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Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA-protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance.
Assuntos
DNA , Mecanorreceptores , Mecanotransdução Celular , DNA/metabolismo , DNA/química , Mecanotransdução Celular/efeitos dos fármacos , Humanos , Mecanorreceptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Caderinas/metabolismo , Caderinas/genéticaRESUMO
In vitro RNA synthesis technologies are crucial in developing therapeutic RNA drugs, such as mRNA vaccines and RNA interference (RNAi) therapies. Enzymatic RNA synthesis, recognized for its sustainability and efficiency, enables the production of extensive RNA sequences under mild conditions. Among the enzymes utilized, T7 RNA polymerase is distinguished by its exceptional catalytic efficiency, enabling the precise and rapid transcription of RNA from DNA templates by recognizing the specific T7 promoter sequence. With the advancement in clinical applications of RNA-based drugs, there is an increasing demand for the synthesis of chemically modified RNAs that are stable and resistant to nuclease degradation. To this end, researchers have applied directed evolution to broaden the enzyme's substrate scope, enhancing its compatibility with non-canonical substrates and reducing the formation of by-products. This review summarizes the progress in engineering T7 RNA polymerase for these purposes and explores prospective developments in the field.
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Bioinspired molecular engineering strategies have emerged as powerful tools that significantly enhance the development of novel therapeutics, improving efficacy, specificity, and safety in disease treatment. Recent advancements have focused on identifying and utilizing disease-associated biomarkers to optimize drug activity and address challenges inherent in traditional therapeutics, such as frequent drug administrations, poor patient adherence, and increased risk of adverse effects. In this review, we provide a comprehensive overview of the latest developments in bioinspired artificial systems (BAS) that use molecular engineering to tailor therapeutic responses to drugs in the presence of disease-specific biomarkers. We examine the transition from open-loop systems, which rely on external cues, to closed-loop feedback systems capable of autonomous self-regulation in response to disease-associated biomarkers. We detail various BAS modalities designed to achieve biomarker-driven therapy, including activatable prodrug molecules, smart drug delivery platforms, autonomous artificial cells, and synthetic receptor-based cell therapies, elucidating their operational principles and practical inâ vivo applications. Finally, we discuss the current challenges and future perspectives in the advancement of BAS-enabled technology and envision that ongoing advancements toward more programmable and customizable BAS-based therapeutics will significantly enhance precision medicine.
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Proteins capable of switching between distinct active states in response to biochemical cues are ideal for sensing and controlling biological processes. Activatable CRISPR-Cas systems are significant in precise genetic manipulation and sensitive molecular diagnostics, yet directly controlling Cas protein function remains challenging. Herein, we explore anti-CRISPR (Acr) proteins as modules to create synthetic Cas protein switches (CasPSs) based on computational chemistry-directed rational protein interface engineering. Guided by molecular fingerprint analysis, electrostatic potential mapping, and binding free energy calculations, we rationally engineer the molecular interaction interface between Cas12a and its cognate Acr proteins (AcrVA4 and AcrVA5) to generate a series of orthogonal protease-responsive CasPSs. These CasPSs enable the conversion of specific proteolytic events into activation of Cas12a function with high switching ratios (up to 34.3-fold). These advancements enable specific proteolysis-inducible genome editing in mammalian cells and sensitive detection of viral protease activities during virus infection. This work provides a promising strategy for developing CRISPR-Cas tools for controllable gene manipulation and regulation and clinical diagnostics.
