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Open vascular reconstructions (OVR), including bypass grafts and dialysis access, are standard treatments for cardiovascular and renal diseases. Unfortunately, OVR often fail largely due to intimal hyperplasia (IH), and there are no clinical methods to prevent this complication. Perivascular drug administration during OVR presents a promising strategy for IH suppression. However, durations of drug release from carriers are generally short whereas sustained efficacy is essential for clinical success. This raises a critical question in clinical translation: can IH suppression be realistically maintained long-term (e.g., over 6 months) with short-term perivascular interventions? To address this question, we modified a rat vein-graft model to prolong IH progression. We then applied Pericelle, a nanoparticle/hydrogel hybrid system that we developed for perivascular delivery of rapamycin, an established IH-inhibitory drug. Surprisingly, despite short (∼3-month) drug release, Pericelle demonstrated IH suppression throughout 3, 6, and 9 months with IH reduced from 115.58 ± 27.89 to 40.34 ± 5.18 at 9 months (P < 0.05, n = 6 rats), as indicated by morphometric analysis. Live animal ultrasonography showed the same trend. Consistently, histone-3 lysine-27 trimethylation, an epigenetic mark associated with IH progression, was decreased at 6 months after Pericelle treatment. Moreover, Pericelle exhibited promising efficacy in mitigating IH in a porcine model of arteriovenous fistula that mimics dialysis access. These results suggest that Pericelle-mediated suppression of IH in rat vein-grafts extends much beyond drug release, offering potential solutions to longstanding translational challenges in reducing OVR failure.

The increasing prevalence of antimicrobial resistance in Staphylococcus aureusnecessitates alternative therapeutic approaches. Neutrophils play a crucial role in the fight against S. aureusbut suffer from deficiencies in function leading to increased infection. Here we report a nanoparticle-mediated immunotherapy aimed at potentiating neutrophils to eliminate S. aureus. The nanoparticles consist of naftifine, haemoglobin (Hb) and a red blood cell membrane coating. Naftifine disrupts staphyloxanthin biosynthesis, Hb reduces bacterial hydrogen sulfide levels and the red blood cell membrane modifies bacterial lipid composition. Collectively, the nanoparticles can sensitize S. aureusto host oxidant killing. Furthermore, in the infectious microenvironment, Hb triggers lipid peroxidation in S. aureus, promoting neutrophil chemotaxis. Oxygen supplied by Hb can also significantly enhance the bactericidal capability of the recruited neutrophils by restoring neutrophil respiratory burst via hypoxia relief. This multimodal nanoimmunotherapy demonstrates excellent therapeutic efficacy in treating antimicrobial-resistant S. aureuspersisters, biofilms and S. aureus-induced infection in mice.

Age-related macular degeneration (AMD) causes blindness due to loss of retinal pigment epithelium (RPE) and photoreceptors (PRs), which comprise the two outermost layers of the retina. Given the small size of the macula and the importance of direct contact between RPE and PRs, the use of scaffolds for targeted reconstruction of the outer retina in later stage AMD and other macular dystrophies is particularly attractive. We developed microfabricated, honeycomb-patterned, biodegradable poly(glycerol sebacate) (PGS) scaffolds to deliver organized, adjacent layers of RPE and PRs to the subretinal space. Furthermore, an optimized process was developed to photocure PGS, shortening scaffold production time from days to minutes. The resulting scaffolds robustly supported the seeding of human pluripotent stem cell-derived RPE and PRs, either separately or as a dual cell-layered construct. These advanced, economical, and versatile scaffolds can accelerate retinal cell transplantation efforts and benefit patients with AMD and other retinal degenerative diseases.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

The in situvaccine effect of radiation therapy (RT) has been shown to be limited in both preclinical and clinical settings, possibly due to the inadequacy of RT alone to stimulate in situvaccination in immunologically “cold” tumor microenvironments (TMEs) and the mixed effects of RT in promoting tumor infiltration of both effector and suppressor immune cells. To address these limitations, we combined intratumoral injection of the radiated site with IL2 and a multifunctional nanoparticle (PIC). The local injection of these agents produced a cooperative effect that favorably immunomodulated the irradiated TME, enhancing the activation of tumor-infiltrating T cells and improving systemic anti-tumor T cell immunity. In syngeneic murine tumor models, the PIC+IL2+RT combination significantly improved the tumor response, surpassing the single or dual combinations of these treatments. Furthermore, this treatment led to the activation of tumor-specific immune memory and improved abscopal effects. Our findings suggest that this strategy can be used to augment the in situvaccine effect of RT in clinical settings.

