A planar electronic acceptor motif contributing to NIR-II AIEgen with combined imaging and therapeutic applications.

Designing molecules with donor-acceptor-donor (D-A-D) architecture plays an important role in obtaining second near-infrared region (NIR-II, 1000-1700 nm) fluorescent dyes for biomedical applications; however, this always comes with a challenge due to very limited electronic acceptors. On the other hand, to endow NIR-II fluorescent dyes with combined therapeutic applications, trivial molecular design is indispensable. Herein, we propose a pyrazine-based planar electronic acceptor with a strong electron affinity, which can be used to develop NIR-II fluorescent dyes. By structurally attaching two classical triphenylamine electronic donors to it, a basic D-A-D module, namely Py-NIR, can be generated. The planarity of the electronic acceptor is crucial to induce a distinct NIR-II emission peaking at ∼1100 nm. The unique construction of the electronic acceptor can cause a twisted and flexible molecular conformation by the repulsive effect between the donors, which is essential to the aggregation-induced emission (AIE) property. The tuned intramolecular motions and twisted D-A pair brought by the electronic acceptor can lead to a remarkable photothermal conversion with an efficiency of 56.1% and induce a type I photosensitization with a favorable hydroxyl radical (OH˙) formation. Note that no additional measures are adopted in the molecular design, providing an ideal platform to realize NIR-II fluorescent probes with synergetic functions based on such an acceptor. Besides, the nanoparticles of Py-NIR can exhibit excellent NIR-II fluorescence imaging towards orthotopic 4T1 breast tumors in living mice with a high sensitivity and contrast. Combined with photothermal imaging and photoacoustic imaging caused by the thermal effect, the imaging-guided photoablation of tumors can be well performed. Our work has created a new opportunity to develop NIR-II fluorescent probes for accelerating biomedical applications.

Highly sensitive and accurate measurement of underivatized phosphoenolpyruvate in plasma and serum via EDTA-facilitated hydrophilic interaction liquid chromatography-tandem mass spectrometry.

Phosphoenolpyruvate (PEP) is an essential intermediate metabolite that is involved in various vital biochemical reactions. However, achieving the direct and accurate quantification of PEP in plasma or serum poses a significant challenge owing to its strong polarity and metal affinity. In this study, a sensitive method for the direct determination of PEP in plasma and serum based on ethylenediaminetetraacetic acid (EDTA)-facilitated hydrophilic interaction liquid chromatography-tandem mass spectrometry was developed. Superior chromatographic retention and peak shapes were achieved using a zwitterionic stationary-phase HILIC column with a metal-inert inner surface. Efficient dechelation of PEP-metal complexes in serum/plasma samples was achieved through the introduction of EDTA, resulting in a significant enhancement of the PEP signal. A PEP isotopically labelled standard was employed as a surrogate analyte for the determination of endogenous PEP, and validation assessments proved the sensitivity, selectivity, and reproducibility of this method. The method was applied to the comparative quantification of PEP in plasma and serum samples from mice and rats, as well as in HepG2 cells, HEK293T cells, and erythrocytes; the results confirmed its applicability in PEP-related biomedical research. The developed method can quantify PEP in diverse biological matrices, providing a feasible opportunity to investigate the role of PEP in relevant biomedical research.

Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) has been validated as a therapeutic target for acute myeloid leukemia (AML). While a number of FLT3 kinase inhibitors have been approved for AML treatment, the clinical data revealed that they cannot achieve complete and sustained suppression of FLT3 signaling at the tolerated dose. Here we report a series of new, potent and selective FLT3 proteolysis targeting chimera degraders. The optimal compound LWY713 potently induced the degradation of FLT3 with a DC50 value of 0.64 nM and a Dmax value of 94.8% in AML MV4-11 cells with FLT3-internal tandem duplication (ITD) mutation. Mechanistic studies demonstrated that LWY713 selectively induced FLT3 degradation in a cereblon- and proteasome-dependent manner. LWY713 potently inhibited FLT3 signaling, suppressed cell proliferation, and induced cell G0/G1-phase arrest and apoptosis in MV4-11 cells. Importantly, LWY713 displayed potent in vivo antitumor activity in MV4-11 xenograft models.