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Proteínas Associadas a CRISPR , Edição de Genes , Animais , Sistemas CRISPR-Cas/genética , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Proteínas Associadas a CRISPR/genética , Proteínas Associadas a CRISPR/metabolismo , Endopeptidases/metabolismo , Proteases Virais/genética , Proteases Virais/metabolismo , Mamíferos/metabolismoRESUMO
Viral proteases play a crucial role in viral infection and are regarded as promising targets for antiviral drug development. Consequently, biosensing methods that target viral proteases have contributed to the study of virus-related diseases. This work presents a ratiometric electrochemical sensor that enables highly sensitive detection of viral proteases through the integration of target proteolysis-activated in vitro transcription and the DNA-functionalized electrochemical interface. In particular, each viral protease-mediated proteolysis triggers the transcription of multiple RNA outputs, leading to amplified ratiometric signals on the electrochemical interface. Using the NS3/4A protease of the hepatitis C virus as a model, this method achieves robust and specific NS3/4A protease sensing with sub-femtomolar sensitivity. The feasibility of this sensor was demonstrated by monitoring NS3/4A protease activities in virus-infected cell samples with varying viral loads and post-infection times. This study provides a new approach to analyzing viral proteases and holds the potential for developing direct-acting antivirals and novel therapies for viral infections.
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Técnicas Eletroquímicas , Proteólise , Proteases Virais/metabolismo , Hepatite C/enzimologia , Técnicas Eletroquímicas/métodos , Humanos , Linhagem CelularRESUMO
In situ analysis of biomarkers in the tumor microenvironment (TME) is important to reveal their potential roles in tumor progression and early diagnosis of tumors but remains a challenge. In this work, a bottom-up modular assembly strategy was proposed for a multifunctional protein-nucleic chimeric probe (PNCP) for in situ mapping of cancer-specific proteases. PNCP, containing a collagen anchoring module and a target proteolysis-responsive isothermal amplification sensor module, can be anchored in the collagen-rich TME and respond to the target protease in situ and generate amplified signals through rolling cycle amplification of tandem fluorescent RNAs. Taking matrix metalloproteinase 2 (MMP-2), a tumor-associated protease, as the model, the feasibility of PNCP was demonstrated for the in situ detection of MMP-2 activity in 3D tumor spheroids. Moreover, in situ in vivo mapping of MMP-2 activity was also achieved in a metastatic solid tumor model with high sensitivity, providing a useful tool for evaluating tumor metastasis and distinguishing highly aggressive forms of tumors.
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Metaloproteinase 2 da Matriz , Neoplasias , Humanos , Metaloproteinase 2 da Matriz/genética , Peptídeo Hidrolases , Colágeno , Sondas de Ácido Nucleico , Microambiente TumoralRESUMO
Receptor oligomerization is a highly complex molecular process that modulates divergent cell signaling. However, there is a lack of molecular tools for systematically interrogating how receptor oligomerization governs the signaling response. Here, we developed a DNA origami-templated aptamer nanoarray (DOTA) that enables precise programming of the oligomerization of receptor tyrosine kinases (RTK) with defined valency, distribution, and stoichiometry at the ligand-receptor interface. The DOTA allows for advanced receptor manipulations by arraying either monomeric aptamer ligands (mALs) that oligamerize receptor monomers to elicit artificial signaling or dimeric aptamer ligands (dALs) that preorganize the receptor dimer to recapitulate natural activation. We demonstrated that the multivalency and nanoscale spacing of receptor oligomerization coordinately influence the activation level of receptor tyrosine kinase signaling. Furthermore, we illustrated that DOTA-modulated receptor oligomerization could function as a signaling switch to promote the transition from epithelia to mesenchymal-like cells, demonstrating robust control over cellular behaviors. Together, we present a versatile all-in-one DNA nanoplatform for the systematical investigation and regulation of receptor-mediated cellular response.
