Rust‐Mediated Continuous Assembly of Metal–Phenolic Networks

The use of natural compounds for preparing hybrid molecular films—such as surface coatings made from metal–phenolic networks (MPNs)—is of interest in areas ranging from catalysis and separations to biomedicine. However, to date, the film growth of MPNs has been observed to proceed in discrete steps (≈10 nm per step) where the coordination‐driven interfacial assembly ceases beyond a finite time (≈1 min). Here, it is demonstrated that the assembly process for MPNs can be modulated from discrete to continuous by utilizing solid‐state reactants (i.e., rusted iron objects). Gallic acid etches iron from rust and produces chelate complexes in solution that continuously assemble at the interface of solid substrates dispersed in the system. The result is stable, continuous growth of MPN films. The presented double dynamic process—that is, etching and self‐assembly—provides new insights into the chemistry of MPN assembly while enabling control over the MPN film thickness by simply varying the reaction time.     

Self‐Assembly of Graphene Oxide at Interfaces

Due to its amphiphilic property, graphene oxide (GO) can achieve a variety of nanostructures with different morphologies (for example membranes, hydrogel, crumpled particles, hollow spheres, sack‐cargo particles, Pickering emulsions, and so on) by self‐assembly. The self‐assembly is mostly derived from the self‐concentration of GO sheets at various interfaces, including liquid‐air, liquid‐liquid and liquid‐solid interfaces. This paper gives a comprehensive review of these assembly phenomena of GO at the three types of interfaces, the derived interfacial self‐assembly techniques, and the as‐obtained assembled materials and their properties. The interfacial self‐assembly of GO, enabled by its fantastic features including the amphiphilicity, the negatively charged nature, abundant oxygen‐containing groups and two‐dimensional flexibility, is highlighted as an easy and well‐controlled strategy for the design and preparation of functionalized carbon materials, and the use of self‐assembly for uniform hybridization is addressed for preparing hybrid carbon materials with various functions. A number of new exciting and potential applications are also presented for the assembled GO‐based materials. This contribution concludes with some personal perspectives on future challenges before interfacial self‐assembly may become a major strategy for the application‐targeted design and preparation of functionalized carbon materials.     

Metal Ion‐Induced Self‐Assembly of a Multi‐Responsive Block Copolypeptide into Well‐Defined Nanocapsules

Protein cages are an interesting class of biomaterials with potential applications in bionanotechnology. Therefore, substantial effort is spent on the development of capsule‐forming designer polypeptides with a tailor‐made assembly profile. The expanded assembly profile of a triblock copolypeptide consisting of a metal ion chelating hexahistidine‐tag, a stimulus‐responsive elastin‐like polypeptide block, and a pH‐responsive morphology‐controlling viral capsid protein is presented. The self‐assembly of this multi‐responsive protein‐based block copolymer is triggered by the addition of divalent metal ions. This assembly process yields monodisperse nanocapsules with a 20 nm diameter composed of 60 polypeptides. The well‐defined nanoparticles are the result of the emergent properties of all the blocks of the polypeptide. These results demonstrate the feasibility of hexahistidine‐tags to function as supramolecular cross‐linkers. Furthermore, their potential for the metal ion‐mediated encapsulation of hexahistidine‐tagged proteins is shown.     

Layer‐by‐Layer Hydrogen‐Bonded Polymer Films: From Fundamentals to Applications

Recent years have seen increasing interest in the construction of nanoscopically layered materials involving aqueous‐based sequential assembly of polymers on solid substrates. In the booming research area of layer‐by‐layer (LbL) assembly of oppositely charged polymers, self‐assembly driven by hydrogen bond formation emerges as a powerful technique. Hydrogen‐bonded (HB) LbL materials open new opportunities for LbL films, which are more difficult to produce than their electrostatically assembled counterparts. Specifically, the new properties associated with HB assembly include: 1) the ease of producing films responsive to environmental pH at mild pH values, 2) numerous possibilities for converting HB films into single‐ or two‐component ultrathin hydrogel materials, and 3) the inclusion of polymers with low glass transition temperatures (e.g., poly(ethylene oxide)) within ultrathin films. These properties can lead to new applications for HB LbL films, such as pH‐ and/or temperature‐responsive drug delivery systems, materials with tunable mechanical properties, release films dissolvable under physiological conditions, and proton‐exchange membranes for fuel cells. In this report, we discuss the recent developments in the synthesis of LbL materials based on HB assembly, the study of their structure–property relationships, and the prospective applications of HB LbL constructs in biotechnology and biomedicine.     

