVs) as a protocell model, we found that single-stranded DNA (ssDNA) with a parallel G-quadruplex structure could functionally cooperate with a G-quadruplex-binding protein to form speckle-like puncta inside the GMVs. The clustering behavior is dependent on the structural diversity of G-quadruplexes, and the reversible clustering behavior implicated a new pathway in dynamically regulating the formation of biomolecular condensates. This finding represents a potential link between G-quadruplex-binding proteins and the resulting G-quadruplex-mediated biomolecular phase separation, which would gain insight into a wide range of biological processes associated with nucleic acid-modulated phase separation inside living cells.

15.
ACS Appl Mater Interfaces ; 13(26): 30397-30403, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34161059

RESUMO

Engineering cell-derived nanovesicles with active-targeting ligands is an important strategy to enhance the targeting efficiency. However, the enhanced binding capability to targeting cells also leads to the binding with nontarget cells that share the same biomarkers. DNA-based logic gate is a kind of molecular system that responds to chemical inputs by generating output signals, and the relationship between the input and the output is based on a certain logic. Thus, the DNA-based logic gate could provide a new approach to improve the delivery efficiency of the nanovesicle. In this work, we developed a DNA logic-gated module that coupled two tumor cell-targeting factors (e.g., low pH and a tumor cell biomarker) in a Boolean manner. Immobilization of this module on the surface of the nanovesicle enables the nanovesicle to sense tumor cell-targeting factors and regard these cues as inputs AND logic gate. With the guide of DNA-based logic gate, gold carbon dots (GCDs) encapsulated within nanovesicles were delivered into target cells, and then the intracellular redox status variation was reflected by fluorescence change of GCDs. Overall, we developed DNA logic-gated nanovesicles that contract different targeting factors into a unique tag for target cells. This facile functionalization strategy can pave the way for constructing smart nanovesicles and would broaden their application in the field of precision medicine and personalized treatment.


Assuntos
Computadores Moleculares , DNA/química , Lipossomos/química , Lógica , Nanoestruturas/química , Motivos de Aminoácidos , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Carbono/química , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , DNA/metabolismo , Corantes Fluorescentes/química , Ouro/química , Humanos , Concentração de Íons de Hidrogênio , Estudo de Prova de Conceito , Pontos Quânticos/química , Receptores Proteína Tirosina Quinases/metabolismo
16.
J Am Chem Soc ; 143(23): 8559-8564, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34097382

RESUMO

The unique merits of aptamers, including specificity, high binding affinity, easy cell internalization, and rapid tissue accumulation abilities, have led aptamer-drug conjugates to evolve into one of the most attractive strategies for targeted drug delivery purposes. Nevertheless, the critical role of linkers in regulating anticancer efficacy of these conjugates, especially those engineered by automated modular synthesis techniques, has been rarely explored. In this work, we utilized Sgc8c aptamer and combretastatin A4 to develop three conjugates with either a phosphodiester bond linker, a disulfide bond linker, or a carbamate linker to study their payload release mechanisms and the influence on anticancer efficacy. These investigations allowed us to identify the unique activation pathway of the phosphodiester bond linker that is activated by both nucleophilic attack of glutathione and degradation caused by phosphodiesterase, which is highly associated with the higher cytotoxicity of the conjugate. Importantly, the understanding of the chemistry of phosphodiester bond linker activation allowed us to further design another XQ-2d-CA4 conjugate that can induce pancreatic cancer cells apoptosis in a more efficient manner.

17.
Angew Chem Int Ed Engl ; 60(38): 20943-20951, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34137148

RESUMO

Amplifying free radical production by chemical dynamic catalysis to cause oxidative damage to cancer cells has received extensive interest for cancer-specific therapy. The major challenge is inevitable negative modulation on the tumor microenvironment (TME) by these species, hindering durable effectiveness. Here we show for the first time an oxygen vacancy-rich Bi-based regulator that allows environment-adaptive free radical catalysis. Specifically, the regulator catalyzes production of highly toxic O2 .- and . OH in cancer cells via logic enzymatic reactions yet scavenges accumulation of free radicals and immunosuppressive mediators in TME-associated noncancerous cells. Atomic-level mechanistic studies reveal that such dual-modal regulating behavior is dominated by oxygen vacancies that well fit for free radical catalytic kinetics, along with distinguished cellular fates of this regulator. With this smart regulator, a "two birds with one shot" cancer dynamic therapy can be expected.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Oxigênio/farmacologia , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Radicais Livres/química , Radicais Livres/farmacologia , Humanos , Neoplasias/patologia , Oxigênio/química , Tamanho da Partícula , Espectrofotometria Ultravioleta
18.
Brief Bioinform ; 22(6)2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34117734