Genome editing mediated by the CRISPR-Cas system holds great promise for the treatment of genetic diseases. However, safe and efficient in vivo delivery of CRISPR genome editing machinery remains a challenge. Here, we report a lipopeptide-based nanoparticle (LNP) that can efficiently deliver the CRISPR Cas9/sgRNA ribonucleoprotein (RNP) and enable efficient genome editing both in vitroand in vivo. An artificial lipopeptide, GD-LP, was constructed by linking a hydrophilic guanidinium-rich head to an oleic acid-based hydrophobic tail viaa disulfide bond. LNP formed by the self-assembly of GD-LP can easily form a complex with RNP with a loading content of up to 20 wt %. The resulting RNP-LNP nanocomplex led to 72.6% gene editing efficiency in GFP-HEK cells with negligible cytotoxicity. The LNP also showed significantly higher transfection efficiencies than Lipofectamine 2000 for the delivery of mRNA in NIH 3T3 and RAW 264.7 and the delivery of plasmid DNA in B78 cells. In vivo studies showed that intramuscular injection of the RNP-LNP nanocomplex in Ai14 mice induced efficient gene editing in muscular tissues. Moreover, the delivery of Cas9 RNP and donor DNA by LNP (i.e., RNP/ssODN-LNP nanocomplex) restored dystrophin expression, reduced skeletal muscle fibrosis, and significantly improved muscle strength in a Duchenne muscular dystrophy (DMD) mouse model.

Ultrasonic energy harvesting technologies have gained much attention for biomedical applications due to their several desirable features including low-energy attenuation and strong penetration capability. In this work, flexible piezoelectric poly(vinylidenefluoride-co-trifluoroethylene) (P(VDF–TrFE))/barium titanate (BaTiO3, BT) membranes, capable of converting ultrasound energy to electric energy, were fabricated by an electrospinning process and their effects on the wound healing behaviors with/without ultrasonic stimulation were investigated. The piezoelectric membranes showed excellent electric outputs and can be used as a sustainable power source to quickly charge LEDs and capacitors. The penetration capability of ultrasound waves was investigated by implanting the membranes at different depths of porcine tissue. The membrane was able to generate a high voltage of 8.22 V even at a depth of 4.5 cm. Furthermore, ultrasonic stimulation on the piezoelectric membranes facilitated the proliferation and migration of the fibroblasts, and a cell migration rate of 92.6% was obtained after 24 h in the cell migration test. Under ultrasonic vibration, the electric field generated from the membranes accelerated the wound closure rate in an animal wound model. These results demonstrated the effectiveness of the flexible piezoelectric membranes in stimulating cellular behaviors, which may provide a new therapeutic strategy for wound care.

Sepsis is a life-threatening organ dysfunction responsible for nearly 270,000 deaths annually in the United States alone. Nicotinamide adenine dinucleotide (NAD+), an immunomodulator, can potentially treat sepsis; however, clinical application of NAD+is hindered by its inability to be directly taken up by cells. To address this challenge, a family of nanoparticles (NPs) loaded with either NAD+or the reduced form of NAD+(NADH), hereafter NAD(H)-loaded NPs, were engineered to enable direct cellular transport and replenishment of NAD(H). The NAD(H)-loaded NPs improved cellular energy supply, suppressed inflammation and prevented inflammation-induced cell pyroptosis and apoptosis. Therefore, the NPs can help maintain immune homoeostasis and vascular function, two key factors in the pathogenesis of sepsis. The NAD(H)-loaded NPs demonstrated excellent therapeutic efficacies in treating endotoxemia and multidrug-resistant pathogen-induced bacteremia. In addition, the NAD(H)-loaded NPs prevented caecal ligation and puncture-induced multiorgan injury and improved outcomes of secondary Pseudomonas aeruginosainfections following caecal ligation and puncture, thus potentially leading to a highly innovative and translational approach to treat sepsis efficiently and safely.