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DNA , Receptores Proteína Tirosina Quinases , Ligantes , Receptores Proteína Tirosina Quinases/genética , Oligonucleotídeos , Transdução de SinaisRESUMO
MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers and therapeutic targets in various diseases. However, there is currently a lack of molecular strategies that can effectively use disease-associated extracellular miRNAs as input signals to drive therapeutic functions. Herein, we present a modular and programmable miRNA-responsive chimeric DNA receptor (miRNA-CDR) capable of biomarker-driven therapy. By grafting a miRNA-responsive DNA nanodevice on a natural membrane receptor via aptamer anchoring, miRNA-CDR can sense extracellular miRNA levels and autonomously induce dimerization-mediated receptor activation via the complementary-mediated strand displacement reaction-induced dynamic DNA assembly. The sequence programmability of miRNA-CDR allows it to sense and respond to a user-defined miRNA with tunable sensitivity. Moreover, the miRNA-CDR is versatile and customizable to reprogram desirable signaling output via adapting a designated receptor, such as MET and FGFR1. Using a mouse model of drug-induced acute liver injury (DILI), we demonstrate the functionality of a designer miRNA-CDR in rewiring the recognition of the DILI-elevated miR-122 to promote MET signaling of hepatocytes for biomarker-driven in situ repair and liver function restoration. Our synthetic miRNA-CDR platform provides a novel molecular device enabling biomarker-driven therapeutic cellular response, potentially paving the way for improving the precision of cell therapy in regenerative medicine.
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Doença Hepática Induzida por Substâncias e Drogas , MicroRNAs , Receptores Artificiais , Humanos , MicroRNAs/genética , Biomarcadores , Hepatócitos , DNARESUMO
The CRISPR/Cas12a system has been repurposed as a versatile nuclei acid bio-imaging tool, but its utility in sensing non-nucleic acid analytes in living cells has been less exploited. Herein, we demonstrated the ability of Mn2+ to accelerate cleavage kinetics of Cas12a and deployed for live-cell Mn2+ sensing by leveraging the accelerated trans-cleavage for signal reporting. In this work, we found that Mn2+ could significantly boost both the cis-cleavage and trans-cleavage activities of Cas12a. On the basis of this phenomenon, we harnessed CRISPR-Cas12a as a direct sensing system for Mn2+, which achieved robust Mn2+ detection in the concentration range of 0.5-700 µM within 15 min in complex biological samples. Furthermore, we also demonstrated the versatility of this system to sense Mn2+ in the cytoplasm of living cells. With the usage of a conditional guide RNA, this Cas12a-based sensing method was applied to study the cytotoxicity of Mn2+ in living nerve cells, offering a valuable tool to reveal the cellular response of nerve cells to Mn2+ disorder and homeostasis.
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Proteínas Associadas a CRISPR , Sistemas CRISPR-Cas , Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas/genética , Homeostase , Cinética , RNA Guia de Cinetoplastídeos/genéticaRESUMO
G-quadruplex (G4) is a noncanonical nucleic acid secondary structure that has implications for various physiological and pathological processes and is thus essential to exploring new approaches to G4 detection in live cells. However, the deficiency of molecular imaging tools makes it challenging to visualize the G4 in ex vivo tissue samples. In this study, we established a G4 probe design strategy and presented a red fluorescent benzothiazole derivative, ThT-NA, to detect and image G4 structures in living cells and tissue samples. By enhancing the electron-donating group of thioflavin T (ThT) and optimizing molecular structure, ThT-NA shows excellent photophysical properties, including red emission (610 nm), a large Stokes shift (>100 nm), high sensitivity selectivity toward G4s (1600-fold fluorescence turn-on ratio) and robust two-photon fluorescence emission. Therefore, these features enable ThT-NA to reveal the endogenous RNA G4 distribution in living cells and differentiate the cell cycle by monitoring the changes of RNA G4 folding. Significantly, to the best of our knowledge, ThT-NA is the first benzothiazole-derived G4 probe that has been developed for imaging G4s in ex vivo cancer tissue samples by two-photon microscopy techniques.
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Quadruplex G , Benzotiazóis/química , Corantes Fluorescentes/química , RNA , Espectrometria de FluorescênciaRESUMO
The advent of DNA nanotechnology has paved the way for the development of nanoscale robotics capable of executing smart and sophisticated tasks in a programmed and automatic manner. The programmability and customizable functionality of designer DNA nanorobots interfacing with biology would offer great potential for basic and applied research in the interdisciplinary fields of chemistry, biology, and medicine. This review aims to summarize the latest progress in designer DNA nanorobotics enabling programmable functions. We first describe the state-of-art engineering principles and the functional modules used in the rational design of a dynamic DNA nanorobot. Subsequently, we summarize the distinct types of DNA nanorobots performing sensing tasks, sensing-and-actuation, or continuous actuation, highlighting the versatility of designer DNA nanorobots in accurate biosensing, targeted drug delivery, and autonomous molecular operations to promote desired cellular behavior. Finally, we discuss the challenges and opportunities in the development of functional DNA nanorobotics for biomedical applications. We envision that significant progress in DNA-enabled nanorobotics with programmable functions will improve precision medicine in the future.
