Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC-microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO's m6A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients.

Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing.

Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection. As such, it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness. Here, based on ultrasound-triggered piezocatalytic therapy, a multifunctional hydrogel is designed to promote bacteria-infected wound healing. Under ultrasonic vibration, the surface of barium titanate (BaTiO3, BT) nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species (ROS) owing to the established strong built-in electric field, endowing the hydrogel with superior antibacterial efficacy. This modality shows intriguing advantages over conventional photodynamic therapy, such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers. Moreover, the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide (THM), N-(3-aminopropyl)methacrylamide hydrochloride (APMH) and oxidized hyaluronic acid (OHA) exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing. Notably, compared with the widely reported mussel-inspired adhesive hydrogels, OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized, giving it long-term and repeatable adhesion performance. Importantly, this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria, markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.

Photoactive Nanomaterials for Wireless Neural Biomimetics, Stimulation, and Regeneration.

Nanomaterials at the neural interface can provide the bridge between bioelectronic devices and native neural tissues and achieve bidirectional transmission of signals with our brain. Photoactive nanomaterials, such as inorganic and polymeric nanoparticles, nanotubes, nanowires, nanorods, nanosheets or related, are being explored to mimic, modulate, control, or even substitute the functions of neural cells or tissues. They show great promise in next generation technologies for the neural interface with excellent spatial and temporal accuracy. In this review, we highlight the discovery and understanding of these nanomaterials in precise control of an individual neuron, biomimetic retinal prosthetics for vision restoration, repair or regeneration of central or peripheral neural tissues, and wireless deep brain stimulation for treatment of movement or mental disorders. The most intriguing feature is that the photoactive materials fit within a minimally invasive and wireless strategy to trigger the flux of neurologically active molecules and thus influences the cell membrane potential or key signaling molecule related to gene expression. In particular, we focus on worthy pathways of photosignal transduction at the nanomaterial-neural interface and the behavior of the biological system. Finally, we describe the challenges on how to design photoactive nanomaterials specific to neurological disorders. There are also some open issues such as long-term interface stability and signal transduction efficiency to further explore for clinical practice.

Thermal management of chips by a device prototype using synergistic effects of 3-D heat-conductive network and electrocaloric refrigeration.

With speeding up development of 5 G chips, high-efficient thermal structure and precise management of tremendous heat becomes a substantial challenge to the power-hungry electronics. Here, we demonstrate an interpenetrating architecture of electrocaloric polymer with highly thermally conductive pathways that achieves a 240% increase in the electrocaloric performance and a 300% enhancement in the thermal conductivity of the polymer. A scaled-up version of the device prototype for a single heat spot cooling of 5 G chip is fabricated utilizing this electrocaloric composite and electromagnetic actuation. The continuous three-dimensional (3-D) thermal conductive network embedded in the polymer acts as nucleation sites of the ordered dipoles under applied electric field, efficiently collects thermal energy at the hot-spots arising from field-driven dipolar entropy change, and opens up the high-speed conduction path of phonons. The synergy of two components, thus, tackles the challenge of sluggish heat dissipation of the electroactive polymers and their contact interfaces with low thermal conductivity, and more importantly, significantly reduces the electric energy for switching the dipolar states during the electrocaloric cycles, and increases the manipulable entropy at the low fields. Such a feasible solution is inevitable to the precisely fixed-point thermal management of next-generation smart microelectronic devices.

Skin-Inspired Pressure Sensor with MXene/P(VDF-TrFE-CFE) as Active Layer for Wearable Electronics.

Multi-functional electronic skin is of paramount significance for wearable electronics in health monitoring, medical analysis, and human-machine interfacing systems. In order to achieve the function of natural skin, mechanical sensing with high sensitivity is an important feature of electronic skin. Inspired by the spinosum structure under the skin, herein, we fabricate a new capacitive pressure sensor with two-dimensional transition-metal carbides and nitrides (MXene) and ferroelectric polymer (P(VDF-TrFE-CFE)) as an active layer and micropatterned Cr-Au deposited on polydimethylsiloxane as flexible electrodes. Such a method is facile, effective, easily operated, and low-cost. The device design provides great capacitive change as a consequence of large deformation under pressure. Benefiting from the randomly distributed microstructure and high dielectric constant of the active layer, the device demonstrates high sensitivity with great linearity (16.0 kPa-1 for less than 10 kPa), that is, a low detection limit of 8.9 Pa, and quick response. A series of dynamic physiological signals, including typing, knuckle motion, and voice recognition can be facilely detected, making it a competitive candidate in the field of wearable electronics.

