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1.
Nat Chem ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152477

RESUMO

Stimuli-responsive biomaterials that contain logic gates hold great potential for detecting and responding to pathological markers as part of clinical therapies. However, a major barrier is the lack of a generalized system that can be used to easily assemble different ligand-responsive units to form programmable nanodevices for advanced biocomputation. Here we develop a programmable polymer library by including responsive units in building blocks with similar structure and reactivity. Using these polymers, we have developed a series of smart nanocarriers with hierarchical structures containing logic gates linked to self-immolative motifs. Designed with disease biomarkers as inputs, our logic devices showed site-specific release of multiple therapeutics (including kinase inhibitors, drugs and short interfering RNA) in vitro and in vivo. We expect that this 'plug and play' platform will be expanded towards smart biomaterial engineering for therapeutic delivery, precision medicine, tissue engineering and stem cell therapy.

2.
Nat Commun ; 11(1): 1347, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32165631

RESUMO

Protein-dominant cellular processes cannot be fully decoded without precise manipulation of their activity and localization in living cells. Advances in optogenetics have allowed spatiotemporal control over cellular proteins with molecular specificity; however, these methods require recombinant expression of fusion proteins, possibly leading to conflicting results. Instead of modifying proteins of interest, in this work, we focus on design of a tunable recognition unit and develop an aptamer-based near-infrared (NIR) light-responsive nanoplatform for manipulating the subcellular localization of specific proteins in their native states. Our results demonstrate that this nanoplatform allows photocontrol over the cytoplasmic-nuclear shuttling behavior of the target RelA protein (a member of the NF-κß family), enabling regulation of RelA-related signaling pathways. With a modular design, this aptamer-based nanoplatform can be readily extended for the manipulation of different proteins (e.g., lysozyme and p53), holding great potential to develop a variety of label-free protein photoregulation strategies for studying complex biological events.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32154704

RESUMO

The near-field effects in the vicinity of metallic nanoparticle surfaces, as induced by electromagnetic radiation with specific wavelength, give rise to a variety of novel optical properties and attractive applications because of surface plasmons, which are the coherent oscillations of conduction electrons on a metal surface. The interdisciplinary field of plasmonics has witnessed vigorous growth, promoting research on the modulation of plasmon resonance by constructing advanced plasmonic nanoarchitectures with controllable size, morphology, or interparticle coupling. Among diversified tools, deoxyribonucleic nucleic acid (DNA) possesses prominent superiority as a result of its designability, programmability, addressability, and ease of nanomaterial modification. In this review, we focus on the methods and optical applications of plasmon resonance modulation accomplished by DNA nanotechnology. Recent developments in the construction of DNA-mediated plasmonic nanoarchitecture and key ongoing research directions utilizing unique optical features are highlighted. Obstacles and challenges in this field are pointed out, followed by preliminary suggestions on some areas of opportunity that deserve attention.

4.
Chem Commun (Camb) ; 56(19): 2901-2904, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32037435

RESUMO

The enzymatic-assisted signal amplification of DNA sensors is rarely applied in living cells due to the difficulties in protein delivery. In this study, we have proposed a biomineralization-based DNA nanoprobe to transport nucleases and DNA sensors for enzyme-assisted imaging of microRNA in living cells.

5.
Nat Commun ; 11(1): 978, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080196

RESUMO

In order to maintain tissue homeostasis, cells communicate with the outside environment by receiving molecular signals, transmitting them, and responding accordingly with signaling pathways. Thus, one key challenge in engineering molecular signaling systems involves the design and construction of different modules into a rationally integrated system that mimics the cascade of molecular events. Herein, we rationally design a DNA-based artificial molecular signaling system that uses the confined microenvironment of a giant vesicle, derived from a living cell. This system consists of two main components. First, we build an adenosine triphosphate (ATP)-driven DNA nanogatekeeper. Second, we encapsulate a signaling network in the biomimetic vesicle, consisting of distinct modules, able to sequentially initiate a series of downstream reactions playing the roles of reception, transduction and response. Operationally, in the presence of ATP, nanogatekeeper switches from the closed to open state. The open state then triggers the sequential activation of confined downstream signaling modules.

6.
Anal Chem ; 92(5): 3620-3626, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013394

RESUMO

Exocytosis and retrieval of synaptic vesicles (SVs) are vital steps during neurotransmitter propagation between neurons. Visualization of this dynamics of SVs is significant for elucidating the mechanisms underlying synaptic transmission but remains challenging without an efficient, reliable, and biocompatible labeling method. In this work, we developed pH-responsive ratiometric DNA tetrahedral nanoprobes (pHadtnps) that could specifically label recycling SVs with high stability and effective background suppression. On the basis of the luminal pH alternation during the recycling of SVs, pHadtnps were able to illustrate their exocytosis and retrieval in real time. Moreover, with the high programmability of DNA nanotechnology, these nanoprobes could be flexibly equipped with different functional moieties, holding great promise for developing various versatile tools for studying communication in neuronal networks.

