Photothermally Sensitive Poly(N‐isopropylacrylamide)/Graphene Oxide Nanocomposite Hydrogels as Remote Light‐Controlled Liquid Microvalves

A photothermally sensitive poly(N‐isopropylacrylamide)/graphene oxide (PNIPAM/GO) nanocomposite hydrogel can be synthesized by in situ γ‐irradiation‐assisted polymerization of an aqueous solution of N‐isopropylacrylamide monomer in the presence of graphene oxide (GO). The colors and phase‐transition temperatures of the PNIPAM/GO hydrogels change with different GO doping levels. Due to the high optical absorbance of the GO, the nanocomposite hydrogel shows excellent photothermal properties, where its phase transitions can be controlled remotely by near‐infrared (NIR) laser irradiation, and it is completely reversible via laser exposure or non‐exposure. With a higher GO loading, the NIR‐induced temperature of the nanocomposite hydrogel increases more quickly than with a lower doping level and the temperature can be tuned effectively by the irradiation time. The nanocomposite hydrogel with its excellent photothermal properties will have great applications in the biomedical field, especially as microfluidic devices; this has been demonstrated in our experiments by way of remote microvalves to control fluidic flow. Such an “easy” and “clean” synthetic procedure initiated by γ‐irradiation can be extended for the efficient synthesis of other nanocomposite materials.     

Tumor Intracellular‐Environment Responsive Materials Shielded Nano‐Complexes for Highly Efficient Light‐Triggered Gene Delivery without Cargo Gene Damage

Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochemical internalization (PCI) has provided the opportunity to overcome endo‐lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo‐oxidation of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light‐triggered gene delivery system is demonstrated based on endo‐lysosomal pH‐responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo‐lysosomal pH‐sensitive de‐shielding ability of the pH‐responsive shielding material incorporated in the ternary gene complexes (pH‐TCs), a more significant photo‐triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH‐insensitive material‐shielded nanocarriers cause photo‐oxidation of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light‐triggered gene delivery system using pH‐TCs is applied to deliver the therapeutic p53 gene in melanoma K‐1735 bearing mice, showing excellent therapeutic potential for cancer.     

Biodegradable Nanoparticles of Polyacrylic Acid–Stabilized Amorphous CaCO3 for Tunable pH‐Responsive Drug Delivery and Enhanced Tumor Inhibition

Inorganic nanoparticles (NPs) are promising drug delivery carriers owing to their high drug loading efficiency, scalable preparation, facile functionalization, and chemical/thermal stability. However, the clinical translation of inorganic nanocarriers is often hindered by their poor biodegradability and lack of controlled pH response. Herein, a fully degradable and pH‐responsive DOX@ACC/PAA NP (pH 7.4–5.6) is developed by encapsulating doxorubicin (DOX) in poly(acrylic acid) (PAA) stabilized amorphous calcium carbonate (ACC) NPs. The DOX‐loaded NPs have small sizes (62 ± 10 nm), good serum stability, high drug encapsulation efficiency (>80%), and loading capacity (>9%). By doping proper amounts of Sr²⁺ or Mg²⁺, the drug release of NPs can be further modulated to higher pH responsive ranges (pH 7.7–6.0), which enables drug delivery to the specific cell domains of tissues with a less acidic microenvironment. Tumor inhibition and lower drug acute toxicity are further confirmed via intracellular uptake tests and zebrafish models, and the particles also improve pharmacokinetics and drug accumulation in mouse xenograft tumors, leading to enhanced suppression of tumor growth. Owing to the excellent biocompatibility, biodegradability, and tunable drug release behavior, the present hybrid nanocarrier may find broad applications in tumor therapy.     

pH‐Responsive Cyanine‐Grafted Graphene Oxide for Fluorescence Resonance Energy Transfer‐Enhanced Photothermal Therapy

Stimuli‐responsive anticancer agents are of particular interest in the field of cancer therapy. Nevertheless, so far stimuli‐responsive photothermal agents have been explored with limited success for cancer photothermal therapy (PTT). In this work, as a proof‐of‐concept, a pH‐responsive photothermal nanoconjugate for enhanced PTT efficacy, in which graphene oxide (GO) with broad NIR absorbance and effective photothermal conversion efficiency is selected as a typical model receptor of fluorescence resonance energy transfer (FRET), and grafted cyanine dye (e.g., Cypate) acts as the donor of near‐infrared fluorescence (NIRF), is reported for the first time. The conjugate of Cypate‐grafted GO exhibits different conformations in aqueous solutions at various pH, which can trigger pH‐dependent FRET effect between GO and Cypate and thus induce pH‐responsive photothermal effect of GO‐Cypate. GO‐Cypate exhibits severe cell damage owing to the enhanced photothermal effect in lysosomes, and thus generate synergistic PTT efficacy with tumor ablation upon photoirradiation after a single‐dose intravenous injection. The photothermal nanoconjugate with broad NIR absorbance as the effective receptor of FRET can smartly convert emitted NIRF energy from donor cyanine dye into additional photothermal effect for improving PTT. These results suggest that the smart nanoconjugate can act as a promising stimuli‐responsive photothermal nanoplatform for cancer therapy.     

