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Esophageal cancer is one of the most frequent malignant tumors of the digestive tract, among which esophageal squamous cell carcinoma (ESCC) is the main pathological type worldwide. Previous studies have shown microbial infections in the upper digestive tract to be a potential risk factor in ESCC etiology. In this study, we identified that Mycoplasma hyorhinis infection promoted the malignancy of ESCC. In response, we generated a single-stranded DNA aptamer, ZY3A, against M. hyorhinis using the cell-SELEX strategy. The underlying recognition mechanism of ZY3A on M. hyorhinis involves its binding to M. hyorhinis-specific p37 protein. This tool allowed us to provide the first proof-of-concept evidence using a nucleic acid aptamer to control mycoplasma infection. More specifically, we found that ZY3A could neutralize M. hyorhinis infection on ESCC cells by blocking the interaction between p37 protein and its receptor TLR4 on the ESCC cell membrane. As a result, ZY3A inhibited the migration and invasion of M. hyorhinis-infected ESCC cells in vitro and metastasis in vivo. Taken together, these findings indicate that aptamer ZY3A is a potential candidate for development into a novel molecular tool for treatment of M. hyorhinis infection and a safe first-in-class M. hyorhinis-targeting antitumor agent.

Hepatocellular carcinoma (HCC) is a type of cancer that has high rates of recurrence and mortality. One of the most important factors that lead to treatment failure of HCC is the acquisition of multidrug resistance (MDR). Development of specific ligands for multidrug-resistant HCC will provide useful molecular tools for precise diagnosis and targeted theranostics. Herein, a multidrug-resistant HCC cell (HepG2/MDR)-specific aptamer was developed through Cell-SELEX (systematic evolution of ligands by exponential enrichment) technology. With dissociation constants lying in the nanomolar range, the molecularly designed PS-ZL-7c aptamer showed great selectivity to drug-resistant cancer cells. The in vivo imaging results illustrated that the PS-ZL-7c specifically accumulated in the drug-resistant tumors but not in drug-sensitive tumors and normal tissues, indicating that the PS-ZL-7c aptamer possessed excellent potential as a targeting ligand for precise diagnosis and target theranostics of multidrug-resistant HCC.

Significance Metastasis generally leads to a dismal prognosis in bladder cancer (BLCA). The mechanical status of the cell membrane has been reported to reflect the potential of the metastatic capacity of cancer cells. However, the molecular profile and corresponding mechanical traits underlying BLCA metastasis remain largely elusive. Our study demonstrates the significance of cytoskeleton-associated protein 4 (CKAP4) in BLCA malignancy through aptamer selection, emphasizes the mechanical dominance of the central-to-peripheral gradient over simply softening or stiffening in cell migration, and shows the role of exosomes in mediating mechanical signaling in BLCA metastasis. Altogether, our work verifies the promising advantages of an aptamer-based approach in cancer research, which ranges from biomarker discovery to the elucidation of biological functions.

Ubiquitin‐specific protease 11 (USP11) has been implicated in the regulation of DNA repair, apoptosis, signal transduction and cell cycle. It belongs to a USP subfamily of deubiquitinases. Although previous research has shown that USP11 overexpression is frequently found in melanoma and is correlated with a poor prognosis, the potential molecular mechanism of USP11 in melanoma remains indefinitive. Here, we report that USP11 and NONO colocalize and interact with each other in the nucleus of melanoma cells. As a result, the knockdown of USP11 decreases NONO levels. Whereas, overexpression of USP11 increases NONO levels in a dose‐dependent manner. Furthermore, we reveal that USP11 protects NONO protein from proteasome‐mediated degradation by removing poly‐ubiquitin chains conjugated onto NONO. Functionally, USP11 mediated melanoma cell proliferation via the regulation of NONO levels because ablation of USP11 inhibits the proliferation which could be rescued by ectopic expression of NONO protein. Moreover, a significant positive correlation between USP11 and NONO concentrations was found in clinical melanoma samples. Collectively, these results demonstrate that USP11 is a new deubiquitinase of NONO and that the signalling axis of USP11‐NONO is significantly involved in melanoma proliferation.