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Nanoestruturas , Robótica , DNA , Sistemas de Liberação de Medicamentos , Nanoestruturas/química , Nanotecnologia , Preparações FarmacêuticasRESUMO
G-quadruplexes (G4s), the noncanonical nucleic acid secondary structure, form within guanine-rich DNA or RNA sequences. G4s formation can affect chromatin architecture and gene regulation and has been associated with various cellular functions, including DNA replication, transcription, and genome maintenance. Visualizing and detecting G4s precisely in such processes is essential to increasing our understanding of G4s biology. Considerable attention has focused on the G4s targeting molecular imaging studies. Besides, fluorescent light-up aptamers (FLAPs, also referred to as fluorogenic aptamers) have gained momentum, which commonly have a G4 scaffolding for imaging intracellular RNAs and metabolites. In this review, we first introduce several representative fluorescent imaging approaches for tracking G4s in cells and in vivo. We also discuss the potential of G4-containing FLAPs in bioimaging and summarize current developments in this field from the standpoint of fluorescent molecules. Finally, we discuss the present challenges and future potential of G4 imaging and G4-containing FLAPs development.
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Quadruplex G , DNA/química , RNA/química , Oligonucleotídeos , Regulação da Expressão GênicaRESUMO
Engineering of the cell plasma membrane using functional DNA is important for studying and controlling cellular behaviors. However, most efforts to apply artificial DNA interactions on cells are limited to external membrane surface due to the lack of suitable synthetic tools to engineer the intracellular side, which impedes many applications in cell biology. Inspired by the natural extracellular vesicle-cell fusion process, we have developed a fusogenic spherical nucleic acid construct to realize robust DNA functionalization on both external and internal cell surfaces via liposome fusion-based transport (LiFT) strategy, which enables applications including the construction of heterotypic cell assembly for programmed signaling pathway and detection of intracellular metabolites. This approach can engineer cell membranes in a highly efficient and spatially controlled manner, allowing one to build anisotropic membrane structures with two orthogonal DNA functionalities.
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Materiais Biomiméticos/química , Engenharia Celular , Membrana Celular/química , DNA/química , Células HeLa , Humanos , Lipossomos/química , Tamanho da PartículaRESUMO
Synthetically directing T-cells against tumors emerges as a promising strategy in immunotherapy, while it remains challenging to smartly engage T cells with tunable immune response. Herein, we report an intelligent molecular platform to engineer T-cell recognition for selective activation to potently kill cancer cells. To this end, we fabricated a hybrid conjugate that uses a click-type DNA-protein conjugation to equip the T cell-engaging antibody with two distinct programmable DNA nanoassemblies. By integrating multiple aptameric antigen-recognitions within a dynamic DNA circuit, we achieved combinatorial recognition of triple-antigens on cancer cells for selective T-cell activation after high-order logic operation. Moreover, by coupling a DNA nanostructure, we precisely defined the valence of the antigen-binding aptamers to tune avidity, realizing effective tumor elimination in vitro and in vivo. Together, we present a versatile and programmable strategy for synthetic immunotherapy.