One‐step Preparation of Monodisperse Multifunctional Macroporous Particles through a Spontaneous Physical Process

Macroporous particles that combine the property features of spherical structures and porous materials are expected to find use over micro‐ and macroscopic length scales from miniaturized systems such as cell imaging, drug and gene delivery to industrial applications. However, the capacity for de novo design of such materials is still limited. Here, a spontaneous process to fabricate monodisperse multifunctional macroporous particles (MMMPs) by high internal phase emulsion templating is reported. An interesting physical phenomenon involving self‐emulsification and synergistic effects between nanoparticles and amphiphilic diblock copolymers is observed in this process. These MMMPs, featured with tailor‐made pore structures, pH responsiveness, and magnetic response, could be used as stimuli‐responsive carriers for multiple functional molecules with a high loading and releasing efficiency. This new understanding regarding the underlying phenomena that control self‐emulsification behavior and synergistic action in emulsion systems provides a unique outlook and a novel approach to the design of potentially multifunctional porous materials for controllable release and delivery processes.     

Multifunctional Mesoporous Silica Nanoparticles with Thermal‐Responsive Gatekeeper for NIR Light‐Triggered Chemo/Photothermal‐Therapy

In this work, a matrix metalloproteinase (MMP)‐triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near‐infrared (NIR) photothermal‐responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal‐cleavable gatekeeper (Azo‐CD), which can be decapped by ICG‐generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host–guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor‐triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.     

Gadolinium Metallofullerene‐Based Activatable Contrast Agent for Tumor Signal Amplification and Monitoring of Drug Release

Activatable imaging probes are promising to achieve increased signal‐to‐noise ratio for accurate tumor diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is a noninvasive imaging technique with excellent anatomic spatial resolution and unlimited tissue penetration depth. However, most of the activatable MRI contrast agents suffer from metal ion‐associated potential long‐term toxicity, which may limit their bioapplications and clinical translation. Herein, an activatable MRI agent with efficient MRI performance and high safety is developed for drug (doxorubicin) loading and tumor signal amplification. The agent is based on pH‐responsive polymer and gadolinium metallofullerene (GMF). This GMF‐based contrast agent shows high relaxivity and low risk of gadolinium ion release. At physiological pH, both GMF and drug molecules are encapsulated into the hydrophobic core of nanoparticles formed by the pH‐responsive polymer and shielded from the aqueous environment, resulting in relatively low longitudinal relativity and slow drug release. However, in acidic tumor microenvironment, the hydrophobic‐to‐hydrophilic conversion of the pH‐responsive polymer leads to amplified MR signal and rapid drug release simultaneously. These results suggest that the prepared activatable MRI contrast agent holds great promise for tumor detection and monitoring of drug release.     

pH‐Responsive PEG‐Shedding and Targeting Peptide‐Modified Nanoparticles for Dual‐Delivery of Irinotecan and microRNA to Enhance Tumor‐Specific Therapy

Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA‐200 (miR‐200) has been reported to inhibit metastasis in cancer cells. Herein, pH‐sensitive and peptide‐modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR‐200, respectively. These peptides include one cell‐penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria‐targeting peptide. The peptide‐modified nanoparticles are further coated with a pH‐sensitive PEG‐lipid derivative with an imine bond. These specially‐designed nanoparticles exhibit pH‐responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR‐200 by SLN further increases the cytotoxicity of irinotecan‐loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β‐catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC‐bearing mice, the in vivo results further indicate that irinotecan and miR‐200 in pH‐responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β‐catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH‐responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.     

Non‐Magnetic Injectable Implant for Magnetic Field‐Driven Thermochemotherapy and Dual Stimuli‐Responsive Drug Delivery: Transformable Liquid Metal Hybrid Platform for Cancer Theranostics