Mesoporous Nano-Badminton with Asymmetric Mass Distribution: How Nanoscale Architecture Affects the Blood Flow Dynamics.

While the nanobio interaction is crucial in determining nanoparticles' in vivo fate, a previous work on investigating nanoparticles' interaction with biological barriers is mainly carried out in a static state. Nanoparticles' fluid dynamics that share non-negligible impacts on their frequency of encountering biological hosts, however, is seldom given attention. Herein, inspired by badmintons' unique aerodynamics, badminton architecture Fe3O4&mPDA (Fe3O4 = magnetite nanoparticle and mPDA = mesoporous polydopamine) Janus nanoparticles have successfully been synthesized based on a steric-induced anisotropic assembly strategy. Due to the "head" Fe3O4 having much larger density than the mPDA "cone", it shows an asymmetric mass distribution, analogous to real badminton. Computational simulations show that nanobadmintons have a stable fluid posture of mPDA cone facing forward, which is opposite to that for the real badminton. The force analysis demonstrates that the badminton-like morphology and mass distribution endow the nanoparticles with a balanced motion around this posture, making its movement in fluid stable. Compared to conventional spherical Fe3O4@mPDA nanoparticles, the Janus nanoparticles with an asymmetric mass distribution have straighter blood flow trails and ∼50% reduced blood vessel wall encountering frequency, thus providing doubled blood half-life and ∼15% lower organ uptakes. This work provides novel methodology for the fabrication of unique nanomaterials, and the correlations between nanoparticle architectures, biofluid dynamics, organ uptake, and blood circulation time are successfully established, providing essential guidance for designing future nanocarriers.

Versatile synthesis of metal-compound based mesoporous Janus nanoparticles.

The construction of mesoporous Janus nanoparticles (mJNPs) with controllable components is of great significance for the development of sophisticated nanomaterials with synergistically enhanced functionalities and applications. However, the compositions of reported mJNPs are mainly the functionally inert SiO2 and polymers. The universal synthesis of metal-compound based mJNPs with abundant functionalities is urgently desired, but remains a substantial challenge. Herein, we present a hydrophilicity mediated interfacial selective assembly strategy for the versatile synthesis of metal-compound based mJNPs. Starting from the developed silica-based mJNPs with anisotropic dual-surface of hydrophilic SiO2 and hydrophobic organosilica, metal precursor can selectively deposit onto the hydrophilic SiO2 subunit to form the metal-compound based mJNPs. This method shows good universality and can be used for the synthesis of more than 20 kinds of metal-compound based mJNPs, including alkali-earth metal compounds, transition metal compounds, rare-earth metal compounds etc. Besides, the composition of the metal-compound subunit can be well tuned from single to multiple metal elements, even high-entropy complexes. We believe that the synthesis method and obtained new members of mJNPs provide a very broad platform for the construction and application of mJNPs with rational designed functions and structures.

Type I Photosensitization with Strong Hydroxyl Radical Generation in NIR Dye Boosted by Vigorous Intramolecular Motions for Synergistic Therapy.

Development of type I photosensitizers (PSs) with strong hydroxyl radical (· OH) formation is particularly important in the anaerobic tumor treatment. On the other hand, it is challenging to obtain an efficient solid-state intramolecular motion to promote the development of molecular machine and molecular motor. However, the relationship between them is never revealed. In this work, a pyrazine-based near-infrared type I PS with remarkable donor-acceptor effect is developed. Notably, the intramolecular motions are almost maximized by the combination of intramolecular and intermolecular engineering to simultaneously introduce the unlimited bond stretching vibration and boost the group rotation. The photothermal conversion caused by the intramolecular motions is realized with efficiency as high as 86.8%. The D-A conformation of PS can also induce a very small singlet-triplet splitting of 0.07 eV, which is crucial to promote the intersystem crossing for the triplet sensitization. Interestingly, its photosensitization is closely related to the intramolecular motions, and a vigorous motion may give rise to a strong · OH generation. In view of its excellent photosensitization and photothermal behavior, the biocompatible PS exhibits a superior imaging-guided cancer synergistic therapy. This work stimulates the development of advanced PS for the biomedical application and solid-state intramolecular motions.