RESUMO

Recent studies have demonstrated that the excessive inflammatory response is an important factor of death in coronavirus disease 2019 (COVID-19) patients. In this study, we propose a deep representation on heterogeneous drug networks, termed DeepR2cov, to discover potential agents for treating the excessive inflammatory response in COVID-19 patients. This work explores the multi-hub characteristic of a heterogeneous drug network integrating eight unique networks. Inspired by the multi-hub characteristic, we design 3 billion special meta paths to train a deep representation model for learning low-dimensional vectors that integrate long-range structure dependency and complex semantic relation among network nodes. Based on the representation vectors and transcriptomics data, we predict 22 drugs that bind to tumor necrosis factor-α or interleukin-6, whose therapeutic associations with the inflammation storm in COVID-19 patients, and molecular binding model are further validated via data from PubMed publications, ongoing clinical trials and a docking program. In addition, the results on five biomedical applications suggest that DeepR2cov significantly outperforms five existing representation approaches. In summary, DeepR2cov is a powerful network representation approach and holds the potential to accelerate treatment of the inflammatory responses in COVID-19 patients. The source code and data can be downloaded from https://github.com/pengsl-lab/DeepR2cov.git.


Assuntos
COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Inflamação/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , COVID-19/complicações , COVID-19/genética , COVID-19/virologia , Biologia Computacional , Aprendizado Profundo , Humanos , Inflamação/complicações , Inflamação/genética , Inflamação/virologia , Redes Neurais de Computação , SARS-CoV-2/patogenicidade , Software , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
19.
Natl Sci Rev ; 8(4): nwaa202, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33936748

RESUMO

The use of aptamers in bioanalytical and biomedical applications exploits their ability to recognize cell surface protein receptors. Targeted therapeutics and theranostics come to mind in this regard. However, protein receptors occur on both cancer and normal cells; as such, aptamers are now taxed with identifying high vs. low levels of protein expression. Inspired by the flexible template mechanism and elegant control of natural nucleic acid-based structures, we report an allosteric regulation strategy for constructing a structure-switching aptamer for enhanced target cell recognition by engineering aptamers with DNA intercalated motifs (i-motifs) responsive to the microenvironment, such as pH. Structure-switching sensitivity can be readily tuned by manipulating i-motif sequences. However, structure-switching sensitivity is difficult to estimate, making it equally difficult to effectively screen modified aptamers with the desired sensitivity. To address this problem, we selected a fluorescent probe capable of detecting G-quadruplex in complicated biological media.

20.
J Am Chem Soc ; 143(19): 7261-7266, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33944569

RESUMO

Rapid and sensitive identification of viral pathogens such as SARS-CoV-2 is a critical step to control the pandemic disease. Viral antigen detection can compete with gold-standard PCR-based nucleic acid diagnostics in terms of better reflection of viral infectivity and reduced risk of contamination from enzymatic amplification. Here, we report the development of a one-step thermophoretic assay using an aptamer and polyethylene glycol (PEG) for direct quantitative detection of viral particles. The assay relies on aptamer binding to the spike protein of SARS-CoV-2 and simultaneous accumulation of aptamer-bound viral particles in laser-induced gradients of temperature and PEG concentration. Using a pseudotyped lentivirus model, a limit of detection of ∼170 particles µL-1 (26 fM of the spike protein) is achieved in 15 min without the need of any pretreatment. As a proof of concept, the one-step thermophoretic assay is used to detect synthetic samples by spiking viral particles into oropharyngeal swabs with an accuracy of 100%. The simplicity, speed, and cost-effectiveness of this thermophoretic assay may expand the diagnostic tools for viral pathogens.

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