Cuie Chen

Polyvalent Nucleic Acid/Mesoporous Silica Nanoparticle Conjugates: Dual Stimuli‐Responsive Vehicles for Intracellular Drug Delivery

The distinctive characteristics of mesoporous silica nanoparticles (MSPs) such as thermal stability, tunable pore sizes, large load capacity, and the ease of surface functionalization make these scaffolds ideal for the design of nanodevices and “on-command” delivery applications. To date, several MSPbased controlled-release systems have been synthesized by using different kinds of capping agents including organic molecules, nanoparticles, and supramolecular assemblies. “On-demand” release systems that respond to a range of stimuli, including redox, 4a,5] pH or temperature, enzymes, competitive binding, and photoirradiation 4b,9] have recently been reported. Despite these burgeoning achievements, many of the existing capping systems have disadvantages such as the use of stimuli that are complicated and/or difficult to apply, poor applicability in aqueous solutions and biocompatibility, and the toxicity of the capping agents used. In particular, regardless of recent reports on capped MSPs that can be uncapped by certain enzymes or carbohydrates, the utility of MSP-based devices involving biomolecules for real delivery systems is still in its infancy. Therefore, the search for effective systems that, in particular, respond to internal biological stimuli still remains a big challenge in this field. Herein we describe the design and construction of a stimuli-responsive vehicle for intracellular drug delivery using a polyvalent nucleic acid/MSP “click” conjugate that responds to both external and endogenous activation. Nucleic acids have been recognized as attractive building blocks for nanotechnology and materials science owing to the remarkable specificity and versatility of these units. The unique structural motif and self-recognition properties of duplex DNA, including temperature-dependent assembly, as well as the enzymatic recognition of specific encoded bases, may be applied as triggers for functional DNA manipulation. As shown in Figure 1, self-complementary duplex DNA was anchored to the openings of the MSPs and was utilized as a cap for trapping the guest molecules within the porous

A Simple, Universal Colorimetric Assay for Endonuclease/Methyltransferase Activity and Inhibition Based on an Enzyme-Responsive Nanoparticle System

An enzyme responsive nanoparticle system that uses a DNA-gold nanoparticle (AuNP) assembly as the substrate has been developed for the simple, sensitive, and universal monitoring of restriction endonucleases in real time. This new assay takes advantage of the palindromic recognition sequence of the restriction nucleases and the unique optical properties of AuNPs and is simpler than the procedure previously described by by Xu et al. (Angew. Chem. Int. Ed. Engl. 2007, 46, 3468-3470). Because it involves only one type of ssDNA modified AuNPs, this assay can be directed toward most of the endonucleases by simply changing the recognition sequence found within the linker DNA. In addition, the endonuclease activity could be quantitatively analyzed by the value of the reciprocal of hydrolysis half time (t(1/2)(-1)). Furthermore, our new design could also be applied to the assay of methyltransferase activity since the methylation of DNA inhibits its cleavage by the corresponding restriction endonuclease, and thus, this new methodology can be easily adapted to high-throughput screening of methyltransferase inhibitors.

Stimuli-responsive controlled-release system using quadruplex DNA-capped silica nanocontainers

A novel proton-fueled molecular gate-like delivery system has been constructed for controlled cargo release using i-motif quadruplex DNA as caps onto pore outlets of mesoporous silica nanoparticles. Start from simple conformation changes, the i-motif DNA cap can open and close the pore system in smart response to pH stimulus. Importantly, the opening/closing and delivery protocol is highly reversible and a partial cargo delivery can be easily controlled at will. A pH-switchable nanoreactor has also been developed to validate the potential of our system for on-demand molecular transport. This proof of concept might open the door to a new generation of carrier materials and could also provide a general route to use other functional nucleic acids/peptide nucleic acids as capping agents in the fields of versatile controlled delivery nanodevices.

Mesoporous silica nanoparticle-based H2O2 responsive controlled-release system used for Alzheimer's disease treatment.

Metal ions play important roles in amyloid aggregation and neurotoxicity. Metal-ion chelation therapy has been used in clinical trials for Alzheimers disease (AD) treatment. However, clinical trial studies have shown that long-term use of metal chelator can cause adverse side effect, subacute myelo-optic neuropathy. Nanoparticle engineering processes have become promising approaches for efficiently drugs delivery. A series of modified mesoporous silica nanoparticles (MSNs) using redox, pH, competitive binding, light, and enzyme as actuators have been demonstrated. Recently, significant advances in sensing oxidative stress have been made by taking advantage of specific chemistry between cellular oxidants such as H(2) O(2) . Here we report a biocompatible delivery platform by using H(2) O(2) responsive controlled-release system to realize target delivery of AD therapeutic metal chelator. The advantage of this novel strategy is that metal chelator can only be released by the increased levels of H(2) O(2) , thus, it would not interfere with the healthy metal homeostasis and can overcome strong side effect of metal chelator after long-term use. By taking advantage of the good biocompatibility, cellular uptake properties, and efficient intracellular release of metal chelators, the delivery system is promising for future in vivo controlled-release biomedical applications.

Photosensitizer‐Incorporated Quadruplex DNA‐Gated Nanovechicles for Light‐Triggered, Targeted Dual Drug Delivery to Cancer Cells

A novel light-operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer-incorporated G-quadruplex DNA-capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug-carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell-specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery.

Enzymatic Manipulation of DNA‐Modified Gold Nanoparticles for Screening G‐Quadruplex Ligands and Evaluating Selectivities

Enzymatic manipulation of DNA on well-dispersed gold nanoparticles (AuNPs) offers an ideal system for high-throughput screening of G-quadruplex ligands and evaluation of their selectivity with respect to duplex and quadruplex DNA (see figure). This work has implications for the future use of nanoparticle-based technologies in the discovery of potential cancer therapeutic agents.

Design of proton-fueled tweezers for controlled, multi-function DNA-based molecular device

A novel multi-functional, proton-fueled DNA tweezers has been constructed. Starting from simple conformation change of i-motif DNA, the nanodevice can accomplish movements such as repeatedly capture or release target DNA and protein. The DNA tweezers, driven by the solution pH without the need of injecting external energy, are robust and highly reversible with the responses of 1-2 orders of magnitude faster than the DNA-fueled machine, and does not accumulate duplex waste products to poison the system. Our work has demonstrated the successful combination of the operating principles of DNA-based nanomechanical device with the unique molecular recognition properties of DNA, which we believed could open an exciting avenue in the design and construction of easy-to-handle, cost-efficient, reliable and high efficient functional nanostructure.

A gold nanoparticle-based strategy for label-free and colorimetric screening of DNA triplex binders.

A label-free colorimetric assay, using non-crosslinking AuNP aggregation, has been developed for the screening of specific triplex DNA binders. The relative binding affinities can be simultaneously determined. Our novel assay is simple in design and fast in operation, avoiding either AuNPs modification or oligonucleotide labeling, and easy to implement for visual detection. This strategy may offer a new approach for developing low cost, sensitive and high-throughput screening platform that is likely to be highly useful in a wide range of applications.