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1.
Biosens Bioelectron ; 194: 113629, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34534949

RESUMO

Accurate and accessible nucleic acid diagnostics is critical to reducing the spread of COVID-19 and resuming socioeconomic activities. Here, we present an integrated platform for the direct detection of SARS-CoV-2 RNA targets near patients. Termed electrochemical system integrating reconfigurable enzyme-DNA nanostructures (eSIREN), the technology leverages responsive molecular nanostructures and automated microfluidics to seamlessly transduce target-induced molecular activation into an enhanced electrochemical signal. Through responsive enzyme-DNA nanostructures, the technology establishes a molecular circuitry that directly recognizes specific RNA targets and catalytically enhances signaling; only upon target hybridization, the molecular nanostructures activate to liberate strong enzymatic activity and initiate cascading reactions. Through automated microfluidics, the system coordinates and interfaces the molecular circuitry with embedded electronics; its pressure actuation and liquid-guiding structures improve not only analytical performance but also automated implementation. The developed platform establishes a detection limit of 7 copies of RNA target per µl, operates against the complex biological background of native patient samples, and is completed in <20 min at room temperature. When clinically evaluated, the technology demonstrates accurate detection in extracted RNA samples and direct swab lysates to diagnose COVID-19 patients.


Assuntos
Técnicas Biossensoriais , COVID-19 , Nanoestruturas , Humanos , Microfluídica , RNA Viral/genética , SARS-CoV-2
2.
Nat Commun ; 12(1): 4039, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193867

RESUMO

The controlled assembly of nanomaterials into desired architectures presents many opportunities; however, current preparations lack spatial precision and versatility in developing complex nano-architectures. Inspired by the amphiphilic nature of surfactants, we develop a facile approach to guide nanomaterial integration - spatial organization and distribution - in metal-organic frameworks (MOFs). Named surfactant tunable spatial architecture (STAR), the technology leverages the varied interactions of surfactants with nanoparticles and MOF constituents, respectively, to direct nanoparticle arrangement while molding the growing framework. By surfactant matching, the approach achieves not only tunable and precise integration of diverse nanomaterials in different MOF structures, but also fast and aqueous synthesis, in solution and on solid substrates. Employing the approach, we develop a dual-probe STAR that comprises peripheral working probes and central reference probes to achieve differential responsiveness to biomarkers. When applied for the direct profiling of clinical ascites, STAR reveals glycosylation signatures of extracellular vesicles and differentiates cancer patient prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas Biossensoriais/métodos , Neoplasias Colorretais/diagnóstico , Vesículas Extracelulares/metabolismo , Estruturas Metalorgânicas/química , Nanoestruturas/química , Tensoativos/química , Ascite/metabolismo , Neoplasias Colorretais/metabolismo , Glicosilação , Humanos , Prognóstico
3.
Adv Sci (Weinh) ; 8(18): e2101155, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34278742

RESUMO

Accessible and adaptable nucleic acid diagnostics remains a critical challenge in managing the evolving COVID-19 pandemic. Here, an integrated molecular nanotechnology that enables direct and programmable detection of SARS-CoV-2 RNA targets in native patient specimens is reported. Termed synergistic coupling of responsive equilibrium in enzymatic network (SCREEN), the technology leverages tunable, catalytic molecular nanostructures to establish an interconnected, collaborative architecture. SCREEN mimics the extraordinary organization and functionality of cellular signaling cascades. Through programmable enzyme-DNA nanostructures, SCREEN activates upon interaction with different RNA targets to initiate multi-enzyme catalysis; through system-wide favorable equilibrium shifting, SCREEN directly transduces a single target binding into an amplified electrical signal. To establish collaborative equilibrium coupling in the architecture, a computational model that simulates all reactions to predict overall performance and optimize assay configuration is developed. The developed platform achieves direct and sensitive RNA detection (approaching single-copy detection), fast response (assay reaction is completed within 30 min at room temperature), and robust programmability (across different genetic loci of SARS-CoV-2). When clinically evaluated, the technology demonstrates robust and direct detection in clinical swab lysates to accurately diagnose COVID-19 patients.