7.
Anal Chem ; 92(5): 4108-4114, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32037790

RESUMO

Developing cancer targeted medicine depends on increasing delivery efficiency and tumor site accumulation of theranostic agents. To accomplish this, we report a modification of PTK7 receptor-specific aptamer Sgc8 with the small molecule Evans Blue (EB), thus implementing an albumin binding hitchhike strategy for prolonged blood circulation. The EB molecule could insert into the hydrophobic region of serum albumin and form an aptamer/albumin complex. This complex showed superior physiological stability, facilitating longer blood half-life, and maintaining its targeting capacity. Successful conjugation of EB-aptamers was confirmed by a series of characterization methods. Targeting performance was tested on a xenografted mouse tumor model. Taking advantage of the long circulating aptamer/HSA complex, improved accumulation, and delivery efficiency to the tumor site were achieved. Through ex vivo quantification of the EB-Sgc8 aptamers' biodistribution, the mechanism of improved targeting performance was illuminated. Therefore, the increased aptamers tumor delivery efficiency and accumulation indicate that prolonging blood circulation is a promising strategy to improve aptamers' targeted delivery performance in the future clinical translation.

8.
Chem Commun (Camb) ; 56(21): 3131-3134, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32055812

RESUMO

We propose an aptamer-tethered DNA nanofirecracker probe that realizes molecular recognition-activatable disassembly of the DNA nanostructure for imaging of target molecules in living cells. The design principle offers a new paradigm to develop nucleic acid nanocircuits for live-cell study and manipulation.


Assuntos
Aptâmeros de Nucleotídeos/química , DNA/química , Corantes Fluorescentes/química , Nanoestruturas/química , Imagem Óptica , RNA Mensageiro/análise , Humanos , Células MCF-7
9.
J Am Chem Soc ; 142(8): 3862-3872, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991082

RESUMO

The lack of blood-brain barrier (BBB) penetrating ability has hindered the delivery of many therapeutic agents for tauopathy treatment. In this study, we report the synthesis of a circular bifunctional aptamer to enhance the in vivo BBB penetration for better tauopathy therapy. The circular aptamer consists of one reported transferrin receptor (TfR) aptamer to facilitate TfR-aptamer recognition-induced transcytosis across BBB endothelial cells, and one Tau protein aptamer that we recently selected to inhibit Tau phosphorylation and other tauopathy-related pathological events in the brain. This novel circular Tau-TfR bifunctional aptamer displays significantly improved plasma stability and brain exposure, as well as the ability to disrupt tauopathy and improve traumatic brain injury (TBI)-induced cognitive/memory deficits in vivo, providing important proof-of-principle evidence that circular Tau-TfR aptamer can be further developed into diagnostic and therapeutic candidates for tauopathies.

10.
Chem Commun (Camb) ; 56(12): 1843-1846, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31950937

RESUMO

As the most abundant protein in blood, human serum albumin (HSA) is usually regarded as an interferent in clinical molecular diagnosis. Herein, we report that HSA is an endogenous signal amplifier for the detection of the prostate-specific antigen (PSA) in human plasma. This is the first study to utilize intrinsic biological components as the signal amplifier in blood tests.


Assuntos
Antígeno Prostático Específico/sangue , Albumina Sérica Humana/química , Butiratos/química , Corantes Fluorescentes/química , Humanos , Modelos Moleculares , Espectrometria de Fluorescência
11.
J Am Chem Soc ; 142(5): 2532-2540, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31910340

RESUMO

Mitomycin C (MMC) has been using for the treatment of a variety of digestive tract cancers. However, its nonspecific DNA-alkylating ability usually causes severe side effects, thus largely limiting its clinical applications. The utilization of an efficient active targeted drug delivery technique would address this issue. Accordingly, we report the design and development of aptamer-mitomycin C conjugates that use different cross-linking chemistry. The targeted delivery ability and cytotoxicity of these conjugates were carefully studied. It is worth noting that a linker-dependent cytotoxicity effect was observed for these conjugates. The use of a reductant-sensitive disulfide bond cross-linking strategy resulted in significantly enhanced cytotoxicity of MMC against the target cancer cell lines. Importantly, this cytotoxicity enhancement was suited to different types of aptamers, demonstrating the success of our design. Mechanistic studies of the enhanced cytotoxicity effect indicated that the target recognition, specific binding, and receptor-mediated internalization of aptamer were also critical for the observed effect.