DNA origami has emerged as a highly programmable method to construct customized objects and functional devices in the 10–100 nm scale. Scaling up the size of the DNA origami would enable many potential applications, which include metamaterial construction and surface-based biophysical assays. Here we demonstrate that a six-helix bundle DNA origami nanostructure in the submicrometre scale (meta-DNA) could be used as a magnified analogue of single-stranded DNA, and that two meta-DNAs that contain complementary ‘meta-base pairs’ can form double helices with programmed handedness and helical pitches. By mimicking the molecular behaviours of DNA strands and their assembly strategies, we used meta-DNA building blocks to form diverse and complex structures on the micrometre scale. Using meta-DNA building blocks, we constructed a series of DNA architectures on a submicrometre-to-micrometre scale, which include meta-multi-arm junctions, three-dimensional (3D) polyhedrons, and various 2D/3D lattices. We also demonstrated a hierarchical strand-displacement reaction on meta-DNA to transfer the dynamic features of DNA into the meta-DNA. This meta-DNA self-assembly concept may transform the microscopic world of structural DNA nanotechnology. A six-helix bundle DNA structure called meta-DNA has now been assembled and shown to possess some structural properties similar to those of single-stranded DNA. Two meta-DNAs containing complementary ‘meta-base pairs’ are shown to form double helices. Meta-DNA building blocks are also used to construct a series of DNA architectures and to perform a hierarchical strand-displacement reaction.

Plasmon-mediated photocatalysis provides a novel strategy for harvesting solar energy. Identification of the rate-determining step and its activation energy in plasmon-mediated photocatalysis plays critical roles for understanding the contribution of hot carriers, which facilitates rational designation of catalysts with integrated high photochemical conversion efficiency and catalytic performance. However, it remains a challenge due to a lack of research tools with spatiotemporal resolution that are capable of capturing intermediates. In this work, we used a single-molecule fluorescence approach to investigate a localized surface plasmon resonance (LSPR)-enhanced photocatalytic reaction with subturnover resolution. By introducing variable temperature as an independent parameter in plasmonic photocatalysis, the activation energies of tandem reaction steps, including intermediate generation, product generation, and product desorption, were clearly differentiated, and intermediate generation was found to be the rate-limiting step. Remarkably, the cause of the plasmon-enhanced catalysis performance was found to be its ability of lowering the activation energy of intermediate generation. This study gives new insight into the photochemical energy conversion pathways in plasmon-enhanced photocatalysis and sheds light on designing high-performance plasmonic catalysts.

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.

An integrated trapped device (ITD) capable of removal of circulating tumor cells (CTCs) can assuage or even prevent metastasis. However, adhesion repertoires are ordinarily neglected in the design of ITDs, possibly leading to the omission of highly metastatic CTC and treatment failure. Here a vascular-like ITD with adhesive sites and wireless magnetothermal response to remove highly metastatic CTC in vivo is presented. Such a vascular-like ITD comprises circumferential well-aligned fibers and artificial adhesion repertoires and is optimized for magnetothermal integration. Continuous and repeated capture in a dynamic environment increases capture efficiency over time. Meanwhile, the heat generation of the ITD leads to the capture of CTC death owing to cell heat sensitivity. Furthermore, the constructed bioinspired ultrastructure of the ITD prevents vascular blockage and induces potential vascular regeneration. Overall, this work defines an extendable strategy for constructing adhesion repertoires against intravascular shear forces, provides a vascular-like ITD for reducing CTC counts, and is expected to alleviate the risk of cancer recurrence.

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and have poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.

Currently, the broad use of monovalent aptamers in oncology faces challenges, including insufficient recognition and internalization caused by a finite number of receptors on the cell surface, as well as a 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 enhancing recognition of the target cells. This improvement not only boosts binding and internalization abilities, but also expands the recognition spectrum of these aptamers to 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.

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.