Transformable liquid metal (LM)‐based materials have attracted considerable research interest in biomedicine. However, the potential biomedical applications of LMs have not yet been fully explored. Herein, for the first trial, the inductive heating property of gallium–indium eutectic alloy (EGaIn) under alterative magnetic field is systematically investigated. By virtue of its inherent metallic nature, LM possesses excellent magnetic heating property as compared to the conventional magnetite nanoparticles, therefore enabling its unique application as non‐magnetic agents in magnetic hyperthermia. Moreover, the extremely high surface tension of LM could be dramatically lowered by a rather facile PEGylation approach, making LM an ideal carrier for other theranostic cargos. By incorporating doxorubicin (DOX)‐loaded mesoporous silica (DOX‐MS) within PEGylated LM, a magnetic field‐driven transformable LM hybrid platform capable of pH/AFM dual stimuli‐responsive drug release and magnetic thermochemotherapy are successfully fabricated. The potential application for breast cancer treatment is demonstrated. Furthermore, the large X‐ray attenuation ability of LM endows the hybrid with the promising ability for CT imaging. This work explores a new biomedical use of LM and a promising cancer treatment protocol based on LM hybrid for magnetic hyperthermia combined with dual stimuli‐responsive chemotherapy and CT imaging.     

Dual‐Responsive Breakdown of Nanostructures with High Doxorubicin Payload for Apoptotic Anticancer Therapy

Self‐assembled nanoaggregates co‐encapsulating doxorubicin (DOX) and oligonucleotide are prepared for dual‐responsive breakdown of the nanostructure with complete disappearance characteristics. Four‐arm poly(ethylene glycol) is co‐conjugated with DOX and anti‐bcl‐2 oligonucleotide with reducible linkers and acid‐cleavable linkers, respectively. The conjugate is hydrophobically self‐assembled into nanoaggregates in aqueous solution. Elemental scanning of the nanoaggregates reveals their core–shell structure with DOX and oligonucleotide located at the core and the shell, respectively. The tracking of size modulation suggests the complete disappearance of the particles under reducing conditions and the liberation of oligonucleotide at low pH, which is confirmed by dynamic light scattering and electron microscopy. The release of DOX and oligonucleotide is controlled by the pH and the reducing potential of the medium, and most of the drug and DNA are released in 24 h. The released fractions are analyzed by reversed‐phase chromatography, which indicates facile cleavage of DOX and oligonucleotide from the carriers. The nanoaggregates with both DOX and oligonucleotide show the lowest IC₅₀ value when a cytotoxicity assay is performed against A549 cells. Apoptosis assay also confirms that cells treated with the nanoaggregates having both DOX and oligonucleotide show higher fluorescence intensity of antiapoptotic antibody than native DOX.     

Double‐Emulsion Globules as a Tool to Produce 2D Patterned Metal Deposits Using Electro‐Colloidal Lithography

A technique developed to self assemble solid colloidal particles under a sinusoidal electric field (AC field) is adapted to soft W/O/W double‐emulsion globules, and is exploited for surface patterning. Double‐emulsions containing cupric ions are prepared, placed between two planar ITO electrodes and submitted to a transversal AC field which induced their ordering into hexagonal 2D‐arrays. The characteristic spacing is monitored by varying the globule volume fraction. Such self‐assembly is used to fabricate copper‐depleted arrays, using globules as both a metal precursor reservoir/provider and as a mask. The ordered globule monolayer is then submitted to a DC field to induce metal precursor leakage and its reduction onto the electrode. The organized, oily and dielectric globules generate arrays of holes (c.a. 7 μm) into a thin copper deposit (thickness of 12 nm). Holes are shown to be formed below the globules, and their separation (from 10 to 30 μm) can be tuned as deduced from direct observations using optical and atomic force microscopy.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

Ultrastable Liquid–Liquid Interface as Viable Route for Controlled Deposition of Biodegradable Polymer Nanocapsules

Liquid–liquid interfaces are highly dynamic and characterized by an elevated interfacial tension as compared to solid–liquid interfaces. Therefore, they are gaining an increasing interest as viable templates for ordered assembly of molecules and nanoparticles. However, liquid–liquid interfaces are more difficult to handle compared to solid–liquid interfaces; their intrinsic instability may affect the assembly process, especially in the case of multiple deposition. Indeed, some attempts have been made in the deposition of polymer multilayers at liquid–liquid interfaces, but with limited control over size and stability. This study reports on the preparation of an ultrastable liquid–liquid interface based on an O/W secondary miniemulsion and its possible use as a template for the self‐assembly of polymeric multilayer nanocapsules. Such polymer nanocapsules are made of entirely biodegradable materials, with highly controlled size—well under 200 nm—and multi‐compartment and multifunctional features enriching their field of application in drug delivery, as well as in other bionanotechnology fields.     