Conductive Hydrogel for a Photothermal-Responsive Stretchable Artificial Nerve and Coalescing with a Damaged Peripheral Nerve.

Modern development of flexible electronics has made use of bioelectronic materials as artificial tissue in vivo. As hydrogels are more similar to nerve tissue, functional hydrogels have become a promising candidate for bioelectronics. Meanwhile, interfacing functional hydrogels and living tissues is at the forefront of bioelectronics. The peripheral nerve injury often leads to paralysis, chronic pain, neurologic disorders, and even disability, because it has affected the bioelectrical signal transmission between the brain and the rest of body. Here, a kind of light-stimuli-responsive and stretchable conducting polymer hydrogel (CPH) is developed to explore artificial nerve. The conductivity of CPH can be enhanced when illuminated by near-infrared light, which can promote the conduction of the bioelectrical signal. When CPH is mechanically elongated, it still has high durability of conductivity and, thus, can accommodate unexpected strain of nerve tissues in motion. Thereby, CPH can better serve as an implant of the serious peripheral nerve injury in vivo, especially in the case that the length of the missing nerve exceeds 10 mm.

Electromagnetized-Nanoparticle-Modulated Neural Plasticity and Recovery of Degenerative Dopaminergic Neurons in the Mid-Brain.

The degeneration of dopaminergic neurons is a major contributor to the pathogenesis of mid-brain disorders. Clinically, cell therapeutic solutions, by increasing the neurotransmitter dopamine levels in the patients, are hindered by low efficiency and/or side effects. Here, a strategy using electromagnetized nanoparticles to modulate neural plasticity and recover degenerative dopamine neurons in vivo is reported. Remarkably, electromagnetic fields generated by the nanoparticles under ultrasound stimulation modulate intracellular calcium signaling to influence synaptic plasticity and control neural behavior. Dopaminergic neuronal functions are reversed by upregulating the expression tyrosine hydroxylase, thus resulting in ameliorating the neural behavioral disorders in zebrafish. This wireless tool can serve as a viable and safe strategy for the regenerative therapy of the neurodegenerative disorders.

Folate-Modified Photoelectric Responsive Polymer Microarray as Bionic Artificial Retina to Restore Visual Function.

A high-optical-resolution artificial retina system that accurately communicates with the optic nerve is the main challenge in the modern biological science and bionic field. Here, we developed a bionic artificial retina possessing phototransduction "cells" with measurements even smaller than that of the neural cells. Using the technique of micrometer processing, we constructed a pyramid-shape periodic microarray of a photoreceptor. Each "sensing cell" took advantage of polythiophene derivative/fullerene derivative (PCBM) as a photoelectric converter. Because folic acid played an essential role in eye growth, we particularly modified the polythiophene derivatives with folic acid tags. Therefore, the artificial retina could enlarge the contact area and even recognize the nerve cells to improve the consequence of nerve stimulation. We implanted the artificial retina into blinded rats' eyes. Electrophysiological analysis revealed its recovery of photosensitive function 3 months after surgery. Our work provides an innovative idea for fabricating a high-resolution bionic artificial retina system. It shows great potential in artificial intelligence and biomedicine.

Ferroelectric nanocomposite networks with high energy storage capacitance and low ferroelectric loss by designing a hierarchical interface architecture.

Nanoscale design of nanofillers and interfacial architecture are vital to achieve high-capacity and high-energy-conversion efficiency poly(vinylidene fluoride) [(PVDF)-based] nanocomposite materials for vast potential applications in modern electronic devices and electric power systems. Using traditional methods, the addition of ceramic nanoparticles can only produce one type of interface between the nanoparticles and this matrix, achieving an enhanced dielectric constant and energy density at the expense of the charge-discharge efficiency. Herein, we demonstrate a novel class of cross-linking nanofiller system, poly(vinylidene fluoride-chlorotrifluoroethylene)/γ-methacryloylpropyl trimethoxysilane@BaTiO3 [P(VDF-CTFE)/MPS@BT]. This novel approach can not only provide the interfaces between the nanoparticle and the matrix, but also scale down the size of crystalline domains, which results in producing more additional interfaces between the crystalline and amorphous phases to achieve an improved discharged energy density. Remarkably, the smaller crystalline domains, which were characterized by XRD and FTIR spectroscopy, could be beneficial for improving the dipole switchability from the polar phases to non-polar phases during the charge-discharge cycles, leading to unprecedented charge-discharge efficiency. Furthermore, the addition of MPS@BT NPs can regulate two stages of the discharge rate. The early discharge process can be accelerated, while the following stage is obviously delayed. The simplicity of the hierarchical interfacial engineering method provides a promising path to design ferroelectric polymer nanocomposites for dielectric capacitor applications.

