Chemically Inducible DNAzyme Sensor for Controllable Imaging of Metal Ions.

RNA-cleaving DNAzymes have emerged as a promising tool for metal ion detection. Achieving spatiotemporal control over their catalytic activity is essential for understanding the role of metal ions in various biological processes. While photochemical and endogenous stimuli-responsive approaches have shown potential for controlled metal ion imaging using DNAzymes, limitations such as photocytotoxicity, poor tissue penetration, or off-target activation have hindered their application for safe and precise detection of metal ions in vivo. We herein report a chemically inducible DNAzyme in which the catalytic core is modified to contain chemical caging groups at the selected backbone sites through systematic screening. This inducible DNAzyme exhibits minimal leakage of catalytic activity and can be reactivated by small molecule selenocysteines, which effectively remove the caging groups and restore the activity of DNAzyme. Benefiting from these findings, we designed a fluorogenic chemically inducible DNAzyme sensor for controlled imaging of metal ions with tunable activity and high selectivity in live cells and in vivo. This chemically inducible DNAzyme design expands the toolbox for controlling DNAzyme activity and can be easily adapted to detect other metal ions in vivo by changing the DNAzyme module, offering opportunities for precise biomedical diagnosis.

Site-Specific Bioorthogonal Activation of DNAzymes for On-Demand Gene Therapy.

RNA-cleaving DNAzymes hold great promise as gene silencers, and spatiotemporal control of their activity through site-specific reactions is crucial but challenging for on-demand therapy. We herein report a novel design of a bioorthogonally inducible DNAzyme that is deactivated by site-specific installation of bioorthogonal caging groups on the designated backbone sites but restores the activity via a phosphine-triggered Staudinger reduction. We perform a systematical screening for installing the caging groups on each backbone site in the catalytic core of 10-23 DNAzyme and identify an inducible DNAzyme with very low leakage activity. This design is demonstrated to achieve bioorthogonally controlled cleavage of exogenous and endogenous mRNA in live cells. It is further extended to photoactivation and endogenous stimuli activation for spatiotemporal or targeted control of gene silencing. The bioorthogonally inducible DNAzyme is applied to a triple-negative breast cancer mouse model using a lipid nanoparticle delivery system, demonstrating high efficiency in knockdown of Lcn2 oncogenes and substantial suppression of tumor growth, thus highlighting the potential of precisely controlling the DNAzyme functions for on-demand gene therapy.

Self-Assembled Peptide Amphiphile Nanofibers for Controlled Therapeutic Delivery to the Atherosclerotic Niche.

Atherosclerotic plaque remains the leading contributor to cardiovascular disease and requires invasive surgical procedures for its removal. Nanomedicine offers a minimally invasive approach to alleviate plaque burden by targeted therapeutic delivery. However, nanocarriers are limited without the ability to sense and respond to the diseased microenvironment. In this study, targeted self-assembled peptide amphiphile (PA) nanofibers were developed that cleave in response to biochemical cues expressed in atherosclerotic lesions-reactive oxygen species (ROS) and intracellular glutathione-to deliver a liver X receptor agonist (LXR) to enhance macrophage cholesterol efflux. The PAs released LXR in response to physiological levels of ROS and reducing agents and could be co-assembled with plaque-targeting PAs to form nanofibers. The resulting LXR PA nanofibers promoted cholesterol efflux from macrophages in vitro as well as LXR alone and with lower cytotoxicity. Further, the ApoA1-LXR PA nanofibers targeted plaque within an atherosclerotic mouse model in vivo and activated ATP-binding cassette A1 (ABCA1) expression as well as LXR alone with reduced liver toxicity. Taken together, these results demonstrate the potential of self-assembled PA nanofibers for controlled therapeutic delivery to the atherosclerotic niche.

Development of Poly(1,8-octanediol-co-citrate-co-ascorbate) Elastomers with Enhanced Ascorbate Performance for Use as a Graft Coating to Prevent Neointimal Hyperplasia.