Fluorescent Imaging‐Guided Chemotherapy‐and‐Photodynamic Dual Therapy with Nanoscale Porphyrin Metal–Organic Framework

Imaging‐guided therapy systems (IGTSs) are revolutionary techniques used in cancer treatment due to their safety and efficiency. IGTSs should have tunable compositions for bioimaging, a suitable size and shape for biotransfer, sufficient channels and/or pores for drug loading, and intrinsic biocompatibility. Here, a biocompatible nanoscale zirconium‐porphyrin metal–organic framework (NPMOF)‐based IGTS that is prepared using a microemulsion strategy and carefully tuned reaction conditions is reported. A high content of porphyrin (59.8%) allows the achievement of efficient fluorescent imaging and photodynamic therapy (PDT). The 1D channel of the Kagome topology of NPMOFs provides a 109% doxorubicin loading and pH‐response smart release for chemotherapy. The fluorescence guiding of the chemotherapy‐and‐PDT dual system is confirmed by the concentration of NPMOFs at cancer sites after irradiation with a laser and doxorubicin release, while low toxicity is observed in normal tissues. NPMOFs are established as a promising platform for the early diagnosis of cancer and initial therapy.     

pH‐Responsive Isoniazid‐Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice

Tuberculosis is a major global health problem for which improved therapeutics are needed to shorten the course of treatment and combat emergence of drug resistance. Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of mononuclear phagocytes. As such, it is an ideal pathogen for nanotherapeutics because macrophages avidly ingest nanoparticles even without specific targeting molecules. Hence, a nanoparticle drug delivery system has the potential to target and deliver high concentrations of drug directly into M. tuberculosis‐infected cells—greatly enhancing efficacy while avoiding off‐target toxicities. Stimulus‐responsive mesoporous silica nanoparticles of two different sizes, 100 and 50 nm, are developed as carriers for the major anti‐tuberculosis drug isoniazid in a prodrug configuration. The drug is captured by the aldehyde‐functionalized nanoparticle via hydrazone bond formation and coated with poly(ethylene imine)–poly(ethylene glycol) (PEI–PEG). The drug is released from the nanoparticles in response to acidic pH at levels that naturally occur within acidified endolysosomes. It is demonstrated that isoniazid‐loaded PEI–PEG‐coated nanoparticles are avidly ingested by M. tuberculosis‐infected human macrophages and kill the intracellular bacteria in a dose‐dependent manner. It is further demonstrated in a mouse model of pulmonary tuberculosis that the nanoparticles are well tolerated and much more efficacious than an equivalent amount of free drug.     

Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin‐Coated Mesoporous Silica Nanoparticles for Lysosome‐Targeting Delivery in Mice

Multidrug resistance (MDR) and adverse side effects are the major challenges facing cancer chemotherapy. Here, pH/protease dually responsive, sericin‐coated mesoporous silica nanoparticles (SMSNs) for lysosomal delivery of doxorubicin (DOX) to overcome MDR and reduce systemic toxicity are reported. Sericin, a natural protein from silkworm cocoons, is coated onto MSNs as a gatekeeper via pH sensitive imine linkages. The sericin shell prevents the premature leakage of encapsulated DOX from MSNs in extracellular environment. Once reaching drug‐resistant tumors, sericin's cell‐adhesive bioactivity enhances cellular uptake of SMSNs that are in turn transported into perinuclear lysosomes, thus avoiding drug efflux mediated by membrane‐bound pumps. Lysosomal acidity triggers cleavage of pH sensitive linkage between sericin and MSNs concurrently with lysosomal proteases deconstructing sericin shell. This pH/protease dual responsiveness leads to DOX burst release into cell nuclei, inducing effective cell death, thus reversing MDR. These DOX‐loaded SMSNs not only effectively kill drug‐resistant cells in vitro, but also significantly reduce the growth of DOX‐resistant MCF‐7/ADR (breast cancer cells) tumor by 70% in a preclinical animal model without eliciting systemic toxicity frequently encountered in current clinical therapeutic formulations. Thus, the dually responsive SMSNs are an effective, lysosome‐tropic, and bio‐safe delivery system for chemotherapeutics for combating MDR.     