Vascular embolization provides an effective approach for the treatment of hemorrhage, aneurysms, and other vascular abnormalities. However, current embolic materials, such as metallic coils and liquid embolic agents, are limited by their inability to provide safe, consistent, and controlled embolization. Here, we report an injectable hydrogel that can remain at the injection site and subsequently undergo in situ covalent crosslinking, leading to the formation of a dual-crosslinking network (DCN) hydrogel for endovascular embolization. The DCN hydrogel is simple to prepare, easy to deploy via needles and catheters, and mechanically stable at the target injection site, thereby avoiding embolization of nontarget vessels. It possesses efficient hemostatic activity and good biocompatibility. The DCN hydrogel is also clearly visible under X-ray imaging, thereby allowing for targeted embolization. In vivo tests in a rabbit artery model demonstrates that the DCN hydrogel is effective in achieving immediate embolization of the target artery with long-term occlusion by inducing luminal fibrosis. Collectively, the DCN hydrogel provides a viable, biocompatible, and cost-effective alternative to existing embolic materials with clinical translation potential for endovascular embolization.

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium’s plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled—along with validated datasets—into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit—and the knowledge generated by its applications—as a means to accelerate the clinical development of new therapies for a wide range of conditions.

The CRISPR–Cas9 system is a powerful tool for genome editing, which can potentially lead to new therapies for genetic diseases. To date, various viral and non-viral delivery systems have been developed for the delivery of CRISPR–Cas9 in vivo. However, spatially and temporally controlled genome editing is needed to enhance the specificity in organs/tissues and minimize the off-target effects of editing. In this review, we summarize the state-of-the-art non-viral vectors that exploit external stimuli (i.e., light, magnetic field, and ultrasound) for spatially and temporally controlled genome editing and their in vitroand in vivoapplications.

Occlusion of blood vessels caused by thrombi is the major pathogenesis of various catastrophic cardiovascular diseases. Thrombi can be prevented or treated by antithrombotic drugs. However, free antithrombotic drugs often have relatively low therapeutic efficacy due to a number of limitations such as short half-life, unexpected bleeding complications, low thrombus targeting capability, and negligible hydrogen peroxide (H2O2)-scavenging ability. Inspired by the abundance of H2O2and the active thrombus-targeting property of platelets, a H2O2-responsive platelet membrane-cloaked argatroban-loaded polymeric nanoparticle (PNPArg) was developed for thrombus therapy. Poly(vanillyl alcohol-co-oxalate) (PVAX), a H2O2-degradable polymer, was synthesized to form an argatroban-loaded nanocore, which was further coated with platelet membrane. The PNPArgcan effectively target the blood clots due to the thrombus-homing property of the cloaked platelet membrane, and subsequently exert combined H2O2-scavenging effect viathe H2O2-degradable nanocarrier polymer and antithrombotic effect viaargatroban, the released payload. The PNPArgeffectively scavenged H2O2and protected cells from H2O2-induced cellular injury in RAW 264.7 cells and HUVECs. The PNPArgrapidly targeted the thrombosed vessels and remarkably suppressed thrombus formation, and the levels of H2O2and inflammatory cytokines in the ferric chloride-induced carotid arterial thrombosis mouse model. Safety assessment indicated good biocompatibility of the PNPArg. Taken together, the biomimetic PNPArgoffers multiple functionalities including thrombus-targeting, antioxidation, and H2O2-stimulated antithrombotic action, thereby making it a promising therapeutic nanomedicine for thrombosis diseases.

A double-network nanogel, composed of a silane-cross-linked polyethylenimine (PEI) network (i.e., PEI-S) and a pH-responsive poly(2-(hexamethyleneimino) ethyl methacrylate) (PC7A) polymer, was developed for efficient DNA transfection. The chemical cross-linking and hydrophobic interactions in the two networks led to improved stability outside the cell and also pH-triggered intracellular release of DNA. The nanogel with an optimal PEI-S and PC7A weight ratio of 1.3:1 exhibited significantly higher transfection efficiency than Lipofectamine 2000 in multiple cell lines. The nanogel also possessed a small size with a hydrodynamic diameter of 55 nm, low cytotoxicity, and superior stability in serum-containing media. Moreover, besides the PEI-based gene delivery system, we have also demonstrated that addition of the PC7A polymer to several types of cationic polymers commonly used for gene delivery also led to significant transfection enhancement of the resulting nanoparticles, suggesting that the PC7A polymer may be a universal additive that can benefit versatile cationic polymer-based gene delivery systems.

