A Universal GSH-Responsive Nanoplatform for the Delivery of DNA, mRNA, and Cas9/sgRNA Ribonucleoprotein

The long-sought promise of gene therapy for the treatment of human diseases remains unfulfilled, largely hindered by the lack of an efficient and safe delivery vehicle. In this study, we have developed a universal glutathione-responsive nanoplatform for the efficient delivery of negatively charged genetic biomacromolecules. The cationic block copolymer, poly­(aspartic acid-(2-aminoethyl disulfide)-(4-imidazolecarboxylic acid))–poly­(ethylene glycol), bearing imidazole residues and disulfide bonds, can form polyplexes with negatively charged DNA, mRNA, and Cas9/sgRNA ribonucleoprotein (RNP) through electrostatic interactions, which enable efficient cellular uptake, endosomal escape, and cytosol unpacking of the payloads. To facilitate the nuclear transport of DNA and RNP, the nuclear localization signal peptide was integrated into the DNA or RNP polyplexes. All three polyplex systems were fully characterized and optimized in vitro. Their relatively high transfection efficiency and low cytotoxicity, as well as convenient surface functionalization merit further investigation

Cellulose Nanofibril/Reduced Graphene Oxide/Carbon Nanotube Hybrid Aerogels for Highly Flexible and All-Solid-State Supercapacitors

A novel type of highly flexible and all-solid-state supercapacitor that uses cellulose nanofibril (CNF)/reduced graphene oxide (RGO)/carbon nanotube (CNT) hybrid aerogels as electrodes and H₂SO₄/poly­(vinyl alcohol) (PVA) gel as the electrolyte was developed and is reported here. These flexible solid-state supercapacitors were fabricated without any binders, current collectors, or electroactive additives. Because of the porous structure of the CNF/RGO/CNT aerogel electrodes and the excellent electrolyte absorption properties of the CNFs present in the aerogel electrodes, the resulting flexible supercapacitors exhibited a high specific capacitance (i.e., 252 F g^–1 at a discharge current density of 0.5 A g^–1) and a remarkable cycle stability (i.e., more than 99.5% of the capacitance was retained after 1000 charge–discharge cycles at a current density of 1 A g^–1). Furthermore, the supercapacitors also showed extremely high areal capacitance, areal power density, and energy density (i.e., 216 mF cm^–2, 9.5 mW cm^–2, and 28.4 μWh cm^–2, respectively). In light of its excellent electrical performance, low cost, ease of large-scale manufacturing, and environmental friendliness, the CNF/RGO/CNT aerogel electrodes may have a promising application in the development of flexible energy-storage devices

Flexible Infrared Responsive Multi-Walled Carbon Nanotube/Form-Stable Phase Change Material Nanocomposites

Flexible infrared (IR)-responsive materials, such as polymer nanocomposites, that exhibit high levels of IR responses and short response times are highly desirable for various IR sensing applications. However, the IR-induced photoresponses of carbon nanotube (CNT)/polymer nanocomposites are typically limited to 25%. Herein, we report on a family of unique nanocomposite films consisting of multi-walled carbon nanotubes (MWCNTs) uniformly distributed in a form-stable phase change material (PCM) that exhibited rapid, dramatic, reversible, and cyclic IR-regulated responses in air. The 3 wt % MWCNT/PCM nanocomposite films demonstrated cyclic, IR-regulated on/off electrical conductivity ratios of 11.6 ± 0.6 and 570.0 ± 70.5 times at IR powers of 7.3 and 23.6 mW/mm², respectively. The excellent performances exhibited by the MWCNT/PCM nanocomposite films were largely attributed to the IR-regulated cyclic and reversible form-stable phase transitions occurring in the PCM matrix due to MWCNT’s excellent photoabsorption and thermal conversion capabilities, which subsequently affected the thickness of the interfacial PCM between adjacent conductive MWCNTs and thus the electron tunneling efficiency between the MWCNTs. Our findings suggest that these unique MWCNT/PCM nanocomposites offer promising new options for high-performance and flexible optoelectronic devices, including thermal imaging, IR sensing, and optical communication