Charge‐Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery

DNA‐toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane‐associated but also many intracellular drug‐resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug‐resistance barriers. The cationic polymer poly(L ‐lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in‐vivo applications. Herein, PLL is used to demonstrate a pH‐triggered charge‐reversal carrier to solve this problem. PLL's primary amines are amidized as acid‐labile β‐carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid‐labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer‐cell targeted nuclear‐localization polymer–drug conjugate has, thereby, been developed by introducing folic‐acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA‐PLL/amide‐CPT). The conjugate efficiently enters folate‐receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular cleavable disulfide bonds shows much improved cytotoxicity.     

Virus‐Inspired Mimics Based on Dendritic Lipopeptides for Efficient Tumor‐Specific Infection and Systemic Drug Delivery

Herein, multifunctional mimics of viral architectures and infections self‐assembled from tailor‐made dendritic lipopeptides for programmed targeted drug delivery are reported. These viral mimics not only have virus‐like components and nanostructures, but also possess virus‐like infections to solid tumor and tumor cells. Encouragingly, the viral mimics provide the following distinguished features for tumor‐specific systemic delivery: i) stealthy surface to resist protein interactions and prolong circulation time in blood, ii) well‐defined nanostructure for passive targeting to solid tumor site, iii) charge‐tunable shielding for tumor extracellular pH targeting, iv) receptor‐mediated targeting to enhance tumor‐specific uptake, and v) supramolecular lysine‐rich architectures mimicking viral subcellular targeting for efficient endosomal escape and nuclear delivery. This bioinspired design make in vivo tumor suppression by drug‐loaded viral mimics against BALB/c mice bearing 4T1 tumor greatly exceed the positive control group (more than three times). More importantly, viral mimics hold great potentials to reduce side effects and decrease tumor metastasis after systemic administration.     

Regulating Cellular Behavior on Few‐Layer Reduced Graphene Oxide Films with Well‐Controlled Reduction States

Understanding the effect of graphene on cellular behavior is important for enabling a range of new biological and biomedical applications. However, due to the complexity of cell responses and graphene surface states, regulating cellular behaviors on graphene or its derivatives is still a great challenge. To address this challenge we have developed a novel, facile route to regulate the cellular behaviors on few‐layer reduced graphene oxide (FRGO) films by controlling the reduction states of graphene oxide. Our results indicate that the surface oxygen content of FRGO has a strong influence on cellular behavior, with the best performance for cell attachment, proliferation and phenotype being obtained in moderately reduced FRGO. Cell performance decreased significantly as the FRGO was highly reduced. Moderate performance was found in non‐reduced pure graphene oxide and control glass slides. Our results highlight the important role of surface physicochemical characteristics of graphene and its derivatives in their interactions with biocomponents, and may have great potential in enabling the utility of graphene based materials in various biomedical and bioelectronic applications.     

Remote‐Controlled Hydrogel Depots for Time‐Scheduled Vaccination

Remote‐controlled drug depots represent a highly valuable tool for the timely controlled administration of pharmaceuticals in a patient compliant manner. Here, the first pharmacologically controlled material that allows for the scheduled induction of a medical response in mice is described. To this aim, a novel, humanized biohybrid material that releases its cargo in response to a small‐molecule stimulus licensed for human use is developed. The functionality of the material in mice is demonstrated by the remote‐controlled delivery of a vaccine against the oncogenic human papillomavirus type 16. It is shown that the biohybrid depot‐mediated immunoprotection is equivalent to the classical multi‐injection‐based vaccination. These results indicate that this material can be used as a universal remote‐controlled vehicle for the patient‐compliant delivery of vaccines and pharmaceuticals.     