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

Uniform silver-containing metal nanostructures with strong and stable surface-enhanced Raman scattering (SERS) signals hold great promise for developing ultrasensitive probes for biodetection. Nevertheless, the direct synthesis of such ready-to-use nanoprobes remains extremely challenging. Herein we report a DNA-mediated gold-silver nanomushroom with interior nanogaps directly synthesized and used for multiplex and simultaneous SERS detection of various DNA and RNA targets. The DNA involved in the nanostructures can act as not only gap DNA (mediated DNA) but also probe DNA (hybridized DNA), and DNA's involvement enables the nanostructures to have the inherent ability to recognize DNA and RNA targets. Importantly, we were the first to establish a new method for the generation of multicolor SERS probes using two different strategies. First Raman-labeled alkanethiol probe DNA was assembled on gold nanoparticles, and second, thiol-containing Raman reporters were coassembled with the probe DNA. The ready-to-use probes also give great potential to develop ultrasensitive detection methods for various biological molecules.

DNA origami has emerged as a highly programmable method to construct customized objects and functional devices in the 10-100 nm scale. Scaling up the size of the DNA origami would enable many potential applications, which include metamaterial construction and surface-based biophysical assays. Here we demonstrate that a six-helix bundle DNA origami nanostructure in the submicrometre scale (meta-DNA) could be used as a magnified analogue of single-stranded DNA, and that two meta-DNAs that contain complementary 'meta-base pairs' can form double helices with programmed handedness and helical pitches. By mimicking the molecular behaviours of DNA strands and their assembly strategies, we used meta-DNA building blocks to form diverse and complex structures on the micrometre scale. Using meta-DNA building blocks, we constructed a series of DNA architectures on a submicrometre-to-micrometre scale, which include meta-multi-arm junctions, three-dimensional (3D) polyhedrons, and various 2D/3D lattices. We also demonstrated a hierarchical strand-displacement reaction on meta-DNA to transfer the dynamic features of DNA into the meta-DNA. This meta-DNA self-assembly concept may transform the microscopic world of structural DNA nanotechnology.

The advent of single molecule imaging technologies in 1990s made the dynamics of single molecule enzyme catalysis be successfully probed in real time in vitro . Ever since then, single molecule enzymology entered the golden age of rapid developing. Individual features of single enzyme molecule hidden in the overall average were discovered, and many new catalytic mechanisms were proposed. Single molecule enzymology sheds light on the dynamic interactions between enzyme and substrate or product, deepening the understanding of biochemical reactions.

It is traditionally assumed that enzymatic reaction does not perturb the diffusion of an enzyme itself. Recent studies showed that the diffusivity of enzymes increased in a substrate-dependent manner during catalysis. Thus, the energy released during enzyme catalysis could be used to propel nanoscale objects, e.g. molecule motors driven by enzymatic reactions. Although the dependence of enzyme diffusion on substrate has been reported in several different enzyme systems, the exact origin of this phenomenon is still unknown yet. However, several possible mechanisms were proposed for the enhanced diffusion. This review illustrates recent progress in the research on the influence of enzymatic reaction on the diffusivity of enzymes, including the change of diffusion coefficient of enzymes, potential mechanisms and related applications.

Cancer is one of the leading causes of mortality worldwide, and worse still, the number of cancer cases is startlingly growing every year. The intrinsic complexity of tumors, including intratumor heterogeneity, dynamic evolution, and abnormal tumor microenvironments (TME), often leads to the failure of traditional chemotherapy. Cancer theranostics integrate molecular diagnosis and targeted cancer therapy, promoting the transition from conventional to personalized and precision medicine. Functional nucleic acids (FNAs), such as aptamers, DNAzymes, and DNA-based nanomachines (DNMs), are nucleic acids with functions beyond the well-known genetic roles. In addition to the basic advantages of nucleic acids-based materials, such as low cost, biocompatibility, low immunogenicity, and simplicity of chemical modification. FNAs also possess many superior properties, including high binding affinity and specificity of aptamers, efficient and specific gene editing ability of DNAzymes, and logic-controlled designability of DNA machines, all making FNAs an attractive material for applications in cancer theranostics in recent years. This review highlights the development and most recent applications of FNAs in cancer theranostics, as well as the challenges and opportunities in this research field.