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Neoplasias , Linfócitos T , Anticorpos , Antígenos , DNA/química , Humanos , Imunoterapia , Neoplasias/terapiaRESUMO
GFP-like fluorescent proteins and their molecular mimics have revolutionized bioimaging research, but their emissions are largely limited in the visible to far-red region, hampering the in vivo applications in intact animals. Herein, we structurally modulate GFP-like chromophores using a donor-acceptor-acceptor (D-A-A') molecular configuration to discover a set of novel fluorogenic derivatives with infrared-shifted spectra. These chromophores can be fluorescently elicited by their specific interaction with G-quadruplex (G4), a unique noncanonical nucleic acid secondary structure, via inhibition of the chromophores' twisted-intramolecular charge transfer. This feature allows us to create, for the first time, FP mimics with tunable emission in the near-infrared (NIR) region (Emmax = 664-705 nm), namely, infrared G-quadruplex mimics of FPs (igMFP). Compared with their FP counterparts, igMFPs exhibit remarkably higher quantum yields, larger Stokes shift, and better photostability. In a proof-of-concept application using pathogen-related G4s as the target, we exploited igMFPs to directly visualize native hepatitis C virus (HCV) RNA genome in living cells via their in situ formation by the chromophore-bound viral G4 structure in the HCV core gene. Furthermore, igMFPs are capable of high contrast HCV RNA imaging in living mice bearing a HCV RNA-presenting mini-organ, providing the first application of FP mimics in whole-animal imaging.
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Fluorescência , Corantes Fluorescentes/química , Proteínas Luminescentes/química , Ácidos Nucleicos/química , RNA Viral/análise , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Hepacivirus/genética , Humanos , Raios Infravermelhos , Proteínas Luminescentes/síntese química , Camundongos , RNA Viral/genética , Espectrometria de FluorescênciaRESUMO
Sensitive and facile detection of biomarkers is essential for early diagnosis and treatment of diseases. To this end, we here proposed a colorimetric protease assay by the modular combination of proteolysis-responsive transcription and spherical nucleic acids (SNAs). In this assay, target protease-mediated proteolysis triggers the synthesis of RNAs by in vitro transcription, which subsequently results in the aggregation of SNAs with remarkable redshifts in the wavelength of surface plasmon resonance-related absorption. As a proof of concept, this assay achieved the sensitive and specific detection of matrix metalloprotease-2 (MMP-2) with a limit of detection of 3.3 pM. Moreover, the applicability of this colorimetric assay can be expanded to other protease biomarkers (e.g., thrombin and hepatitis C virus NS3/4A) by tuning the target-responsive RNA polymerase module. Furthermore, by the immobilization of SNAs on a glass fiber membrane, a test strip that enables the portable detection of target protease with a smartphone was developed. With the use of a mobile application to capture and process the colorimetric signals, this portable detection system allowed for sensitive evaluation of MMP-2 levels in biological and clinical specimens, highlighting its potential in point-of-care diagnosis of diseases.
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Colorimetria , Ácidos Nucleicos , Biomarcadores , Peptídeo Hidrolases , Proteólise , SmartphoneRESUMO
Synthetic molecular robots can execute sophisticated molecular tasks at nanometer resolution. However, a molecular robot capable of controlling cellular behavior remains unexplored. Herein, we report a self-propelled DNA robot operating on the cell membrane to control the migration of a cell. Driven by DNAzyme catalytic activity, the DNA robot could autonomously and stepwise move on the membrane-floating cell-surface receptors in a stochastic manner and simultaneously trigger the receptor-dimerization to activate downstream signaling for cell motility. The cell membrane-associated continuous motion and operation of a DNA robot allowed for the ultrasensitive regulation of MET/AKT signaling and cytoskeleton remodeling to enhance cell migration. Finally, we designed distinct conditional DNA robots to orthogonally manipulate the cell migration in a coculture of mixed cell populations. We have developed a novel strategy to engineer a cell-driving molecular robot, representing a promising avenue for precise cell manipulation with nanoscale resolution.