Conjugated Polymer Nanoparticle–Graphene Oxide Charge‐Transfer Complexes

The game‐changing role of graphene oxide (GO) in tuning the excitonic behavior of conjugated polymer nanoparticles is described for the first time. This is demonstrated by using poly(3‐hexylthiophene) (P3HT) as a benchmark conjugated polymer and employing an in situ reprecipitation approach resulting in P3HT nanoparticles (P3HT_NPs) with sizes of 50–100 nm in intimate contact with GO. During the self‐assembly process, GO changes the crystalline packing of P3HT chains in the forming P3HT_NPs from H to H/J aggregates exhibiting exciton coupling constants as low as 2 meV, indicating favorable charge separation along the P3HT chains. Concomitantly, π–π interface interactions between the P3HT_NPs and GO sheets are established resulting in the creation of P3HT_NPs–GO charge‐transfer complexes whose energy bandgaps are lowered by up to 0.5 eV. Moreover, their optoelectronic properties, preestablished in the liquid phase, are retained when processed into thin films from the stable aqueous dispersions, thus eliminating the critical dependency on external processing parameters. These results can be transferred to other types of conjugated polymers. Combined with the possibility of employing water based “green” processing technologies, charge‐transfer complexes of conjugated polymer nanoparticles and GO open new pathways for the fabrication of improved optoelectronic thin film devices.     

Structure‐Properties Relationship in Iron Oxide‐Reduced Graphene Oxide Nanostructures for Li‐Ion Batteries

Non‐aqueous sol‐gel routes involving the reaction of metal oxide precursors in organic solvents (e.g., benzyl alcohol) at moderate temperature and pressure, offer advantages such as high purity, high reproducibility and the ability to control the crystal growth without the need of using additional ligands. In this paper, a study carried out on a series of iron oxide/reduced graphene oxide composites is presented to elucidate a structure‐properties relationship leading to an improved electrochemical performance of such composites. Moreover, it is demonstrated that the easy production of the composites in a variety of temperature and composition ranges, allows a fine control over the final particles size, density and distribution. The materials obtained are remarkable in terms of the particle's size homogeneity and dispersion onto the reduced graphene oxide surface. Moreover, the synthesis method used to obtain the graphene oxide clearly affects the performances of the final composites through the control of the restacking of the reduced graphene oxide sheets. It is shown that a homogeneous and less defective reduced graphene oxide enables good electrochemical performances even at high current densities (over 500 mAh/g delivered at current densities as high as 1600 mA/g). The electrochemical properties of improved samples reach the best compromise between specific capacity, rate capability and cycle stability reported so far.     

Combination of Graphene Oxide and Thiol‐Activated DNA Metallization for Sensitive Fluorescence Turn‐On Detection of Cysteine and Their Use for Logic Gate Operations

In this work, a unique, highly sensitive and selective fluorescence turn‐on approach for cysteine detection using an ensemble of graphene oxide (GO) and metallized DNA is reported. The method is based on the extraordinarily high quenching efficiency of GO and the specific interaction between cysteine and metallized DNA via robust Ag–S bonds. In the presence of GO, the dye‐labeled single‐stranded DNA shows weak fluorescence, while it exhibits a dramatic fluorescence increase upon the formation of the double helix through the “activated” metallized DNA by cysteine. In addition, the protocol shows excellent selectivity for cysteine over various other amino acids found in proteins. Importantly, by exploring GO–DNA interactions and the thiol‐mediated DNA hybridization, our sensing system can also be utilized to design the “OR” and “INHIBIT” logic gates using cysteine and DNA as inputs. To the author's knowledge, this method is the first example of combining GO and DNA metallization to fabricate a turn‐on fluorescent sensor for cysteine and logic gates.     

Biocompatible Poly(2‐hydroxyethyl methacrylate)‐b‐poly(L‐histidine) Hybrid Materials for pH‐Sensitive Intracellular Anticancer Drug Delivery

A series of synthetic polymer bioconjugate hybrid materials consisting of poly(2‐hydroxyethyl methacrylate) (p(HEMA)) and poly(l‐ histidine) (p(His)) are synthesized by combining atom transfer radical polymerization of HEMA with ring opening polymerization of benzyl‐N‐carboxy‐L ‐histidine anhydride. The resulting biocompatible and membranolytic p(HEMA)₂₅‐b‐p(His)_n (n = 15, 25, 35, and 45) polymers are investigated for their use as pH‐sensitive drug‐carrier for tumor targeting. Doxorubicin (Dox) is encapsulated in nanosized micelles fabricated by a self‐assembly process and delivered under different pH conditions. Micelle size is characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM) observations. Dox release is investigated according to pH, demonstrating the release is sensitive to pH. Antitumor activity of the released Dox is assessed using the HCT 116 human colon carcinoma cell line. Dox released from the p(HEMA)‐b‐p(His) micelles remains biologically active and has the dose‐dependent capability to kill cancer cells at acidic pH. The p(HEMA)‐b‐p(His) hybrid materials are capable of self‐assembling into nanomicelles and effectively encapsulating the chemotherapeutic agent Dox, which allows them to serve as suitable carriers of drug molecules for tumor targeting.     