Confined Assembly of Asymmetric Block‐Copolymer Nanofibers via Multiaxial Jet Electrospinning

Multiaxial (triaxial/coaxial) electrospinning is utilized to fabricate block copolymer (poly(styrene‐b‐isoprene), PS‐b‐PI) nanofibers covered with a silica shell. The thermally stable silica shell allows post‐fabrication annealing of the fibers to obtain equilibrium self‐assembly. For the case of coaxial nanofibers, block copolymers with different isoprene volume fractions are studied to understand the effect of physical confinement and interfacial interaction on self‐assembled structures. Various confined assemblies such as co‐existing cylinders and concentric lamellar rings are obtained with the styrene domain next to the silica shell. This confined assembly is then utilized as a template to guide the placement of functional nanoparticles such as magnetite selectively into the PI domain in self‐assembled nanofibers. To further investigate the effect of interfacial interaction and frustration due to the physically confined environment, triaxial configuration is used where the middle layer of the self‐assembling material is sandwiched between the innermost and outermost silica layers. The results reveal that confined block‐copolymer assembly is significantly altered by the presence and interaction with both inner and outer silica layers. When nanoparticles are incorporated into PS‐b‐PI and placed as the middle layer, the PI phase with magnetite nanoparticles migrates next to the silica layers. The migration of the PI phase to the silica layers is also observed for the blend of PS and PS‐b‐PI as the middle layer. These materials not only provide a platform to further study the effect of confinement and wall interactions on self‐assembly but can also help develop an approach to fabricate multilayered, multistructured nanofibers for high‐end applications such as drug delivery.     

Lithium–Graphite Paste: An Interface Compatible Anode for Solid‐State Batteries

All‐solid‐state batteries (ASSBs) with ceramic‐based solid‐state electrolytes (SSEs) enable high safety that is inaccessible with conventional lithium‐ion batteries. Lithium metal, the ultimate anode with the highest specific capacity, also becomes available with nonflammable SSEs in ASSBs, which offers promising energy density. The rapid development of ASSBs, however, is significantly hampered by the large interfacial resistance as a matched lithium/ceramic interface that is not easy to pursue. Here, a lithium–graphite (Li–C) composite anode is fabricated, which shows a dramatic modification in wettability with garnet SSE. An intimate Li–C/garnet interface is obtained by casting Li–C composite onto garnet‐type SSE, delivering an interfacial resistance as low as 11 Ω cm². As a comparison, pure Li/garnet interface gives a large resistance of 381 Ω cm². Such improvement can be ascribed to the experiment‐measured increased viscosity of Li–C composite and simulation‐verified limited interfacial reaction. The Li–C/garnet/Li–C symmetric cell exhibits stable plating/striping performance with small voltage hysteresis and endures a critical current density up to 1.0 mA cm^?2. The full cell paired with LiFePO₄ shows stable cycle performance, comparable to the cell with liquid electrolyte. The present work demonstrates a promising strategy to develop ceramic‐compatible lithium metal‐based anodes and hence low‐impedance ASSBs.     

Manganese Dioxide Coated WS2@Fe3O4/sSiO2 Nanocomposites for pH‐Responsive MR Imaging and Oxygen‐Elevated Synergetic Therapy

Recently, the development of multifunctional theranostic nanoplatforms to realize tumor‐specific imaging and enhanced cancer therapy via responding or modulating the tumor microenvironment (TME) has attracted tremendous interests in the field of nanomedicine. Herein, tungsten disulfide (WS₂) nanoflakes with their surface adsorbed with iron oxide nanoparticles (IONPs) via self‐assembly are coated with silica and then subsequently with manganese dioxide (MnO₂), on to which polyethylene glycol (PEG) is attached. The obtained WS₂‐IO/S@MO‐PEG appears to be highly sensitive to pH, enabling tumor pH‐responsive magnetic resonance imaging with IONPs as the pH‐inert T2 contrast probe and MnO₂ as the pH‐sensitive T1 contrast probe. Meanwhile, synergistic combination tumor therapy is realized with such WS₂‐IO/S@MO‐PEG, by utilizing the strong near‐infrared light and X‐ray absorbance of WS₂ for photothermal therapy (PTT) and enhanced cancer radiotherapy (RT), respectively, as well as the ability of MnO₂ to decompose tumor endogenous H₂O₂ and relieve tumor hypoxia to further overcome hypoxia‐associated radiotherapy resistance. The combination of PTT and RT with WS₂‐IO/S@MO‐PEG results in a remarkable synergistic effect to destruct tumors. This work highlights the promise of developing multifunction nanocomposites for TME‐specific imaging and TME modulation, aiming at precision cancer synergistic treatment.