Assuntos
COVID-19/virologia , DNA Catalítico/genética , Nanoestruturas/química , SARS-CoV-2/genética , Humanos , Limite de Detecção , Técnicas de Diagnóstico Molecular/métodos , Nanotecnologia/métodos , Pandemias/prevenção & controle , RNA Viral/genética , Manejo de Espécimes/métodos
4.
Nat Nanotechnol ; 16(6): 734-742, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33686255

RESUMO

Current technologies to measure drug-target interactions require complex processing and invasive tissue biopsies, limiting their clinical utility for cancer treatment monitoring. Here we develop an analytical platform that leverages circulating extracellular vesicles (EVs) for activity-based assessment of tumour-specific drug-target interactions in patient blood samples. The technology, termed extracellular vesicle monitoring of small-molecule chemical occupancy and protein expression (ExoSCOPE), utilizes bio-orthogonal probe amplification and spatial patterning of molecular reactions within matched plasmonic nanoring resonators to achieve in situ analysis of EV drug dynamics. It measures changes in drug occupancy and protein composition in molecular subpopulations of EVs. When used to monitor various targeted therapies, the ExoSCOPE revealed EV signatures that closely reflected cellular treatment efficacy. We further applied the technology for clinical cancer diagnostics and treatment monitoring. Using a small volume of blood, the ExoSCOPE accurately classified disease status and rapidly distinguished between targeted treatment outcomes, within 24 h after treatment initiation.


Assuntos
Antineoplásicos/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/sangue , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Receptores ErbB/genética , Cloridrato de Erlotinib/sangue , Cloridrato de Erlotinib/uso terapêutico , Vesículas Extracelulares/química , Estudos de Viabilidade , Humanos , Neoplasias Pulmonares/sangue , Razão Sinal-Ruído
5.
Sci Adv ; 7(12)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33731349

RESUMO

Despite the importance of nucleic acid testing in managing the COVID-19 pandemic, current detection approaches remain limited due to their high complexity and extensive processing. Here, we describe a molecular nanotechnology that enables direct and sensitive detection of viral RNA targets in native clinical samples. The technology, termed catalytic amplification by transition-state molecular switch (CATCH), leverages DNA-enzyme hybrid complexes to form a molecular switch. By ratiometric tuning of its constituents, the multicomponent molecular switch is prepared in a hyperresponsive state-the transition state-that can be readily activated upon the binding of sparse RNA targets to turn on substantial enzymatic activity. CATCH thus achieves superior performance (~8 RNA copies/µl), direct fluorescence detection that bypasses all steps of PCR (<1 hour at room temperature), and versatile implementation (high-throughput 96-well format and portable microfluidic assay). When applied for clinical COVID-19 diagnostics, CATCH demonstrated direct and accurate detection in minimally processed patient swab samples.


Assuntos
Teste de Ácido Nucleico para COVID-19 , COVID-19 , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas , Testes Imediatos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/genética , Teste de Ácido Nucleico para COVID-19/instrumentação , Teste de Ácido Nucleico para COVID-19/métodos , Humanos , Limite de Detecção
6.
Sci Adv ; 6(19): eaba2556, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32494726

RESUMO

Exosomes are nanoscale vesicles distinguished by characteristic biophysical and biomolecular features; current analytical approaches, however, remain univariate. Here, we develop a dedicated platform for multiparametric exosome analysis-through simultaneous biophysical and biomolecular evaluation of the same vesicles-directly in clinical biofluids. Termed templated plasmonics for exosomes, the technology leverages in situ growth of gold nanoshells on vesicles to achieve multiselectivity. For biophysical selectivity, the nanoshell formation is templated by and tuned to distinguish exosome dimensions. For biomolecular selectivity, the nanoshell plasmonics locally quenches fluorescent probes only if they are target-bound on the same vesicle. The technology thus achieves multiplexed analysis of diverse exosomal biomarkers (e.g., proteins and microRNAs) but remains unresponsive to nonvesicle biomarkers. When implemented on a microfluidic, smartphone-based sensor, the platform is rapid, sensitive, and wash-free. It not only distinguished biomarker organizational states in native clinical samples but also showed that the exosomal subpopulation could more accurately differentiate patient prognosis.