Emulsion-oriented assembly for Janus double-spherical mesoporous nanoparticles as biological logic gates.

The ability of Janus nanoparticles to establish biological logic systems has been widely exploited, yet conventional non/uni-porous Janus nanoparticles are unable to fully mimic biological communications. Here we demonstrate an emulsion-oriented assembly approach for the fabrication of highly uniform Janus double-spherical MSN&mPDA (MSN, mesoporous silica nanoparticle; mPDA, mesoporous polydopamine) nanoparticles. The delicate Janus nanoparticle possesses a spherical MSN with a diameter of ~150 nm and an mPDA hemisphere with a diameter of ~120 nm. In addition, the mesopore size in the MSN compartment is tunable from ~3 to ~25 nm, while those in the mPDA compartments range from ~5 to ~50 nm. Due to the different chemical properties and mesopore sizes in the two compartments, we achieve selective loading of guests in different compartments, and successfully establish single-particle-level biological logic gates. The dual-mesoporous structure enables consecutive valve-opening and matter-releasing reactions within one single nanoparticle, facilitating the design of single-particle-level logic systems.

Manipulating exchange bias in 2D magnetic heterojunction for high-performance robust memory applications.

The exchange bias (EB) effect plays an undisputed role in the development of highly sensitive, robust, and high-density spintronic devices in magnetic data storage. However, the weak EB field, low blocking temperature, as well as the lack of modulation methods, seriously limit the application of EB in van der Waals (vdW) spintronic devices. Here, we utilized pressure engineering to tune the vdW spacing of the two-dimensional (2D) FePSe3/Fe3GeTe2 heterostructures. The EB field (HEB, from 29.2 mT to 111.2 mT) and blocking temperature (Tb, from 20 K to 110 K) are significantly enhanced, and a highly sensitive and robust spin valve is demonstrated. Interestingly, this enhancement of the EB effect was extended to exposed Fe3GeTe2, due to the single-domain nature of Fe3GeTe2. Our findings provide opportunities for the producing, exploring, and tuning of magnetic vdW heterostructures with strong interlayer coupling, thereby enabling customized 2D spintronic devices in the future.

Camouflaged Virus-Like-Nanocarrier with a Transformable Rough Surface for Boosting Drug Delivery.

Due to non-specific strong nano-bio interactions, it is difficult for nanocarriers with permanent rough surface to cross multiple biological barriers to realize efficient drug delivery. Herein, a camouflaged virus-like-nanocarrier with a transformable rough surface is reported, which is composed by an interior virus-like mesoporous SiO2 nanoparticle with a rough surface (vSiO2 ) and an exterior acid-responsive polymer. Under normal physiological pH condition, the spikes on vSiO2 are hidden by the polymer shell, and the non-specific strong nano-bio interactions are effectively inhibited. While in the acidic tumor microenvironment, the nanocarrier sheds the polymer camouflage to re-expose its rough surface. So, the retention ability and endocytosis efficiency of the nanocarrier are great improved. Owing to it's the dynamically variable rough surface, the rationally designed nanocarrier exhibits extended blood-circulation-time and enhanced tumor accumulation.

Remodeling nanodroplets into hierarchical mesoporous silica nanoreactors with multiple chambers.

Multi-chambered architectures have attracted much attention due to the ability to establish multifunctional partitions in different chambers, but manipulating the chamber numbers and coupling multi-functionality within the multi-chambered mesoporous nanoparticle remains a challenge. Herein, we propose a nanodroplet remodeling strategy for the synthesis of hierarchical multi-chambered mesoporous silica nanoparticles with tunable architectures. Typically, the dual-chambered nanoparticles with a high surface area of ~469 m2 g-1 present two interconnected cavities like a calabash. Furthermore, based on this nanodroplet remodeling strategy, multiple species (magnetic, catalytic, optic, etc.) can be separately anchored in different chamber without obvious mutual-crosstalk. We design a dual-chambered mesoporous nanoreactors with spatial isolation of Au and Pd active-sites for the cascade synthesis of 2-phenylindole from 1-nitro-2-(phenylethynyl)benzene. Due to the efficient mass transfer of reactants and intermediates in the dual-chambered structure, the selectivity of the target product reaches to ~76.5%, far exceeding that of single-chambered nanoreactors (~41.3%).