Light-Induced ROS Generation and 2-DG-Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment.

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2-deoxy-glucose (2-DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2-DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS-sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light-induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.

In-depth understanding of interfacial crystallization via Flash DSC and enhanced energy storage density in ferroelectric P(VDF-CTFE)/Au NRs nanocomposites for capacitor application.

High-capacity or high-power-density capacitors are being actively investigated for portable electronics, electric vehicles, and electric power systems. We describe the filler system in dielectric nanocomposites with a small loading of Au nanorods [NRs] to elucidate the mechanism of interfacial crystallization behavior including the crystallization kinetics, and crystalline morphology and structure, and to investigate the intrinsic causes for concurrent great improvements in the dielectric constant and energy density in the nanocomposite system. Remarkly, at high crystallization temperature, the addition of Au NRs, which are used as heterogeneous nucleators, can reduce the nucleation barrier, resulting in accelerating the crystallization rate. However, the crystallization rate slows down at low temperatures because the addition of Au NRs limited the mobility of poly(vinylidene fluoride-chlorotrifluoroethylene) [P(VDF-CTFE)] chains, and thus enhanced the diffusion barrier. Furthermore, the addition of NRs has a huge impact on the crystalline morphology and structure which changes from large paraelectric α-phase spherulites with TGTG' conformations into minor ferroelectric γ-phase spherulites with T3GT3G' conformations, and also produces more exogenous interfaces between the lamellar crystals and amorphous regions, resulting in a higher dielectric constant and higher electric energy density in P(VDF-CTFE)/Au NRs nanocomposites. Our approach provides a facile and straightforward way to design or understand PVDF-based polymers for their practical applications in high-energy-density capacitors.

Near-Infrared Fluorescent Nanoprobes for Revealing the Role of Dopamine in Drug Addiction.

Brain imaging techniques enable visualizing the activity of central nervous system without invasive neurosurgery. Dopamine is an important neurotransmitter. Its fluctuation in brain leads to a wide range of diseases and disorders, like drug addiction, depression, and Parkinson's disease. We designed near-infrared fluorescence dopamine-responsive nanoprobes (DRNs) for brain activity imaging during drug abuse and addiction process. On the basis of light-induced electron transfer between DRNs and dopamine and molecular wire effect of the DRNs, we can track the dynamical change of the neurotransmitter level in the physiological environment and the releasing of the neurotransmitter in living dopaminergic neurons in response to nicotine stimulation. The functional near-infrared fluorescence imaging can dynamically track the dopamine level in the mice midbrain under normal or drug-activated condition and evaluate the long-term effect of addictive substances to the brain. This strategy has the potential for studying neural activity under physiological condition.

Conjugated polymer nanomaterials for theranostics.

Conjugated polymer nanomaterials (CPNs), as optically and electronically active materials, hold promise for biomedical imaging and drug delivery applications. This review highlights the recent advances in the utilization of CPNs in theranostics. Specifically, CPN-based in vivo imaging techniques, including near-infrared (NIR) imaging, two-photon (TP) imaging, photoacoustic (PA) imaging, and multimodal (MM) imaging, are introduced. Then, CPN-based photodynamic therapy (PDT) and photothermal therapy (PTT) are surveyed. A variety of stimuli-responsive CPN systems for drug delivery are also summarized, and the promising trends and translational challenges are discussed.

Anaerobe-Inspired Anticancer Nanovesicles.

Anaerobic bacteria, such as Clostridium and Salmonella, can selectively invade and colonize in tumor hypoxic regions (THRs) and deliver therapeutic products to destroy cancer cells. Herein, we present an anaerobe nanovesicle mimic that can not only be activated in THRs but also induce hypoxia in tumors by themselves. Moreover, inspired by the oxygen metabolism of anaerobes, we construct a light-induced hypoxia-responsive modality to promote dissociation of vehicles and activation of bioreductive prodrugs simultaneously. In vitro and in vivo experiments indicate that this anaerobe-inspired nanovesicle can efficiently induce apoptotic cell death and significantly inhibit tumor growth. Our work provides a new strategy for engineering stimuli-responsive drug delivery systems in a bioinspired and synergistic fashion.

Bioinspired Ferroelectric Polymer Arrays as Photodetectors with Signal Transmissible to Neuron Cells.

A bioinspired photodetector with signal transmissible to neuron cells is fabricated. Photoisomerization of the dye molecules embedded in the ferroelectric polymer membrane achieves electric polarization change under visible light. The photodetector realizes high sensitivity, color recognition, transient response, and 3D visual detection with resolution of 25 000 PPI, and, impressively, directly transduces the signal to neuron cells.

