RESUMEN

Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.

Asunto(s)

Apoptosis , Telómero , Telómero/metabolismo , Apoptosis/efectos de los fármacos , Humanos , Animales , Línea Celular Tumoral , Ratones , G-Cuádruplex/efectos de los fármacos , Ratones Desnudos , Polietilenglicoles/química , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Femenino , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Nanoestructuras/química

RESUMEN

A theranostic strategy of multiple microRNA (miRNA)-triggered in-situ delivery of small interfering RNA (siRNA) can effectively improve the precise therapy of cancer cells. Benefiting from the advantages of programmability, specific molecular recognition, easy functionalization and marked biocompatibility of DNA nanostructures, we designed a three-dimensional (3D) DNA nano-therapeutic platform for dual miRNA-triggered in-situ delivery of siRNA. The 3D DNA nanostructure (TY1Y2) was constructed based on the self-assembly of a DNA tetrahedra scaffold, two sets of Y-shaped DNA (Y1 and Y2), and EpCAM-aptamer which functionalized as the ligand molecule for the recognition of specific cancer cells. After being specifically internalized into the targeted cancer cells, TY1Y2 was triggered by two endogenous miRNAs (miR-21 and miR-122), resulting in the generation of strong fluorescence resonance energy transfer fluorescent signal for dual miRNAs imaging. Meanwhile, the therapeutic siRNAs (siSurvivin and siBcl2) could also be in-situ generated and released from TY1Y2 through the strand-displacement reactions for the synergistic gene therapy of cancer cells. This 3D DNA nanostructure integrated the specific imaging of endogenous biomarkers and the in-situ delivery of therapeutic genes into the multifunctional nanoplatform, revealing the promising applications for the diagnosis and treatment of cancer. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s40843-022-2420-y.

RESUMEN

Accurate analysis of microRNA (miRNA) is promising for elucidation of cancer processes and therapeutic effects. In this study, we reported a new target-activated, light-actuated three-dimensional (3D) DNA walker on gold nanoparticles for sensitive detection of miRNA using pyrene-incorporated DNAzyme analogues. In this design, the target miRNA activated the 3D DNA walker system to releases the walking arm. Then, under ultraviolet light irradiation, the pyrene DNAzyme on the walking arm would consecutively cleave the disulfide bonds of substrate strands and recover the fluorescence signal, thus achieving the amplified miRNA detection. The sophisticated design of the light-actuated 3D DNA walker was systematically investigated. Furthermore, this strategy could also be employed for miRNA analysis in serum samples with satisfactory reproducibility. Notably, the proposed light-actuated 3D DNA walker-based technique eliminated the need of enzymes, cofactors, and RNA backbones, thereby significantly improving the stability and efficiency. Overall, the light-actuated 3D DNA walker-based strategy enabled facile, sensitive, and specific detection of miRNA and provided new perspectives in diagnostics.

Asunto(s)

Técnicas Biosensibles , ADN Catalítico , Nanopartículas del Metal , MicroARNs , ADN/genética , Oro , Límite de Detección , MicroARNs/genética , Reproducibilidad de los Resultados

RESUMEN

Multifunctional cancer treatments based on gas therapy combined with other cancer treatments have gained tremendous attention and hold great promise in biomedical applications. In this study, a carbon monoxide-releasing nanoplatform combined with near-infrared (NIR) laser-triggered photothermal therapy (PTT) was constructed. The nanoplatform was composed of manganese pentacarbonyl bromide (MnCO)-loaded g-carbon nitride/polypyrrole (CNPpy) nanomaterials (MnCO@CNPpy). MnCO can be triggered to produce CO under H2O2 conditions. Upon exogenous NIR light stimulation and tumor microenvironment-overexpressed H2O2, MnCO@CNPpy exhibited excellent CO generation performance and photothermal effect. The generation of CO induced intracellular oxidative stress and caused cell apoptosis. Additionally, photoacoustic (PA) imaging was performed to track the delivery and accumulation of the nanomaterial in tumor sites because of the great photothermal conversion of CNPpy. The presented MnCO@CNPpy nanoplatform displayed desirable PTT and CO therapy in the inhibition of tumor growth and may provide a promising strategy for multifunctional antitumor synergistic treatments.

Asunto(s)

Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Monóxido de Carbono/farmacología , Nanopartículas/química , Técnicas Fotoacústicas , Terapia Fototérmica , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Monóxido de Carbono/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ensayo de Materiales , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Tamaño de la Partícula , Profármacos/síntesis química , Profármacos/química

RESUMEN

In this paper, an optimal semi-continuous process for vinegar production from edible alcohol through biotransformation by acetic acid bacteria (AAB) WUST-01 was developed. The optimized medium composition for the starting-up stage was glucose 5.1 g/L, yeast extract 26.2 g/L, and ethanol 11.9 mL/L, and the optimal ethanol for the following semi-continuous stage was 50 mL/L. In the semi-continuous biotransformation process, the optimal withdraw ratio was 50% of working volume with 12 h cycle time. With these conditions, the total acidity could reach to 77.3 g/L and the acidity productivity could reach to 3.0 g/(L h) in a 5 L reactor. Furthermore, it was investigated to strengthen vinegar synthesis through enhancing alcohol dehydrogenase and aldehyde dehydrogenase activity in AAB by ferrous ion and pueraria flower extract as the enzyme regulators. With these regulators, the vinegar synthesis efficiency can be improved 16.3 and 13.2% respectively.