12.
J Am Chem Soc ; 142(5): 2129-2133, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31955575

RESUMO

Labile heme (LH) is an important signaling molecule in virtually all organisms. However, specifically detecting LH remains an outstanding challenge. Herein, by learning from the bioactivation mechanism of artemisinin, we have developed the first LH-responsive small-molecule fluorescent probe, HNG, based on a 4-amino-1,8-naphthalimide (NG) fluorophore. HNG showed high selectivity for LH without interference from hemin, protein-interacting heme, and zinc protoporphyrin. Using HNG, the changes of LH levels in live cells were imaged, and a positive correlation of LH level with the degree of hemolysis was uncovered in hemolytic mice. Our study not only presents the first molecular probe for specific LH detection but also provides a strategy to construct probes with high specificity through a bioinspired approach.

13.
J Am Chem Soc ; 142(6): 2699-2703, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31910009

RESUMO

Triple-negative breast cancer (TNBC) lacks three important receptors, ER, PR, and HER2. It is more aggressive and more likely to relapse after treatment, thus has been identified as one of the most malignant breast cancer types. The development of efficient targeted TNBC therapy is an important research topic in TNBC treatment. We report the development of a new aptamer-drug conjugate (ApDC), AS1411-triptolide conjugate (ATC), as targeted therapy for the treatment of TNBC with high efficacy. The conjugate possesses excellent specificity and high cytotoxicity against the MDA-MB-231 cell line. The advantages of our newly invented ATC are further highlighted by its excellent in vivo anti-TNBC efficacy and negligible side effects toward healthy organs.

14.
J Am Chem Soc ; 142(1): 382-391, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31801020

RESUMO

The inner region of solid tumors is found to be high-pressure, hypoxic, and immunosuppressive, providing a breeding ground for tumor aggressiveness and metastasis. While intratumoral accumulation of nanomedicines combined with immunomodulation would significantly enhance therapeutic efficacy, such potential is challenged by the compressed environment and distinct heterogeneity of the tumor bulk. By using an apoptotic body (AB) as the carrier, we develop an effective and universal intratumoral nanomedicine delivery system for the long-lasting remission of tumors. Our results show that the AB-encapsulated nanomedicine (using CpG immunoadjuvant-modified gold-silver nanorods as a model), after intravenous injection, can be specifically phagocytosed by inflammatory Ly-6C+ monocytes, which then actively infiltrate the tumor center via their natural tumor-homing tendency. With the integration of AB-facilitated intratumoral accumulation, the nanorod-based photothermal effect, and CpG-promoted immunostimulation, this cell-mediated delivery system can not only efficiently ablate primary tumors but also elicit a potent immunity to prevent tumors from metastasizing and recurring.

15.
Angew Chem Int Ed Engl ; 59(7): 2628-2633, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31793153

RESUMO

Deepening our understanding of mammalian gut microbiota has been greatly hampered by the lack of a facile, real-time, and in vivo bacterial imaging method. To address this unmet need in microbial visualization, we herein report the development of a second near-infrared (NIR-II)-based method for in vivo imaging of gut bacteria. Using d-propargylglycine in gavage and then click reaction with an azide-containing NIR-II dye, gut microbiota of a donor mouse was strongly labeled with NIR-II fluorescence on their peptidoglycan. The bacteria could be readily visualized in recipient mouse gut with high spatial resolution and deep tissue penetration under NIR irradiation. The NIR-II-based metabolic labeling strategy reported herein, provides, to the best of our knowledge, the first protocol for facile in vivo visualization of gut microbiota within deep tissues, and offers an instrumental tool for deciphering the complex biology of these gut "dark matters".

16.
Angew Chem Int Ed Engl ; 59(2): 663-668, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31650689

RESUMO

Expanding the number of nucleotides in DNA increases the information density of functional DNA molecules, creating nanoassemblies that cannot be invaded by natural DNA/RNA in complex biological systems. Here, we show how six-letter GACTZP DNA contributes this property in two parts of a nanoassembly: 1) in an aptamer evolved from a six-letter DNA library to selectively bind liver cancer cells; and 2) in a six-letter self-assembling GACTZP nanotrain that carries the drug doxorubicin. The aptamer-nanotrain assembly, charged with doxorubicin, selectively kills liver cancer cells in culture, as the selectivity of the aptamer binding directs doxorubicin into the aptamer-targeted cells. The assembly does not kill untransformed cells that the aptamer does not bind. This architecture, built with an expanded genetic alphabet, is reminiscent of antibodies conjugated to drugs, which presumably act by this mechanism as well, but with the antibody replaced by an aptamer.