ATP-Responsive and Near-Infrared-Emissive Nanocarriers for Anticancer Drug Delivery and Real-Time Imaging.

Stimuli-responsive and imaging-guided drug delivery systems hold vast promise for enhancement of therapeutic efficacy. Here we report an adenosine-5'-triphosphate (ATP)-responsive and near-infrared (NIR)-emissive conjugated polymer-based nanocarrier for the controlled release of anticancer drugs and real-time imaging. We demonstrate that the conjugated polymeric nanocarriers functionalized with phenylboronic acid tags on surface as binding sites for ATP could be converted to the water-soluble conjugated polyelectrolytes in an ATP-rich environment, which promotes the disassembly of the drug carrier and subsequent release of the cargo. In vivo studies validate that this formulation exhibits promising capability for inhibition of tumor growth. We also evaluate the metabolism process by monitoring the fluorescence signal of the conjugated polymer through the in vivo NIR imaging.

Dual-Color Fluorescence Imaging of Magnetic Nanoparticles in Live Cancer Cells Using Conjugated Polymer Probes.

Rapid growth in biological applications of nanomaterials brings about pressing needs for exploring nanomaterial-cell interactions. Cationic blue-emissive and anionic green-emissive conjugated polymers are applied as dual-color fluorescence probes to the surface of negatively charged magnetic nanoparticles through sequentially electrostatic adsorption. These conjugated polymers have large extinction coefficients and high fluorescence quantum yield (82% for PFN and 62% for ThPFS). Thereby, one can visualize trace amount (2.7 µg/mL) of fluorescence-labeled nanoparticles within cancer cells by confocal laser scanning microscopy. Fluorescence labeling by the conjugated polymers is also validated for quantitative determination of the internalized nanoparticles in each individual cell by flow cytometry analysis. Extensive overlap of blue and green fluorescence signals in the cytoplasm indicates that both conjugated polymer probes tightly bind to the surface of the nanoparticles during cellular internalization. The highly charged and fluorescence-labeled nanoparticles non-specifically bind to the cell membranes, followed by cellular uptake through endocytosis. The nanoparticles form aggregates inside endosomes, which yields a punctuated staining pattern. Cellular internalization of the nanoparticles is dependent on the dosage and time. Uptake efficiency can be enhanced three-fold by application of an external magnetic field. The nanoparticles are low cytotoxicity and suitable for simultaneously noninvasive fluorescence and magnetic resonance imaging application.

Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy.

A light-activated hypoxia-responsive conjugated polymer-based nanocarrier is developed for efficiently producing singlet oxygen ((1) O2 ) and inducing hypoxia to promote release of its cargoes in tumor cells, leading to enhanced antitumor efficacy. This dual-responsive nanocarrier provides an innovative design guideline for enhancing traditional photodynamic therapeutic efficacy integrated with a controlled drug-release modality.

Smart conjugated polymer nanocarrier for healthy weight loss by negative feedback regulation of lipase activity.

Healthy weight loss represents a real challenge when obesity is increasing in prevalence. Herein, we report a conjugated polymer nanocarrier for smart deactivation of lipase and thus balancing calorie intake. After oral administration, the nanocarrier is sensitive to lipase in the digestive tract and releases orlistat, which deactivates the enzyme and inhibits fat digestion. It also creates negative feedback to control the release of itself. The nanocarrier smartly regulates activity of the lipase cyclically varied between high and low levels. In spite of high fat diet intervention, obese mice receiving a single dose of the nanocarrier lose weight over eight days, whereas a control group continues the tendency to gain weight. Daily intragastric administration of the nanocarrier leads to lower weight of livers or fat pads, smaller adipocyte size, and lower total cholesterol level than that of the control group. Near-infrared fluorescence of the nanocarrier reveals its biodistribution.

Conjugated Polymer Nanoparticles for Fluorescence Imaging and Sensing of Neurotransmitter Dopamine in Living Cells and the Brains of Zebrafish Larvae.

Nanoscale materials are now attracting a great deal of attention for biomedical applications. Conjugated polymer nanoparticles have remarkable photophysical properties that make them highly advantageous for biological fluorescence imaging. We report on conjugated polymer nanoparticles with phenylboronic acid tags on the surface for fluorescence detection of neurotransmitter dopamine in both living PC12 cells and brain of zebrafish larvae. The selective enrichment of dopamine and fluorescence signal amplification characteristics of the nanoparticles show rapid and high-sensitive probing such neurotransmitter with the detection limit of 38.8 nM, and minimum interference from other endogenous molecules. It demonstrates the potential of nanomaterials as a multifunctional nanoplatform for targeting, diagnosis, and therapy of dopamine-relative disease.