Programmable Assembly of Multivalent DNA-Protein Superstructures for Tumor Imaging and Targeted Therapy.

Programmable DNA materials hold great potential in biochemical and biomedical researches, yet the complicated synthesis, and the low stability and targeting efficacy in complex biological milieu limit their clinical translations. Here we show a one-pot assembly of DNA-protein superstructures as drug vehicles with specifically high affinity and stability for targeted therapy. This is achieved by biomimetic assembly of programmable polymer DNA wire into densely packed DNA nanosphere with an alkaline protein, protamine. Multivalent DNA nanostructures encoded with different types and densities of aptamers exhibit high affinity to targeted cells through polyvalent interaction. Our results show high cancer cell selectivity, reduced side effect, excellent therapeutic efficacy, and sensitive tumor imaging in both subcutaneous and orthotopic non-small-cell lung cancer murine models. This biomimetic assembly approach provides practical DNA nanomaterials for further clinical trials and may advance oligonucleotide drug delivery.

Visualization of Vaccine Dynamics with Quantum Dots for Immunotherapy.

The direct visualization of vaccine fate is important to investigate its immunoactivation process to elucidate the detailed molecular reaction process at single-molecular level. Yet, visualization of the spatiotemporal trafficking of vaccines remains poorly explored. Here, we show that quantum dot (QD) nanomaterials allow for monitoring vaccine dynamics and for amplified immune response. Synthetic QDs enable efficient conjugation of antigen and adjuvants to target tissues and cells, and non-invasive imaging the trafficking dynamics to lymph nodes and cellular compartments. The nanoparticle vaccine elicits potent immune responses and anti-tumor efficacy alone or in combination with programmed cell death protein 1 blockade. The synthetic QDs showed high fluorescence quantum yield and superior photostability, and the reliable and long-term spatiotemporal tracking of vaccine dynamics was realized for the first time by using the synthetic QDs, providing a powerful strategy for studying immune response and evaluating vaccine efficacy.

Biosynthesized Quantum Dot for Facile and Ultrasensitive Electrochemical and Electrochemiluminescence Immunoassay.

Nanomaterials are commonly utilized for amplified immunoassay of biomarkers. However, traditional nanomaterial-based immunoassay usually requires a time-consuming and labor-intensive nanoparticle modification and conjugation process, which impedes their practical applications. Here, a new immunoassay method based on biosynthesized nanomaterials is developed with versatile functions for facile and ultrasensitive detection of cancer biomarker. In this method, the utilized biosynthesized quantum dots (BQDs) allow convenient antibody conjugation and electrode modification, and demonstrate excellent electrochemical and electrochemiluminescent responses. The differential pulse voltammetric, faradaic impedance spectroscopy, and electrochemiluminescent measurements with the BQD-modified electrode show detection limits at picomolar levels as well as good specificity toward human prostate-specific antigen detection. The inherent recognization capability as well as the inherent electrochemical and electrochemiluminescence features thus enable BQDs as good candidates for facile immunosensors with high sensitivity. Such a biosynthesized nanomaterial-based approach opens up the possibility of using innovative designs for nanoparticle-based assays, and developing reliable and practical methods for early disease diagnosis.

High-fidelity ATP imaging via an isothermal cascade catalytic amplifier.

Artificial catalytic DNA circuits that can identify, transduce and amplify the biomolecule of interest have supplemented a powerful toolkit for visualizing various biomolecules in cancer cells. However, the non-specific response in normal tissues and the low abundance of analytes hamper their extensive biosensing and biomedicine applications. Herein, by combining tumor-responsive MnO2 nanoparticles with a specific stimuli-activated cascade DNA amplifier, we propose a multiply guaranteed and amplified ATP-sensing platform via the successive cancer-selective probe exposure and stimulation procedures. Initially, the GSH-degradable MnO2 nanocarrier, acting as a tumor-activating module, ensures the accurate delivery of the cascade DNA amplifier into GSH-rich cancer cells and simultaneously provides adequate Mn2+ cofactors for facilitating the DNAzyme biocatalysis. Then, the released cascade amplifier, acting as an ATP-monitoring module, fulfills the precise and sensitive analysis of low-abundance ATP in cancer cells where the catalyzed hairpin assembly (CHA) is integrated with the DNAzyme biocatalyst for higher signal gain. Additionally, the cascade catalytic amplifier achieved tumor-specific activated photodynamic therapy (PDT) after integrating an activatable photosensitizer into the system. This homogeneous cascade catalytic aptasensing circuit can detect low-abundance endogenous ATP of cancer cells, due to its intrinsically rich recognition repertoire and avalanche-mimicking hierarchical acceleration, thus demonstrating broad prospects for analyzing clinically important biomolecules and the associated physiological processes.

Portable and sensitive detection of non-glucose target by enzyme-encapsulated metal-organic-framework using personal glucose meter.