17.
Angew Chem Int Ed Engl ; 59(2): 695-699, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31628815

RESUMO

Fluorescence visualization (FV) in the near-infrared (NIR) window promises to break through the signal-to-background ratio (SBR) bottleneck of traditional visible-light-driven FV methods. However, straightforward NIR-FV has not been realized, owing to the lack of methods to readily transduce NIR responses into instrument-free, naked eye-recognizable outputs. Now, an initiation-input-transduction platform comprising a well-designed NIR fluorophore as the signal initiator and lanthanide-doped nanocrystals as the transducer for facile NIR-FV is presented. The analyte-induced off-on NIR signal serves as a sensitizing switch of transducer visible luminescence for naked-eye readout. The design is demonstrated for portable, quantitative detection of phosgene with significantly improved SBR and sensitivity. By further exploration of initiators, this strategy holds promise to create advanced NIR-FV probes for broad sensing applications.

18.
Biomaterials ; 230: 119618, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757530

RESUMO

Drug-loaded implants have attracted considerable attention in cancer treatment due to their precise delivery of drugs into cancer tissues. Contrary to injected drug delivery, the application of drug-loaded implants remains underutilized given the requirement for a surgical operation. Nevertheless, drug-loaded implants have several advantages, including a reduction in frequency of drug administration, minimal systemic toxicity, and increased delivery efficacy. Herein, we developed a new, precise, drug delivery device for orthotopic breast cancer therapy able to suppress breast tumor growth and reduce pulmonary metastasis using combination chemotherapy. Poly-lactic-co-glycolic acid scaffolds were fabricated by 3D printing to immobilize 5-fluorouracil and NVP-BEZ235. The implantable scaffolds significantly reduced the required drug dosages and ensured curative drug levels near tumor sites for prolonged period, while drug exposure to normal tissues was minimized. Moreover, long-term drug release was achieved, potentially allowing one-off implantation and, thus, a major reduction in the frequency of drug administration. This drug-loaded scaffold has great potential in anti-tumor treatment, possibly paving the way for precise, effective, and harmless cancer therapy.

19.
Bioconjug Chem ; 31(1): 37-42, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31815437

RESUMO

Nucleic acid aptamers, also known as "chemical antibodies", have been widely employed in targeted cancer therapy and diagnosis. For example, aptamer-drug conjugates (ApDCs), through covalent conjugation of cytotoxic warheads to aptamers, have demonstrated anticancer efficacy both in vitro and in vivo. However, a general strategy to endow ApDCs with enhanced biostability, prolonged circulation half-life, and high drug loading content remained elusive. Herein, we present a polymeric approach to engineer ApDCs via conjugation of cell-targeting aptamers with water-soluble polyprodrugs containing a reductive environmentally sensitive prodrug and biocompatible brush-like backbone. The resultant high-drug loading Aptamer-PolyproDrug Conjugates (ApPDCs) exhibited high nuclease resistance, extended in vivo circulation time, specific recognition, and cellular uptake to target cells, reduction-triggered and fluorescent-reporting drug release, and effective cytotoxicity. We could also further expand this design principle toward combination therapy by using two kinds of therapeutic drugs with distinct pharmacological mechanisms.

20.
J Am Chem Soc ; 142(2): 937-944, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31858794

RESUMO

Chemodynamic therapy (CDT) has demonstrated new possibilities for selective and logical cancer intervention by specific manipulation of dysregulated tumorous free radical homeostasis. Current CDT methods largely rely on conversion of endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals via classical Fenton or Haber-Weiss chemistry. However, their anticancer efficacies are greatly limited by the requirement of strong acidity for efficient chemical reactions, insufficient tumorous H2O2, and upregulated antioxidant defense to counteract free radical-caused oxidative damage. Here, we present a new concept whereby bioorthogonal chemistry and prodrug are combined to create a new type of aptamer drug conjugate (ApDC): aptamer-prodrug conjugate (ApPdC) micelle for improved and cancer-targeted CDT. The hydrophobic prodrug bases can not only promote self-assembly of aptamers but also act as free radical generators via bioorthogonal chemistry. In depth mechanistic studies reveal that, unlike traditional CDT systems, ApPdC micelles enable in situ activation and self-cycling generation of toxic C-centered free radicals in cancer cells through cascading bioorthogonal reactions, with no dependence on either H2O2 or pH, yet concurrently with diminished cancerous antioxidation by GSH depletion for a synergistic CDT effect. We expect this work to provide new insights into the design of targeted cancer therapies and studies of free radical-related molecular mechanisms.

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