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Membrana Celular/metabolismo , DNA Catalítico/metabolismo , DNA/metabolismo , Células A549 , Membrana Celular/química , Movimento Celular , DNA/química , HumanosRESUMO
Selective modulation of ligand-receptor interaction is essential in targeted therapy. In this study, we design an intelligent "scan and unlock" DNA automaton (SUDA) system to equip a native protein-ligand with cell-identity recognition and receptor-mediated signaling in a cell-type-specific manner. Using embedded DNA-based chemical reaction networks (CRNs) on the cell surface, SUDA scans and evaluates molecular profiles of cell-surface proteins via Boolean logic circuits. Therefore, it achieves cell-specific signal modulation by quickly unlocking the protein-ligand in proximity to the target cell-surface to activate its cognate receptor. As a proof of concept, we non-genetically engineered hepatic growth factor (HGF) with distinct logic SUDAs to elicit target cell-specific HGF signaling and wound healing behaviors in multiple heterogeneous cell types. Furthermore, the versatility of the SUDA strategy was shown by engineering tumor necrotic factor-α (TNFα) to induce programmed cell death of target cell subpopulations through cell-specific modulation of TNFR1 signaling.
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DNA/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , DNA/química , Fator de Crescimento de Hepatócito/química , Humanos , Ligantes , Modelos Moleculares , Receptores Tipo I de Fatores de Necrose Tumoral/química , Transdução de SinaisRESUMO
Post-translational modifications (PTMs) refer to the chemical modifications of proteins coordinated by PTM enzymes, and they play a key role in numerous physiological and pathological processes. Herein, chimeric peptide-functionalized titanium carbide MXenes (Pep-Ti3C2) were devised for the activity assay of PTM enzymes by integration with carboxypeptidase Y (CPY)-mediated peptide cleavage. The Pep-Ti3C2 is fabricated by self-assembly of chimeric peptide probes on the surface of phospholipid-coated Ti3C2 MXenes and works as the fluorescent nanoprobe for the sensing of PTM enzymes. In the presence of a target PTM enzyme, the modification groups in the peptide probes are removed along with the digestion of the peptides by CPY, thereby leading to the release of labeled fluorophores. Consequently, fluorescent analysis of PTM enzymes, including deacetylase sirtuin-1 and protein phosphatase 2C at low-nanomolar concentrations was achieved. Furthermore, the versatility of the nanoprobes was also demonstrated in simultaneous profiling of the activities of the two PTM enzymes in different cells, as well as in evaluation of the inhibition on PTMs by small molecules in complicated biological samples. Therefore, this work deploys peptide-functionalized MXenes as a generic biosensing interface for the activity assay of PTM enzymes, providing a useful tool for biochemical research and clinical diagnosis.
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Técnicas Biossensoriais/métodos , Catepsina A/metabolismo , Peptídeos/química , Titânio/química , Linhagem Celular , Corantes Fluorescentes/química , Humanos , Nanoestruturas/química , Peptídeos/metabolismo , Fosfolipídeos/química , Processamento de Proteína Pós-Traducional , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
The label-free assay has drawn extensive attention because it does not require a labeling step and enables direct interaction and signal transduction between the sensing unit and target analytes. Herein, we demonstrate a proof-of-principle concept of a label-free and visualized nanoplasmonic strategy for silver ions sensing, where only Ti3C2 MXenes are employed by exploring their excellent adsorption affinity and reductive property toward metal ions. Ag+ was adsorbed onto the surface of Ti3C2 MXene nanosheets, followed by the Ti3C2 MXenes mediated in situ silver nanoparticles (Ag NPs) generation without adding any extra stabilizing or reducing agent. The excellent localized surface plasmon resonances at a particular wavelength provide Ag NPs the capability for colorimetric assay with a detection limit of 0.615 µM. With the assistance of a smartphone, RGB analysis exhibited visualized results consistent with the results measured on a UV-vis spectrometer, promising a budget, simple-operating on-site detection. Moreover, the detection of Ag+ in real samples was achieved with satisfactory results meeting the analysis demand for the Drinking Water Standards of the World Health Organization (WHO) and the United States Environmental Protection Agency (U.S. EPA). These results reveal that Ti3C2 MXenes possess great potential in building convenient label-free colorimetry nanoplatforms and may evoke more inspirations to explore strategies for the direct sensing of analytes.