Flexible Transparent Reduced Graphene Oxide Sensor Coupled with Organic Dye Molecules for Rapid Dual‐Mode Ammonia Gas Detection

Flexible chemical sensors utilizing chemically sensitive nanomaterials are of great interest for wearable sensing applications. However, obtaining high performance flexible chemical sensors with high sensitivity, fast response, transparency, stability, and workability at ambient conditions is still challenging. Herein, a newly designed flexible and transparent chemical sensor of reduced graphene oxide (R‐GO) coupled with organic dye molecules (bromophenol blue) is introduced. This device has promising properties such as high mechanical flexibility (>5000 bending cycles with a bending radius of 0.95 cm) and optical transparency (>60% in the visible region). Furthermore, stacking the water‐trapping dye layer on R‐GO enables a higher response as well as workability in a large relative humidity range (up to 80%), and dual‐mode detection capabilities of colorimetric and electrical sensing for NH₃ gas (5–40 ppm). These advantageous attributes of the flexible and transparent R‐GO sensor coupled with organic dye molecules provide great potential for real‐time monitoring of toxic gas/vapor in future practical chemical sensing at room conditions in wearable electronics.     

Revisiting the Structure of Graphene Oxide for Preparing New‐Style Graphene‐Based Ultraviolet Absorbers

Despite sustained effort over the years, the exploration of an effective strategy toward understanding the structure and properties of graphene oxide (GO) is still highly desirable. Herein, a facile route to revisit the structure of GO is demonstrated by elucidating its chemical‐conversion process solely in the presence of ammonia. Such a strategy can contribute to settling some arguments in recent models of GO, and also offers a prerequisite to identify critical components that can act as ultraviolet absorbers (UVAs) in resulting dispersions of nitrogen‐doped graphene sheets (NGSs). Inspired by this, for the first time, the performance of NGSs, serving as new‐style UVAs, is investigated through directly assessing the effect of NGSs on the photofastness of azo dyes (Food Black). These studies reveal that, distinct from the common understanding, the as‐prepared NGSs can dramatically enhance the photostability of Food Black under UV irradiation and exhibit greatly applied potential as a multifunctional UVA for new‐generation inkjet inks that can simultaneously integrate the advantages of dye‐based and pigment‐based inks.     

A Flexible Reduced Graphene Oxide Field‐Effect Transistor for Ultrasensitive Strain Sensing

A new kind of flexible strain sensor based on a reduced graphene oxide field‐effect transistor (rGO FET) with ultrasensitivity, stability, and repeatability for the detection of tensile and compressive strains is demonstrated. The novelty of the rGO FET strain sensor is the incorporation of a rGO channel as a sensing layer in which the electrical resistance can be greatly modified upon application of an extremely low level of strain resulting in an intrinsically amplified sensing signal. The rGO FET device is ultrasensitive to extremely low strain levels, as low as 0.02%. Due to weak coupling between adjacent nanosheets, therefore, upon applying small levels of strain into the rGO thin film, a modulation of the internanosheet resistance (R_inter) is expected, inducing a large change in the transconductance of the rGO FET. Using a simple printing and self‐assembly process, the facile fabrication of an rGO FET array over a large area is also demonstrated. In addition, the device can detect small and rapid physical movements of the human body.     

Self‐Healing Reduced Graphene Oxide Films by Supersonic Kinetic Spraying

The industrial scale application of graphene and other functional materials in the field of electronics has been limited by inherent defects, and the lack of simple deposition methods. A simple spray deposition method is developed that uses a supersonic air jet for a commercially available reduced graphene oxide (r‐GO) suspension. The r‐GO flakes are used as received, which are pre‐annealed and pre‐hydrazine‐treated, and do not undergo any post‐treatment. A part of the considerable kinetic energy of the r‐GO flakes entrained by the supersonic jet is used in stretching the flakes upon impact with the substrate. The resulting “frozen elastic strains” heal the defects (topological defects, namely Stone‐Wales defect and C₂ vacancies) in the r‐GO flakes, which is reflected in the reduced ratio of the intensities of the D and G bands in the deposited film. The defects can also be regenerated by annealing.