Graphene/Phase Change Material Nanocomposites: Light-Driven, Reversible Electrical Resistivity Regulation via Form-Stable Phase Transitions

Innovative photoresponsive materials are needed to address the complexity of optical control systems. Here, we report a new type of photoresponsive nanomaterial composed of graphene and a form-stable phase change material (PCM) that exhibited a 3 orders of magnitude change in electrical resistivity upon light illumination while retaining its overall original solid form at the macroscopic level. This dramatic change in electrical resistivity also occurred reversibly through the on/off control of light illumination. This was attributed to the reversible phase transition (i.e., melting/recrystallization) behavior of the microscopic crystalline domains present in the form-stable PCM. The reversible phase transition observed in the graphene/PCM nanocomposite was induced by a reversible temperature change through the on/off control of light illumination because graphene can effectively absorb light energy and convert it to thermal energy. In addition, this graphene/PCM nanocomposite also possessed excellent mechanical properties. Such photoresponsive materials have many potential applications, including flexible electronics

Quantum-Dot-Based Theranostic Micelles Conjugated with an Anti-EGFR Nanobody for Triple-Negative Breast Cancer Therapy

A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near-infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for <i>in vivo</i> nanoparticle biodistribution studies. The anti-EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs

CuS-Based Theranostic Micelles for NIR-Controlled Combination Chemotherapy and Photothermal Therapy and Photoacoustic Imaging

Cancer remains a major threat to human health due to low therapeutic efficacies of currently available cancer treatment options. Nanotheranostics, capable of simultaneous therapy and diagnosis/monitoring of diseases, has attracted increasing amounts of attention, particularly for cancer treatment. In this study, CuS-based theranostic micelles capable of simultaneous combination chemotherapy and photothermal therapy (PTT), as well as photoacoustic imaging, were developed for targeted cancer therapy. The micelle was formed by a CuS nanoparticle (NP) functionalized by thermosensitive amphiphilic poly­(acrylamide-acrylonitrile)–poly­(ethylene glycol) block copolymers. CuS NPs under near-infrared (NIR) irradiation induced a significant temperature elevation, thereby enabling NIR-triggered PTT. Moreover, the hydrophobic core formed by poly­(acrylamide-acrylonitrile) segments used for drug encapsulation exhibited an upper critical solution temperature (UCST; ∼38 °C), which underwent a hydrophobic-to-hydrophilic transition once the temperature rose above the UCST induced by NIR-irradiated CuS NPs, thereby triggering a rapid drug release and enabling NIR-controlled chemotherapy. The CuS-based micelles conjugated with GE11 peptides were tested in an epidermal growth factor receptor-overexpressing triple-negative breast cancer model. In both two-dimensional monolayer cell and three-dimensional multicellular tumor spheroid models, GE11-tagged CuS-based micelles under NIR irradiation, enabling the combination chemotherapy and PTT, exhibited the best therapeutic outcome due to a synergistic effect. These CuS-based micelles also displayed a good photoacoustic imaging ability under NIR illumination. Taken together, this multifunctional CuS-based micelle could be a promising nanoplatform for targeted cancer nanotheranostics

Polyvinyl Alcohol-Cellulose Nanofibrils-Graphene Oxide Hybrid Organic Aerogels

Hybrid organic aerogels consisting of polyvinyl alcohol (PVA), cellulose nanofibrils (CNFs), and graphene oxide nanosheets (GONSs) were prepared using an environmentally friendly freeze-drying process. The material properties of these fabricated aerogels were measured and analyzed using various characterization techniques including compression testing, scanning electron microscopy, thermogravimetric (TGA) analysis, Brunauer–Emmet–Teller (BET) surface area analysis, and contact angle measurements. These environmentally friendly, biobased hybrid organic aerogels exhibited a series of desirable properties including a high specific compressive strength and compressive failure strain, ultralow density and thermal conductivity, good thermal stability, and moisture resistance, making them potentially useful for a broad range of applications including thermal insulation

Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats

At present, there are no clinical options for preventing neointima-caused (re)­stenosis after open surgery such as bypass surgery for treating flow-limiting vascular disease. Perivascular drug delivery is a promising strategy, but in translational research, it remains a major challenge to achieve long-term (e.g., > 3 months) anti­(re)­stenotic efficacy. In this study, we engineered a unique drug delivery system consisting of durable unimolecular micelles, formed by single multiarm star amphiphilic block copolymers with only covalent bonds, and a thermosensitive hydrogel formed by a poly­(lactide-co-glycolide)–poly­(ethylene glycol)–poly­(lactide-co-glycolide) triblock copolymer (abbreviated as triblock gel) that is stable for about 4 weeks <i>in vitro</i>. The drug-containing unimolecular micelles (UMs) suspended in Triblock gel were able to sustain rapamycin release for over 4 months. Remarkably, even 3 months after perivascular application of the rapamycin-loaded micelles in Triblock gel in the rat model, the intimal/medial area ratio (a restenosis measure) was still 80% inhibited compared to the control treated with empty micelle/gel (no drug). This could not be achieved by applying rapamycin in Triblock gel alone, which reduced the intimal/medial ratio only by 27%. In summary, we created a new UM/Triblock gel hybrid system for perivascular drug delivery, which produced a rare feat of 3-month restenosis inhibition in animal tests. This system exhibits a real potential for further translation into an anti­(re)­stenotic application with open surgery

Periadventitial Application of Rapamycin-Loaded Nanoparticles Produces Sustained Inhibition of Vascular Restenosis

<div><p>Open vascular reconstructions frequently fail due to the development of recurrent disease or intimal hyperplasia (IH). This paper reports a novel drug delivery method using a rapamycin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs)/pluronic gel system that can be applied periadventitially around the carotid artery immediately following the open surgery. <i>In vitro</i> studies revealed that rapamycin dispersed in pluronic gel was rapidly released over 3 days whereas release of rapamycin from rapamycin-loaded PLGA NPs embedded in pluronic gel was more gradual over 4 weeks. In cultured rat vascular smooth muscle cells (SMCs), rapamycin-loaded NPs produced durable (14 days versus 3 days for free rapamycin) inhibition of phosphorylation of S6 kinase (S6K1), a downstream target in the mTOR pathway. In a rat balloon injury model, periadventitial delivery of rapamycin-loaded NPs produced inhibition of phospho-S6K1 14 days after balloon injury. Immunostaining revealed that rapamycin-loaded NPs reduced SMC proliferation at both 14 and 28 days whereas rapamycin alone suppressed proliferation at day 14 only. Moreover, rapamycin-loaded NPs sustainably suppressed IH for at least 28 days following treatment, whereas rapamycin alone produced suppression on day 14 with rebound of IH by day 28. Since rapamycin, PLGA, and pluronic gel have all been approved by the FDA for other human therapies, this drug delivery method could potentially be translated into human use quickly to prevent failure of open vascular reconstructions.</p></div

Accumulation of FITC-loaded NPs in cultured smooth muscle cells and in the arterial wall of the injured rat carotid artery after periadventitial application.

<p>(A). Representative fluorescence microscopic images demonstrate timein the arterial wall of the injured rat carotid arteµg FITC/ml) by cultured rat vascular smooth muscle cells (SMCs) (n = 3). Scale bar represents 10 µm. (B). FITC-NPs were applied around the rat carotid artery immediately after injury (see methods). Representative fluorescence microscopic images of carotid arteries demonstrate the in vivo distribution of FITC-NPs <i>(n = 3)</i> (1 mg FITC-NPs in 300 µl pluronic gel/artery). The first panel of B is a low-magnification longitudinal image of the artery showing perivascular application of NPs. Panels 2–4 are images of cross sections. The last panel shows the auto-fluorescence background of laminas. Scale bar represents 120 µm.</p