Delivery technologies for the CRISPR-Cas9 (CRISPR, clustered regularly interspaced short palindromic repeats) gene editing system often require viral vectors, which pose safety concerns for therapeutic genome editing1. Alternatively, cationic liposomal components or polymers can be used to encapsulate multiple CRISPR components into large particles (typically >100 nm diameter); however, such systems are limited by variability in the loading of the cargo. Here, we report the design of customizable synthetic nanoparticles for the delivery of Cas9 nuclease and a single-guide RNA (sgRNA) that enables the controlled stoichiometry of CRISPR components and limits the possible safety concerns in vivo. We describe the synthesis of a thin glutathione (GSH)-cleavable covalently crosslinked polymer coating, called a nanocapsule (NC), around a preassembled ribonucleoprotein (RNP) complex between a Cas9 nuclease and an sgRNA. The NC is synthesized by in situ polymerization, has a hydrodynamic diameter of 25 nm and can be customized via facile surface modification. NCs efficiently generate targeted gene edits in vitro without any apparent cytotoxicity. Furthermore, NCs produce robust gene editing in vivo in murine retinal pigment epithelium (RPE) tissue and skeletal muscle after local administration. This customizable NC nanoplatform efficiently delivers CRISPR RNP complexes for in vitro and in vivo somatic gene editing.

Cellulose-derived materials have gained a lot of attention for applications in advanced electronics because they are abundant, low cost, lightweight, and sustainable. Herein, we report a paper-based triboelectric nanogenerator (P-TENG) using commercially available materials derived from cellulose by a facile and cost-effective approach. Print paper is used as the substrate, while crepe cellulose paper (CCP) paired with a nitrocellulose membrane (NCM) are used as the friction layers of the P-TENG. CCP and NCM have significantly different tribopolarities and microstructures (i.e., corrugated and porous structures for CPP and NCM, respectively), thereby yielding P-TENGs with outstanding triboelectric performance. For instance, we have demonstrated P-TENGs with an output voltage and current of 196.8 V and 31.5 μA, respectively, a high power density of 16.1 W/m2, and a robust durability of more than 10,000 cycles. The P-TENGs, as a sustainable power source, can power various electronic devices. Moreover, their great potential applications in self-powered sensing and human–machine interfaces have been demonstrated. Human motion, like a finger touch, can be detected by the P-TENG. A keyboard based on an array of P-TENGs is able to achieve self-powered, real-time communication between a Paper Piano and a computer. This study not only combines the advantages of CCP and NCM to produce high-performance P-TENGs, but also demonstrates the feasibility of using commercially available products to prepare green and sustainable electronics.

Gene therapy holds great promise for various medical and biomedical applications. Nonviral gene delivery systems formed by cationic polymer and nucleic acids (e.g., polyplexes) have been extensively investigated for targeted gene therapy; however, their in vitro and in vivo stability is affected by both their intrinsic properties such as chemical compositions (e.g., polymer molecular weight and structure, and N/P ratio) and a number of environmental factors (e.g., shear stress during circulation in the bloodstream, interaction with the serum proteins, and physiological ionic strength). In this review, we surveyed the effects of a number of important intrinsic and environmental factors on the stability of polymeric gene delivery systems, and discussed various strategies to enhance the stability of polymeric gene delivery systems, thereby enabling efficient gene delivery into target cells. Future opportunities and challenges of polymeric nucleic acid delivery nanosystems were also briefly discussed.

Gene therapy holds great promise for the treatment of many diseases, but clinical translation of gene therapies has been slowed down by the lack of safe and efficient gene delivery systems. Here, we report two versatile redox-responsive polyplexes (i.e., cross-linked and non-crosslinked) capable of efficiently delivering a variety of negatively charged payloads including plasmid DNA (DNA), messenger RNA, Cas9/sgRNA ribonucleoprotein (RNP), and RNP–donor DNA complexes (S1mplex) without any detectable cytotoxicity. The key component of both types of polyplexes is a cationic poly(N,N′-bis(acryloyl)cystamine-co-triethylenetetramine) polymer [a type of poly(N,N′-bis(acryloyl)cystamine–poly(aminoalkyl)) (PBAP) polymer] containing disulfide bonds in the backbone and bearing imidazole groups. This composition enables efficient encapsulation, cellular uptake, controlled endo/lysosomal escape, and cytosolic unpacking of negatively charged payloads. To further enhance the stability of non-crosslinked PBAP polyplexes, adamantane (AD) and β-cyclodextrin (β-CD) were conjugated to the PBAP-based polymers. The cross-linked PBAP polyplexes formed by host–guest interaction between β-CD and AD were more stable than non-crosslinked PBAP polyplexes in the presence of polyanionic polymers such as serum albumin, suggesting enhanced stability in physiological conditions. Both cross-linked and non-crosslinked polyplexes demonstrated either similar or better transfection and genome-editing efficiencies, and significantly better biocompatibility than Lipofectamine 2000, a commercially available state-of-the-art transfection agent that exhibits cytotoxicity.

