Intracellular zinc ions are essential for various biological cell processes and are often dysregulated in many diseases de‐pending on their location, protein binding affinity, and concentration in the cell. Due to their prevalence in diseases, it is important to not only effectively sense but chelate the often excess amount of zinc in a cell to alleviate further disease progression. N, N, N′, N′‐tetrakis (2‐pyridinylmethyl)‐1,2‐ethanediamine (TPEN) is a selective zinc chelator but its water‐insoluble nature and general cytotoxicity limit its therapeutic potential. To address these challenges, TPEN loaded nucleic acid nanocapsules (TL‐NANs) were synthesized, and its dual ability to sense and suppress zinc levels intracellularly were evaluated. Additionally, TL‐NANs were incubated in lung cells and shown to down regulate Eotaxin, a protein up‐regulated during asthma, at significantly reduced concentrations of TPEN showcasing the therapeutic potential of this drug for asthma.
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Abstract -
Multi-layered stimuli responsive DNA micelles for the stepwise controlled release of small moleculesControllable release of multiple distinct cargoes from a nanomaterial is crucial to a variety of therapeutic and catalytic applications. In this study, we describe a DNA functionalized multi-layered surface crosslinked micelle (mlSCM) consisting of individually degradable layers. The DNA modified mlSCM has the ability to encapsulate separate small molecule cargo in distinct compartments within the nanocapsule, separated by chemical crosslinkers. Through a multistep self-assembly process, we show physical separation of internalized cargo as evidenced by electron microscopy, along with observation of chemical control over release, and chemical reaction conditions, as seen by fluorescence spectroscopy and a high-performance liquid chromatography mass spectrometry assay. Additionally, we evaluated the ability of these DNA crosslinked micelles to co-release two separate cargoes into the same cellular environment through an in vitro confocal microscopy assay. We show individualized targeting of two distinct but related dyes for the detection of ATP and mitochondria. The colocalization of these dyes indicates that unique locations and signals related to cellular respiration can be identified using a single mlSCM. Through these studies we ultimately show that the mlSCM has a tailorable design with the potential to be applied to numerous applications, ranging from sensing to drug delivery.more » « less
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null (Ed.)Herein we report a thermoresponsive crosslinker that can be utilized to stabilize the surface of micelles through a “click” reaction and to trigger the disassembly via a retro Diels Alder (rDA) mechanism. The micelles generated were 100 nm in size and monodispersed. Above 60 °C, rDA dissociation of crosslinker occurs resulting to the degradation of the micelles and release of hydrophobic cargo.more » « less
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null (Ed.)Intracellular trafficking and delivery of nucleic acids is an area of growing interest, particularly as it relates to therapeutic applications. Spectroscopic methods have been used to observe and quantitatively measure the delivery of oligonucleotides both in vitro and in vivo . Herein we demonstrate the use of a new fluorophore labeled surfactant presenting a solvatochromatic chromophore for tracking the assembly and degradation of a hybrid biomaterial we refer to as a nucleic acid nanocapsule (NAN). We show that the surfactant enables critical micelle concentration determination, monitoring of NAN disassembly in vitro , and the ability to track the cellular movement and activity of surfactant–oligonucleotide conjugates in cells when coupled with quantitative PCR analysis.more » « less
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This work highlights a multifunctional nanoscale material which can effectively compartmentalize small molecules and biomolecules into a single, micellar structure with programmable degradation properties resulting in highly controllable release properties. The nanomaterial consists of a ZIF-8 metal organic framework (MOF) encapsulated within a DNA surfactant micelle assembly, referred to as a nucleic acid nanocapsule (NAN). NANs have been demonstrated to enter cells through endocytosis and result in intracellular cargo release upon enzyme-triggered degradation. By combining the favorable properties of MOFs (large storage capacity) with those of NANs (triggerable release), we show diverse molecular cargo can be integrated into a single, highly programmable nanomaterial with controllable release profiles. The hybrid MOF–NANs exhibit double-gated regulation capabilities as evidenced by kinetic studies of encapsulated enzymes that indicate individual layers of the particle influence the overall enzymatic rate of turnover. The degradation of MOF–NANs can be controlled under multiple combined stimuli ( i.e. varying pH, enzymes), enabling selective release profiles in solutions representative of more complex biological systems. Lastly, the enhanced control over the release of small molecules, proteins and plasmids, is evaluated through a combination of cell culture and in vitro fluorescence assays, indicating the potential of MOF–NANs for both therapeutic and diagnostic applications.more » « less