Self-Powered Engineering of Cell Membrane Receptors to On-Demand Regulate Cellular Behaviors.

On-demand engineering of cell membrane receptors to nongenetically intervene in cellular behaviors is still a challenge. Herein, a membraneless enzyme biofuel cell-based self-powered biosensor (EBFC-SPB) was developed for autonomously and precisely releasing Zn2+ to initiate DNAzyme-based reprogramming of cell membrane receptors, which further mediates signal transduction to regulate cellular behaviors. The critical component of EBFC-SPB is a hydrogel film on a biocathode which is prepared using a Fe3+-cross-linked alginate hydrogel film loaded with Zn2+ ions. In the working mode in the presence of glucose/O2, the hydrogel is decomposed due to the reduction of Fe3+ to Fe2+, accompanied by rapid release of Zn2+ to specifically activate a Zn2+-responsive DNAzyme nanodevice on the cell surface, leading to the dimerization of homologous or nonhomologous receptors to promote or inhibit cell proliferation and migration. This EBFC-SPB platform provides a powerful "sensing-actuating-treating" tool for chemically regulating cellular behaviors, which holds great promise in precision biomedicine.

Dual-mode optical biosensor based on multi-functional DNA structures for detecting bioactive small molecules.

Semiconducting polymer dots and hemin-functionalized DNA nanoflowers with excellent peroxidase-like activity and high fluorescent brightness are prepared for fluorescent/colorimetric dual-mode sensing of dopamine and glutathione as low as nM and µM, respectively. This biosensor is readily applied to the analysis of complicated biological samples with high selectivity and accuracy, which opens up promising prospects in clinical applications.

Functional Nucleic Acids-Engineered Bio-Barcode Nanoplatforms for Targeted Synergistic Therapy of Multidrug-Resistant Cancer.

Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy of cancers. Herein, we have constructed the functional nucleic acids (FNAs)-engineered nanoplatforms based on the concept of a bio-barcode (BBC) for synergistic targeted therapy of multidrug-resistant (MDR) cancer. In this study, the platinum(IV) prodrug is synthesized to covalently link two kinds of FNAs at a rational ratio to fabricate three-dimensional BBC-like DNA nanoscaffolds, accompanied by the one-pot encapsulation of ZnO nanoparticles (NPs) through electrostatic interaction. The multivalent AS1411 aptamers equipped in ZnO@BBCs facilitate specific and efficient endocytosis into MDR human lung adenocarcinoma cells (A549/DDP). In response to the intracellular environment of A549/DDP cells, such as the lysosome-acidic pH and overexpressed GSH, the ZnO NPs are degraded into Zn2+ ions for generating reactive oxygen species (ROS), while the Pt(IV) prodrugs are reduced into Pt(II) active species by glutathione (GSH), followed by the release of therapeutic DNAzymes for chemotherapy and gene therapy. In particular, the designed system plays an important role in remodeling the intracellular environment to reverse cancer MDR. On the one hand, the depletion of GSH promotes the downregulation of glutathione peroxidase 4 (GPX4) for amplifying oxidative stress and increasing lipid peroxidation (LPO), resulting in the activation of ferroptosis. On the other hand, the silence of early growth response protein 1 (Egr-1) mRNA by Zn2+-dependent DNAzymes directly inhibits the proliferation and migration of MDR cells, which further suppresses the P-glycoprotein (P-gp)-mediated drug efflux. Thus, the proposed nanoplatforms show great promise for the development of versatile therapeutic tools and personalized nanomedicines for MDR cancers.

Novel binuclear and trinuclear metal (II) complexes: DNA interactions and in vitro anticancer activity through apoptosis.

A water soluble trinuclear copper(II) complex and a binuclear cobalt(II) complex, namely Cu3(ppbm)2(SO4)3 (1) and Co2(ppbm)2(NO3)4 (2) (ppbm = 2-(pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-benzo[d]imidazole), have been successfully synthesized and characterized by elemental analysis, IR Spectroscopy, electrospray ionization mass spectra (ESI-MS). The interaction of the new complexes with DNA has been explored using spectroscopy methods, indicating that the complexes 1 and 2 bind to DNA via noncovalent interactions. DNA cleavage experiment suggested that the complex 1 exhibits efficient DNA cleavage activities in the presence of ascorbate (Asc), hydrogen peroxide may serve as the major cleavage active species. The cytotoxicity assay showed that complex 1 exhibited significant inhibitory activity toward the proliferation of several tumor cell lines, with a lower IC50 value than cisplatin and complex 2, indicating that it had the potential to act as effective anticancer agent. The morphological staining assays showed that 1 apparently induced the TFK-1 cells apoptosis. Besides, cellular uptake experiment on TFK-1 cells revealed that complex 1 accumulates primarily inside the nucleus. The apoptosis was attributable to the metal-assisted generation of reactive oxygen species (ROS).

Synthesis and anticancer evaluation of benzo-N-heterocycles transition metal complexes against esophageal cancer cell lines.

Three novel transition metal complexes, Cu(p-2-bmq)Cl2 (1), Zn(p-2-bmq)Cl2 (2) and [Co(p-2-bmq)Cl2]2 (3) (where p-2-bmq = 2-((1-(pyridin-2-yl)-1H-benzoimidazol-2-yl)methyl) quinolone, have been synthesized. The complexes were detected for their cytotoxicity in vitro against four human esophageal cancer cell lines (SMMC7721, BGC823, HCT116 and HT29) by MTT assay. The results showed that they all have anti-tumor cell proliferation activity. E specially, complex 1 exhibited significant cytotoxicity with IC50 value of 15.89 µM against SMMC7721 cells for 72 h. The morphological changes of nuclei by fluorescence staining methods proved that complex 1 could induce intracellular DNA damage. The flow cytometry analysis revealed that the treatment of SMMC7721 cells with complex 1 induced intracellular ROS increased, mitochondrial potential collapse, G2/M-phase arrest, and even apoptosis. These studies should highly valuable for the development of transition metal-based compounds to the potential anticancer medicinal applications.

Chemical biology suggests pleiotropic effects for a novel hexanuclear copper(ii) complex inducing apoptosis in hepatocellular carcinoma cells.

A novel hexanuclear copper(ii)-based complex, [Cu6(tpbb)2(NO3)12] (1), was synthesized, which shows potent cytotoxicity to hepatoma carcinoma cells by inducing apoptosis and apoptosis-related processes. Furthermore, mechanistic investigations based on proteomes revealed that the induced apoptosis was mediated by acting on several targets and multiple pathways in a pleiotropic way.