Triboelectric nanogenerators (TENGs) have been attracting a tremendous amount of attention since their discovery in 2012. Finding new means to enhance energy output is an ongoing pursuit. Herein, we introduce a new type of high-performance TENG composed of highly porous polyamide (PA) nanofiber mats and polyimide aerogel films. We have demonstrated that the thickness of the porous triboelectric materials, which is attained by stacking multiple layers of triboelectric materials, has a profound effect on the triboelectric output performance of TENGs. The triboelectric output increased when PA increased from one layer to six layers. However, it decreased when PA was further increased to 12 layers. With an optimum material thickness, a TENG with only a 2 cm2effective device size achieved a high output voltage of 115 V and a current of 9.5 μA under a small compressive pressure (30 kPa). A peak power density of 1.84 W/m2was achieved on a 4.7 MΩ external load. The TENG was able to light 60 light-emitting diodes easily and quickly charge capacitors with different capacitance to 6 V, indicating an outstanding energy harvesting ability. In addition, the performance of multiple TENGs connected in different ways, as well as the performance of TENGs in resistive/inductive/capacitive circuits, were investigated. These findings provide new insight into the working principles of TENGs in complex circuits.

Finding new means to enhance the performance of triboelectric nanogenerators (TENGs) is an ongoing pursuit. We report a novel flexible TENG made of highly porous cellulose nanofibril (CNF)/polyethylenimine (PEI) aerogel film paired with polyvinylidene fluoride (PVDF) nanofiber mats that exhibits outstanding triboelectric outputs. Modifying CNF with PEI not only enhances the mechanical properties of the CNF/PEI aerogel, but also greatly improves the power density by 14.4 times due to the enhanced tribopositivity. The triboelectric performance is further improved by employing multiple layers of PVDF mats. The TENG made of the CNF/PEI aerogel paired with four layers of PVDF mats exhibited an 18.3 times and 97.6 times improvement in output voltage and power density, respectively, compared to the TENG made of one layer of PVDF mat. The peak output power density reached 13.3 W/m2at a load resistance of 106Ω. Furthermore, the novel TENG displays extraordinary sensitivity when used as a self-powered sensor. It can detect not only human motion like arm bending and footsteps, but also small forces like finger tapping, water dripping, and the vibration of the substrate it is attached to. Therefore, this study not only demonstrates a high performance TENG, but also provides new insights into the design, fabrication, and application of TENGs.

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.

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.

Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1–PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.

Flexible nanogenerators (NGs) that are capable of harvesting ubiquitous mechanical energy from ambient environments have attracted significant attention during the past decade. Herein, a simple and scalable technique has been demonstrated to fabricate a new class of high-performance flexible compact triboelectric NGs using porous aerogel films. These porous aerogel film-based NGs can exhibit significant electric outputs without the use of traditional piezoelectric materials or traditional triboelectric assembly (i.e., the need of airgap). To explain the high electric outputs generated from the porous aerogel film-based generators, a mechanoradical-based mechanism was proposed and a series of systematic studies were carried out to substantiate this new mechanism. These systematic studies have demonstrated that high-performance flexible NGs can be made from porous mechanoradical-generating polymer films. The outstanding electric outputs from this new family of compact triboelectric NGs can be attributed to the reversible and transient mechanoradicals resulting from bond breaking of polymer chain, thus leading to a significant amount of transient dipole moments, as well as the permanent electric dipole moments possessed by the mechanoradical-induced polar groups. The elucidation of the potential mechanisms for this family of porous mechanoradical-generating polymers will lead to a new class of energy harvesting materials and high-performance, low-cost, and flexible energy generation devices.

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 in vivonanoparticle 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.