Aptamers are often compared with antibodies since both types of molecules function as targeting ligands for specific cancer cell recognition. However, aptamers offer several advantages, including small size, facile chemical modification, high chemical stability, low immunogenicity, rapid tissue penetration, and engineering simplicity. Despite these advantages, several crucial factors have delayed their clinical translation, such as concerns over inherent physicochemical stability and safety. Meanwhile, steps have been taken to make aptamer-drug conjugates, or ApDCs, a clinically practical tool. In this review, we highlight the development of ApDCs and discuss how researchers are solving some problems associated with their clinical application for targeted therapy.

Explosive detection is a critical element in preventing terrorist attacks, especially in crowded and influential areas. It is probably more important to establish the connection of explosive loading with a carrier's personal identity. In the present work, we introduce fingerprinting as physical personal identification and develop a nondestructive nanoplasmonic method for the imaging of latent fingerprints. We further integrate the nanoplasmonic response of catalytic growth of Au NPs with NADH-mediated reduction of 1,3,5-trinitro-1,3,5-triazinane (RDX) for the quantitative analysis of RDX explosive residues in latent fingerprints. This generic nanoplasmonic strategy is expected to be used in forensic investigation to distinguish terrorists that carry explosives.

We report the development of an ultrasensitive nanoplasmonic probe for discriminative detection and imaging of dopamine released from living cells. The sensing mechanism is based on the dopamine-induced seeded-growth of Au nanoparticles (Au NPs) that leads to the shift of the plasmon band. This platform allows for the detection of dopamine with a detection limit down to 0.25 pM within 1 min. This nanoplasmonic assay is further applied to visualize the release of dopamine from living rat pheochromocytoma (PC12) cells under ATP-stimulation with dark-field microscopy (DFM). The DFM results together with real time fluorescence imaging of PC12 cells stained with the Fluo calcium indicator, suggested that ATP stimulated-release of dopamine is concomitant with the Ca(2+) influx, and the influx of Ca(2+) is through ATP-activated channels instead of the voltage-gated Ca(2+) channel (VGC).

Studying the activity of individual nanocata- lysts, especially with high spatiotemporal resolution of single-molecule and single-turnover scale, is essential for the understanding of catalytic mechanism and the design- ing of effective catalysts. Several approaches have been developed to monitor the catalytic reaction on single catalysts. In this review, we summarized the updated progresses of several new spectroscopic and microscopic approaches, including single-molecule fluorescence micro- scopy, surface-enhanced Raman spectroscopy, surface plasmon resonance microscopy and X-ray microscopy, for the study of single-molecule and single-particle catalysis.

It is highly demanding to design active nanomotors that can move in response to specific signals with controllable rate and direction. A catalysis-driven nanomotor was constructed by designing catalytically and plasmonically active Janus gold nanoparticles (Au NPs), which generate an asymmetric temperature gradient of local solvent surrounding NPs in catalytic reactions. The self-thermophoresis behavior of the Janus nanomotor is monitored from its inherent plasmonic response. The diffusion coefficient of the self-thermophoresis motion is linearly dependent on chemical reaction rate, as described by a stochastic model.

Surface plasmon resonance of coinage metal nanoparticles is extensively exploited to promote catalytic reactions via harvesting solar energy. Previous efforts on elucidating the mechanisms of enhanced catalysis are devoted to hot electron-induced photothermal conversion and direct charge transfer to the adsorbed reactants. However, little attention is paid to roles of hot holes that are generated concomitantly with hot electrons. In this work, 13 nm spherical Au nanoparticles with small absorption cross-section are employed to catalyze a well-studied glucose oxidation reaction. Density functional theory calculation and X-ray absorption spectrum analysis reveal that hot holes energetically favor transferring catalytic intermediates to product molecules and then desorbing from the surface of plasmonic catalysts, resulting in the recovery of their catalytic activities. The studies shed new light on the use of the synergy of hot holes and hot electrons for plasmon-promoted catalysis.