MOF-Like 3D Graphene-Based Catalytic Membrane Fabricated by One-Step Laser Scribing for Robust Water Purification and Green Energy Production.

Increasing both clean water and green energy demands for survival and development are the grand challenges of our age. Here, we successfully fabricate a novel multifunctional 3D graphene-based catalytic membrane (3D-GCM) with active metal nanoparticles (AMNs) loading for simultaneously obtaining the water purification and clean energy generation, via a "green" one-step laser scribing technology. The as-prepared 3D-GCM shows high porosity and uniform distribution with AMNs, which exhibits high permeated fluxes (over 100 L m-2 h-1) and versatile super-adsorption capacities for the removal of tricky organic pollutants from wastewater under ultra-low pressure-driving (0.1 bar). After adsorption saturating, the AMNs in 3D-GCM actuates the advanced oxidization process to self-clean the fouled membrane via the catalysis, and restores the adsorption capacity well for the next time membrane separation. Most importantly, the 3D-GCM with the welding of laser scribing overcomes the lateral shear force damaging during the long-term separation. Moreover, the 3D-GCM could emit plentiful of hot electrons from AMNs under light irradiation, realizing the membrane catalytic hydrolysis reactions for hydrogen energy generation. This "green" precision manufacturing with laser scribing technology provides a feasible technology to fabricate high-efficient and robust 3D-GCM microreactor in the tricky wastewater purification and sustainable clean energy production as well.

Versatile synthesis of dendritic mesoporous rare earth-based nanoparticles.

Rare earth-based nanomaterials that have abundant optical, magnetic, and catalytic characteristics have many applications. The controllable introduction of mesoporous channels can further enhance its performance, such as exposing more active sites of rare earth and improving the loading capacity, yet remains a challenge. Here, we report a universal viscosity-mediated assembly strategy and successfully endowed rare earth-based nanoparticles with central divergent dendritic mesopores. More than 40 kinds of dendritic mesoporous rare earth-based (DM-REX) nanoparticles with desired composition (single or multiple rare earth elements, high-entropy compounds, etc.), particle diameter (80 to 500 nanometers), pore size (3 to 20 nanometers), phase (amorphous hydroxides, crystalline oxides, and fluorides), and architecture were synthesized. Theoretically, a DM-REX nanoparticle library with 393,213 kinds of possible combinations can be constructed on the basis of this versatile method, which provides a very broad platform for the application of rare earth-based nanomaterials with rational designed functions and structures.

Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis.

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-ß expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

Modular super-assembly of hierarchical superstructures from monomicelle building blocks.

Manipulating the super-assembly of polymeric building blocks still remains a great challenge due to their thermodynamic instability. Here, we report on a type of three-dimensional hierarchical core-satellite SiO2@monomicelle spherical superstructures via a previously unexplored monomicelle interfacial super-assembly route. Notably, in this superstructure, an ultrathin single layer of monomicelle subunits (~18 nm) appears in a typically hexagon-like regular discontinuous distribution (adjacent micelle distance of ~30 nm) on solid spherical interfaces (SiO2), which is difficult to achieve by conventional super-assembled methods. Besides, the number of the monomicelles on colloidal SiO2 interfaces can be quantitatively controlled (from 76 to 180). This quantitative control can be precisely manipulated by tuning the interparticle electrostatic interactions (the intermicellar electrostatic repulsion and electrostatic attractions between the monomicelle units and the SiO2 substrate). This monomicelle interfacial super-assembly strategy will enable a controllable way for building multiscale hierarchical regular micro- and/or macroscale materials and devices.

Click Synthesis Enabled Sulfur Atom Strategy for Polymerization-Enhanced and Two-Photon Photosensitization.

Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen photodynamic therapy (PDT) applications. Herein, a catalyst-free thiol-yne click reaction was employed to develop the sulfur atom-based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such an effect can be remarkably magnified by the polymerization. The introduction of a tetraphenylpyrazine-based aggregation-induced emission (AIE) unit was also advantageous in PS design by suppressing their non-radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with a double-bond π bridge and AIE electron acceptor, created a donor-π-acceptor (D-π-A) molecular system with good two-photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two-photon-excited PDT towards cancer cells, therefore possessing a huge potential for the deep-tissue disease therapy.

The development of HEC-866 and its analogues for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a typical survival time between three to five years. Two drugs, pirfenidone and nintedanib have been approved for the treatment of IPF, but they have limited efficacy. Thus, the development of new drugs to treat IPF is an urgent medical need. In this paper we report the discovery of a series of orally active pyrimidin-4(3H)-one analogs which exhibit potent activity in in vitro assays. Among them, HEC-866 showed promising efficacy in rat IPF models. Since HEC-866 also had good oral bioavailability, a long half-life and favorable long-term safety profiles, it was selected for further clinical evaluation.

2D materials-based homogeneous transistor-memory architecture for neuromorphic hardware.

In neuromorphic hardware, peripheral circuits and memories based on heterogeneous devices are generally physically separated. Thus, exploration of homogeneous devices for these components is key for improving module integration and resistance matching. Inspired by the ferroelectric proximity effect on two-dimensional (2D) materials, we present a tungsten diselenide­on­lithium niobate cascaded architecture as a basic device that functions as a nonlinear transistor, assisting the design of operational amplifiers for analog signal processing (ASP). This device also functions as a nonvolatile memory cell, achieving memory operating (MO) functionality. On the basis of this homogeneous architecture, we also investigated an ASP-MO integrated system for binary classification and the design of ternary content-addressable memory for potential use in neuromorphic hardware.

Imparting multi-functionality to covalent organic framework nanoparticles by the dual-ligand assistant encapsulation strategy.

The potential applications of covalent organic frameworks (COFs) can be further developed by encapsulating functional nanoparticles within the frameworks. However, the synthesis of monodispersed core@shell structured COF nanocomposites without agglomeration remains a significant challenge. Herein, we present a versatile dual-ligand assistant strategy for interfacial growth of COFs on the functional nanoparticles with abundant physicochemical properties. Regardless of the composition, geometry or surface properties of the core, the obtained core@shell structured nanocomposites with controllable shell-thickness are very uniform without agglomeration. The derived bowl-shape, yolk@shell, core@satellites@shell nanostructures can also be fabricated delicately. As a promising type of photosensitizer for photodynamic therapy (PDT), the porphyrin-based COFs were grown onto upconversion nanoparticles (UCNPs). With the assistance of the near-infrared (NIR) to visible optical property of UCNPs core and the intrinsic porosity of COF shell, the core@shell nanocomposites can be applied as a nanoplatform for NIR-activated PDT with deep tissue penetration and chemotherapeutic drug delivery.

Precisely Controlled Vertical Alignment in Mesostructured Carbon Thin Films for Efficient Electrochemical Sensing.

Two-dimensional carbon materials, incorporating a large mesoporosity, are attracting considerable research interest in various fields such as catalysis, electrochemistry, and energy-related technologies owing to their integrated functionalities. However, their potential applications, which require favorable mass transport within mesopore channels, are constrained by the undesirable and finite mesostructural configurations due to the immense synthetic difficulties. Herein, we demonstrate an oriented monomicelle assembly strategy, for the facile fabrication of highly ordered mesoporous carbon thin films with vertically aligned and permeable mesopore channels. Such a facile and reproducible approach relies on the swelling and fusion effect of hydrophobic benzene homologues for directional monomicelle assembly. The orientation assembly process shows precise controllability and great universality, affording mesoporous carbon films with a cracking-free structure over a centimeter in size, highly tunable thicknesses (13 to 85 nm, an interval of ∼12 nm), mesopore size (8.4 to 13.5 nm), and switchable growth substrates. Owing to their large permeable mesopore channels, electrochemical sensors based on vertical mesoporous carbon films exhibit an ultralow limit of detection (50 nmol L-1) and great sensitivity in dopamine detection.