A technique that can be used to viably create triaxially strained bilayer graphene on any desirable location by simple patterning was developed. Unlike the conventional graphene strain engineering methods, the photolithographically defined spoke patterns and compressive strained Si3N4layer deposited by plasma-enhanced chemical vapor deposition (PECVD) system enable the creation of locally confined triaxial strained bilayer graphene at the desire location by forming a unique tristar shaped wrinkle. The tristar shaped wrinkle was investigated with high resolution micro-Raman spectroscopy and atomic force microscopy (AFM) analyses, and confirmed that 0.38% of maximum triaxial compressive strain was created. Mechanical simulation was used to verify the strain distribution and confirm the strain value which was calculated from the Raman spectroscopy and AFM profile. The technique presented here not only provides a practical route to the creation of strained graphene at desired locations but also offers the potential of the creation of multiaxial strain in the graphene for various types of graphene-based electronic and optoelectronic devices.

A novel, simple, cost-effective, and scalable technique was developed to fabricate high-performance flexible piezoelectric nanogenerators (NGs) using porous cellulose nanofibril (CNFs)/poly(dimethylsiloxane) (PDMS) aerogel film. The porous CNF/PDMS aerogel film was prepared by coating a layer of PDMS on the porous surface of a compressed CNF aerogel film produced via an environmentally friendly freeze-drying process. The porous CNF/PDMS aerogel film was then sandwiched between two thin PDMS films, followed by two aluminum foils, to form the flexible NGs. Under periodic external mechanical deformation by an oscillator, the resulting flexible porous CNF/PDMS aerogel film-based NGs exhibited very stable and high output piezoelectric signals; namely, an open-circuit voltage (Voc) of 60.2V, a short-circuit current (Isc) of 10.1μA, and a corresponding power density of 6.3mW/cm3. The electric power generated by these NGs was able to directly turn on 19 blue light-emitting diodes (LEDs) and charge a capacitor up to 3.7V. Furthermore, these NGs also demonstrated excellent stability and durability. Considering their excellent piezoelectric performance, ease of large-scale manufacturing, and environmental friendliness, this technology provides a promising solution for developing practical, flexible, and self-powered electronic devices.

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.

Superhydrophobic poly(vinyl alcohol) (PVA)/cellulose nanofibril (CNF) aerogels with a unidirectionally aligned microtubular porous structure were prepared using a unidirectional freeze-drying process, followed by the thermal chemical vapor deposition of methyltrichlorosilane. The silanized aerogels were characterized using various techniques including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and contact angle measurements. The structure of the aerogels fully filled with polydimethylsiloxane (PDMS) was confirmed by SEM and optical microscopy. The mechanical properties of the resulting PDMS/aerogel composites were examined using both compressive and tensile tests. The compressive and tensile Young’s moduli of the fully filled PDMS/aerogel composites were more than 2-fold and 15-fold higher than those of pure PDMS. This study provides a novel alternative approach for preparing high performance polymer nanocomposites with a bicontinuous structure.

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–1at 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.

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.

Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for 64Cu-labeling to generate multifunctional theranostic unimolecular micelles. The backbone of the brush-shaped amphiphilic block copolymer was poly(2-hydroxyethyl methacrylate) (PHEMA) and the side chains were poly(l-lactide)-poly(ethylene glycol) (PLLA-PEG). The doxorubicin (DOX)-loaded unimolecular micelles showed a pH-dependent drug release profile and a uniform size distribution. A significantly higher cellular uptake of TRC105-conjugated micelles was observed in CD105-positive human umbilical vein endothelial cells (HUVEC) than nontargeted micelles due to CD105-mediated endocytosis. In contrast, similar and extremely low cellular uptake of both targeted and nontargeted micelles was observed in MCF-7 human breast cancer cells (CD105-negative). The difference between the in vivo tumor accumulation of 64Cu-labeled TRC105-conjugated micelles and that of nontargeted micelles was studied in 4T1 murine breast tumor-bearing mice, by serial positron emission tomography (PET) imaging and validated by biodistribution studies. These multifunctional unimolecular micelles offer pH-responsive drug release, noninvasive PET imaging capability, together with both passive and active tumor-targeting abilities, thus making them a desirable nanoplatform for cancer theranostics.

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.