Small-diameter expanded polytetrafluoroethylene (ePTFE) graft surfaces have poor long-term patency due to limited endothelial cell (EC) coverage and anastomotic intimal hyperplasia. Multifunctional elastomers that coat the ePTFE graft surface to promote EC adhesion while simultaneously inhibiting intimal hyperplasia are highly desirable. Poly(diol-co-citrate) (PDC), a thermoset elastomer, is biodegradable, biocompatible, and mimics vascular mechanical properties. Engineering antioxidant components into PDC polymeric structures improves biocompatibility by attenuating oxidative stress yet is limited by bioavailability. Herein, we develop a new ascorbate protection and deprotection strategy (APDS) for loading bioactive ascorbic acid into the structure of PDC elastomers to improve poly(1,8-octanediol-co-citrate-co-ascorbate) (POCA) prepolymer ascorbate activity. Elastomers cured from APDS POCA prepolymers provide twice the active ascorbate sites on the elastomer surface (35.19 ± 1.64 ng mg-1 cm-2) versus unprotected POCA (Un.POCA, 18.31 ± 0.97 ng mg-1 cm-2). APDS POCA elastomers displayed suitable mechanical properties for vascular graft coating [Young's modulus (2.15-2.61 MPa), elongation (189.5-214.6%) and ultimate tensile strength (2.73-3.61 MPa)], and superior surface antioxidant performance through 1,1-diphenyl-2-picrylhydrazyl free radical scavenging and lipid peroxidation inhibition as compared to poly(1,8-octanediol-co-citrate) (POC) and Un.POCA. Hydrolytic degradation of APDS POCA occurred within 12 weeks under physiological conditions with a mass loss of 25.8 ± 3.4% and the degradation product retaining ascorbate activity. APDS POCA elastomer surfaces supported human aortic endothelial cell proliferation while inhibiting human aortic smooth muscle cell proliferation in vitro. APDS POCA elastomer surfaces displayed superior decomposition of S-nitrosothiols compared to POC and Un.POCA. Taken together, these findings indicate the potential of APDS POCA elastomers to serve as bioactive, therapeutic coatings that enhance the long-term patency of small diameter ePTFE grafts.

"Roller-Wheel"-Type Pt-Containing Small Molecules and the Impact of "Rollers" on Material Crystallinity, Electronic Properties, and Solar Cell Performance.

We report the synthesis, characterization, and detailed comparison of a series of novel Pt-bisacetylide containing conjugated small molecules possessing an unconventional "roller-wheel" shaped structure that is distinctly different from the "dumbbell" designs in traditional Pt-bisacetylide containing conjugated polymers and small molecules. The relationships between the chemical nature and length of the "rollers" and the electronic and physical properties of the materials are carefully studied by steady-state spectroscopy, cyclic voltammetry, differential scanning calorimetry, single-crystal X-ray diffraction, transient absorption spectroscopy, theoretical calculation, and device application. It was revealed that if the roller are long enough, these molecules can "slip-stack" in the solid state, leading to high crystallinity and charge mobility. Organic solar cells were fabricated and showed power conversion efficiencies up to 5.9%, out-performing all existing Pt-containing materials. The device performance was also found to be sensitive to optimization conditions and blend morphologies, which are a result of the intricate interplay among materials crystallinity, phase separation, and the relative positions of the lowest singlet and triplet excited states.

A "roller-wheel" Pt-containing small molecule that outperforms its polymer analogs in organic solar cells.

A novel Pt-bisacetylide small molecule (Pt-SM) featuring "roller-wheel" geometry was synthesized and characterized. When compared with conventional Pt-containing polymers and small molecules having "dumbbell" shaped structures, Pt-SM displays enhanced crystallinity and intermolecular π-π interactions, as well as favorable panchromatic absorption behaviors. Organic solar cells (OSCs) employing Pt-SM achieve power conversion efficiencies (PCEs) up to 5.9%, the highest reported so far for Pt-containing polymers and small molecules.

Rational design of a ratiometric fluorescent probe with a large emission shift for the facile detection of Hg2+.

A new ratiometric and colorimetric fluorescent probe for the highly selective, sensitive and facile detection of Hg(2+) has been rationally developed.

Periodic mesoporous organometallic silicas with unary or binary organometals inside the channel walls as active and reusable catalysts in aqueous organic reactions.

A new type of heterogenized organometallic catalysts, periodic mesoporous organometallic silicas with organometals and organic groups embedded in silica walls have been developed using surfactant-directed co-condensation. These catalysts exhibit high efficiencies and strong durability in water-medium organic reactions. Moreover, a bifunctional catalyst containing both Pd(II) and Ru(II) organometals inside pore walls can catalyze the water-medium "one-pot" cascade reaction effectively. These catalysts can be conveniently recycled and reused without significant loss of catalytic activities.