Personal glucose meter (PGM) is one of the most commercially available POC (point-of-care) devices for monitoring the level of glucose reliably, yet its non-glucose quantification ability is limited since such strategy needs ingenious interface design and tedious enzyme conjugation. Herein, we constructed a portable and sensitive platform that can detect non-glucose target by combining enzyme-encapsulated zeolitic imidazole framework-90 (ZIF-90) with personal glucose meter. ZIF-90 is an ideal carrier and susceptor due to the extraordinary capability of packaging enzyme and stimuli-responsiveness. We selected adenosine-5'-triphosphate (ATP) as the target model of non-glucose analytes. Upon ATP-induced decomposition of MOF, the released enzyme (glucose oxidase or invertase) catalyzed substrate and gave rise to the change of the glucose concentration for PGM assay. This method determined ATP with a remarkably sensitivity of 233 nM and effective recovery in real serum samples. Our strategy provides a facile and practical approach for measuring the non-glucose target using PGM, and could potentially be applied in bimolecular detection in point-of-care diagnosis.

A dynamic DNA nanosponge for triggered amplification of gene-photodynamic modulation.

Nucleic acid therapeutics has reached clinical utility through modulating gene expression. As a potential oligonucleotide drug, DNAzyme has RNA-cleaving activity for gene silencing, but faces challenges due to the lack of a safe and effective delivery vehicle and low in vivo catalytic activity. Here we describe DNAzyme-mediated gene regulation using dynamic DNA nanomaterials with intrinsic biocompatibility, stability, tumor-targeted delivery and uptake, and self-enhanced efficacy. We assemble programmable DNA nanosponges to package and deliver diverse nucleic acid drugs and therapeutic agents such as aptamer, DNAzyme and its cofactor precursor, and photosensitizer in one pot through the rolling circle amplification reaction, formulating a controllable nanomedicine using encoded instructions. Upon environmental stimuli, DNAzyme activity increases and RNA cleavage accelerates by a supplementary catalytic cofactor. In addition, this approach induces elevated O2 and 1O2 generation as auxiliary treatment, achieving simultaneously self-enhanced gene-photodynamic cancer therapy. These findings may advance the clinical trial of oligonucleotide drugs as tools for gene modulation.

Precision photothermal therapy and photoacoustic imaging by in situ activatable thermoplasmonics.

Phototherapy holds great promise for disease treatment; however, traditional "always-on" photoagents have been restricted to clinical translation due to their nonspecific response and side effects on normal tissues. Here, we show a tumor microenvironment activated photothermal and photoacoustic agent as an activatable prodrug and probe that allows precise cancer diagnosis and treatment. Such an in situ revitalized therapeutic and contrast agent is achieved via controllable plasmonic heating for thermoplasmonic activation. This enables monitoring of signal molecule dynamics, real-time photothermal and photoacoustic imaging of tumors and lymph node metastasis, and targeted photothermal therapy without unwanted phototoxicity to normal tissues. Our study provides a practical solution to the non-specificity problem in phototherapy and offers precision cancer therapeutic and theranostic strategies. This work may advance the development of ultrasensitive disease diagnosis and precision medicine.

Quantum dot-pulsed dendritic cell vaccines plus macrophage polarization for amplified cancer immunotherapy.

Dendritic cell (DC) vaccines hold great potential in cancer immunotherapy, but the suboptimal design of DC vaccines and the immunosuppressive tumor microenvironment largely impair their anti-tumor efficacy. Here, quantum dot (QD) pulsed-DC vaccines integrating with tumor-associated macrophage polarization are developed for amplified anti-tumor immunity. Semiconductor QDs are engineered with diverse functions to act as fluorescence nanoprobes, immunomodulatory adjuvants, and nanocarriers to load tumor antigens and Toll-like receptor 9 agonists. The QD-pulsed DC vaccines enable spatiotemporal tracking of lymphatic drainage and efficacy evaluation of DC immunotherapy, and trigger potent immunoactivation. Specifically, designer DC vaccine plus macrophage polarization elicits potent immune response to stimulate innate and adaptive antitumor immunity and ameliorate the immunosuppressive tumor microenvironment. As a new combination therapy, this strategy greatly boosts antigen-specific T-cell immunity and thus strongly inhibits local tumor growth and tumor metastasis in vivo. This study may provide an applicable treatment for cancer immunotherapy.

A sensitive electrochemical sensor for bisphenol A on the basis of the AuPd incorporated carboxylic multi-walled carbon nanotubes.

A sensitive electrochemical sensor for BPA based on the AuPd incorporated carboxylic multi-walled carbon nanotubes (MWCNT) with synergetic amplified current signal was developed, where MWCNT was used as supporter to improve electron transport and poly (diallyldimethylammonium chloride) (PDDA) was used as dispersant for MWCNT and overcome the intrinsic van der Waals interactions between MWCNT and further increase metal NPs loading. The prepared MWCNT-PDDA-AuPd showed enhanced electrocatalytic performance toward BPA, which is better than those of homologous monometallic counterparts and MWCNT-PDDA though the content of AuPd is really low. The peak currents of BPA increased with BPA concentration in linear range of 0.18-18 µM and the detection limit of 60 nM. The sensor showed high sensitivity, good stability, repeatability and can be used to detect BPA in milk and water samples with good performance, which demonstrate that MWCNTs-PDDA-AuPd nanocomposite may be an attractive material in applications of environmental and food analysis.