Abstract

A multifunctional stable and pH-responsive polymer vesicle nanocarrier system was developed for combined tumor-targeted delivery of an anticancer drug and superparamagnetic iron oxide (SPIO) nanoparticles (NPs). These multifunctional polymer vesicles were formed by heterofunctional amphiphilic triblock copolymers, that is, R (folate (FA) or methoxy)-poly(ethylene glycol)(Mw:5000)-poly(glutamate hydrozone doxorubicin)-poly(ethylene glycol) (Mw:2000)-acrylate (i.e., R (FA or methoxy)-PEG114-P(Glu-Hyd-DOX)-PEG46-acrylate). The amphiphilic triblock copolymers can self-assemble into stable vesicles in aqueous solution. It was found that the long PEG segments were mostly segregated into the outer hydrophilic PEG layers of the vesicles, thereby providing active tumor targeting viaFA, while the short PEG segments were mostly segregated into the inner hydrophilic PEG layer of the vesicles, thereby making it possible to cross-link the inner PEG layer viathe acrylate groups for enhanced in vivostability. The therapeutic drug, DOX, was conjugated onto the polyglutamate segment, which formed the hydrophobic membrane of the vesicles using a pH-sensitive hydrazone bond to achieve pH-responsive drug release, while the hydrophilic SPIO NPs were encapsulated into the aqueous core of the stable vesicles, allowing for ultrasensitive magnetic resonance imaging (MRI) detection. The SPIO/DOX-loaded vesicles demonstrated a much higher r2relaxivity value than Feridex, a commercially available SPIO-based T2contrast agent, which was attributed to the high SPIO NPs loading level and the SPIO clustering effect in the aqueous core of the vesicles. Results from flow cytometry and confocal laser scanning microscopy (CLSM) analysis showed that FA-conjugated vesicles exhibited higher cellular uptake than FA-free vesicles which also led to higher cytotoxicity. Thus, these tumor-targeting multifunctional SPIO/DOX-loaded vesicles will provide excellent in vivostability, pH-controlled drug release, as well as enhanced MRI contrast, thereby making targeted cancer therapy and diagnosis possible.

High-dielectric-constant carbon nanotube−polymer composites are developed using core−shell multiwalled carbon nanotubes (MWNTs) as a filler, in which the outer graphene layer is covalently functionalized to become nonconducting, whereas the inner graphene layers are unfunctionalized and remain electrically conducting. Hydroxylated MWNTs represent one of the simplest types of core−shell MWNTs. In this article, we report a comparative study of the electrical and dielectric properties of MWNT−polydimethylsiloxane composites based on pristine MWNTs and hydroxylated MWNTs, respectively. We demonstrate for the first time the feasibility of using core−shell MWNTs as a filler to increase the dielectric constant and reduce the dielectric loss of nanotube−polymer composites.

An original, substrate‐selective nanoreactor is designed and characterized. The nanoreactor made of a 4‐nitrophonel (NP)‐imprinted polymer and Ag nanoparticles, can specifically recognize NP compared with its analogues 4‐nitrophenyl acetate (NPA) and 2,6‐dimethyl‐4‐nitrophenol (DNP). Under comparable conditions, this nanoreactor significantly accelerated the reduction of NP; however, much less acceleration is shown for its analogues. Unlike traditional Ag nanoreactors, which lack molecular recognition abilities, this unique nanoreactor is composed of molecularly imprinted networks, making substrate‐selective catalysis feasible.

We report a novel composite electrode made of chitosan‐SiO2‐multiwall carbon nanotube (CHIT‐SiO2‐MWNT) composite coated on the indium‐tin oxide (ITO) glass substrate. Cholesterol oxidase (ChOx) was covalently immobilized on the CHIT‐SiO2‐MWNT/ITO electrode that resulted in a ChOx/CHIT‐SiO2‐MWNT/ITO cholesterolactive bioelectrode. The CHIT‐SiO2‐MWNT/ITO and ChOx/CHIT‐SiO2‐MWNT/ITO electrodes were characterized with Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The influence of various parameters was investigated, including the applied potential, pH of the medium, and the concentration of the enzyme on the performance of the biosensor. The cholesterol bioelectrode exhibited a sensitivity of 3.4 nA/ mgdL−1with a response time of five seconds. The biosensor using ChOx/CHIT‐SiO2‐MWNT/ITO as the working electrode retained its original response after being stored for six months. The biosensor using ChOx/CHIT‐SiO2‐MWNT/ITO as the working electrode showed a linear current response to the cholesterol concentration in the range of 50–650 mg/dL.