7.
Adv Biosyst ; 4(12): e1900309, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32597034

RESUMO

Neurodegenerative diseases are heterogeneous disorders characterized by a progressive loss of function and/or death of nerve cells, leading to severe cognitive and functional decline. Due to the complex pathology, early detection and intervention are critical to the development of successful treatments; however, current diagnostic approaches are limited to subjective, late-stage clinical findings. Extracellular vesicles (EVs) have recently emerged as a promising circulating biomarker for neurodegenerative diseases. Actively released by diverse cells, EVs are nanoscale membrane vesicles. They abound in blood, readily cross the blood-brain barrier, and carry diverse molecular cargoes in different organizational states: these molecular cargoes are inherited from the parent cells or bound to the EV membrane through surface associations. Specifically, EVs have been found to be associated with several important pathogenic proteins of neurodegenerative diseases, and their involvement could alter disease progression. This article provides an overview of EVs as circulating biomarkers of neurodegenerative diseases and introduces new technological advances to characterize the biophysical properties of EV-associated biomarkers for accurate, blood-based detection of neurodegenerative diseases.

8.
Nat Biomed Eng ; 3(9): 684-694, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31285580

RESUMO

Massively parallel DNA sequencing is established, yet high-throughput protein profiling remains challenging. Here, we report a barcoding approach that leverages the combinatorial sequence content and the configurational programmability of DNA nanostructures for high-throughput multiplexed profiling of the subcellular expression and distribution of proteins in whole cells. The barcodes are formed by in situ hybridization of tetrahedral DNA nanostructures and short DNA sequences conjugated with protein-targeting antibodies, and by nanostructure-assisted ligation (either enzymatic or chemical) of the nanostructures and exogenous DNA sequences bound to nanoparticles of different sizes (which cause these localization sequences to differentially distribute across subcellular compartments). Compared with linear DNA barcoding, the nanostructured barcodes enhance the signal by more than 100-fold. By implementing the barcoding approach on a microfluidic device for the analysis of rare patient samples, we show that molecular subtypes of breast cancer can be accurately classified and that subcellular spatial markers of disease aggressiveness can be identified.


Assuntos
Código de Barras de DNA Taxonômico/métodos , DNA/química , DNA/classificação , Perfilação da Expressão Gênica/métodos , Nanoestruturas , Anticorpos/imunologia , Anticorpos/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Código de Barras de DNA Taxonômico/instrumentação , Humanos , Cinética , Dispositivos Lab-On-A-Chip , Proteínas , Coloração e Rotulagem
9.
Quant Imaging Med Surg ; 8(9): 957-970, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30505724

RESUMO

Sensitive and quantitative characterization of clinically relevant biomarkers can facilitate disease diagnosis and treatment evaluation. Magnetic nanomaterials and their biosensing strategies have recently received considerable attention. Magnetic signals experience little interference from native biological background as most biological molecules have negligible magnetic susceptibilities and thus appear transparent to external magnetic fields. Because of this unique property, magnetic sensing can be applied to both in vivo deep tissue imaging as well as ex vivo point-of-care diagnostics. To exploit this mode of magnetic detection, new advancements in both magnetic material syntheses and sensing technologies have been made. This review focuses on recent developments of magnetic nanomaterials as image contrast agents and diagnostic sensors. These developments have not only enabled precise control of magnetic nanomaterial properties but also expanded the reach of magnetic detection for biomedical diagnostics.

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