Bioinspired Adaptive Microdrugs Enhance the Chemotherapy of Malignant Glioma: Beyond Their Nanodrugs.

Solid nanoparticle-mediated drug delivery systems are usually confined to nanoscale due to the enhanced permeability and retention (EPR) effect. However, they remain a great challenge for malignant glioma chemotherapy because of poor drug delivery efficiency and insufficient tumor penetration resulting from the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB). Inspired by biological microparticles (e.g., cells) with excellent adaptive deformation, we demonstrate that the adaptive microdrugs (even up to 3.0 µm in size) are more efficient than their nanodrugs (less than 200 nm in size) to cross BBB/BBTB and penetrate into tumor tissues, achieving highly efficient chemotherapy of malignant glioma. The distinct delivery of the adaptive microdrugs is mainly attributed to the enhanced interfacial binding and endocytosis via adaptive deformation. As expected, the obtained adaptive microdrugs exhibited enhanced accumulation, deep penetration, and cellular internalization into tumor tissues in comparison with nanodrugs, significantly improving the survival rate of glioblastoma mice. We believe that the bioinspired adaptive microdrugs enable them to efficiently cross physiological barriers and deeply penetrate tumor tissues for drug delivery, providing an avenue for the treatment of solid tumors. This article is protected by copyright. All rights reserved.

Orange-derived extracellular vesicles nanodrugs for efficient treatment of ovarian cancer assisted by transcytosis effect.

Extracellular vesicles (EVs) have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size, biocompatibility, and high stability. Herein, we demonstrate orange-derived extracellular vesicles (OEV) nanodrugs (DN@OEV) by modifying cRGD-targeted doxorubicin (DOX) nanoparticles (DN) onto the surface of OEV, enabling significantly enhancing tumor accumulation and penetration, thereby efficiently inhibiting the growth of ovarian cancer. The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells, which presented the average above 10-fold transcytosis effect compared with individual DN. It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway, thereby inducing the enhanced transcytosis. In particular, the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process. Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of the drug delivery system.

Janus particle-engineered structural lipiodol droplets for arterial embolization.

Embolization (utilizing embolic materials to block blood vessels) has been considered one of the most promising strategies for clinical disease treatments. However, the existing embolic materials have poor embolization effectiveness, posing a great challenge to highly efficient embolization. In this study, we construct Janus particle-engineered structural lipiodol droplets by programming the self-assembly of Janus particles at the lipiodol-water interface. As a result, we achieve highly efficient renal embolization in rabbits. The obtained structural lipiodol droplets exhibit excellent mechanical stability and viscoelasticity, enabling them to closely pack together to efficiently embolize the feeding artery. They also feature good viscoelastic deformation capacities and can travel distally to embolize finer vasculatures down to 40 µm. After 14 days post-embolization, the Janus particle-engineered structural lipiodol droplets achieve efficient embolization without evidence of recanalization or non-target embolization, exhibiting embolization effectiveness superior to the clinical lipiodol-based emulsion. Our strategy provides an alternative approach to large-scale fabricate embolic materials for highly efficient embolization and exhibits good potential for clinical applications.

Fruit-Derived Extracellular-Vesicle-Engineered Structural Droplet Drugs for Enhanced Glioblastoma Chemotherapy.

Existing solid-nanoparticle-based drug delivery systems remain a great challenge for glioblastoma chemotherapy due to their poor capacities in crossing the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB). Herein, fruit-derived extracellular-vesicle (EV)-engineered structural droplet drugs (ESDDs) are demonstrated by programming the self-assembly of fruit-derived EVs at the DOX@squalene-PBS interface, greatly enhancing the antitumor efficacy against glioblastoma. The ESDDs experience a flexible delivery via deformation-amplified macropinocytosis and membrane fusion, enabling them to highly efficiently cross the BBB/BBTB and deeply penetrate glioblastoma tissues. As expected, the ESDDs exhibit approximately 2.5-fold intracellular uptake, 2.2-fold transcytosis, and fivefold membrane fusion higher than cRGD-modified EVs (REs), allowing highly efficient accumulation, deep penetration, and cellular internalization into the glioblastoma tissues, and thereby significantly extending the survival time of glioblastoma mice.

cRGD-targeted heparin nanoparticles for effective dual drug treatment of cisplatin-resistant ovarian cancer.

Resistance to the chemotherapeutic agent cisplatin (DDP) is the primary reason for invalid chemotherapy of ovarian cancer. Given the complex mechanisms underlying chemo-resistance, the design of combination therapies based on blocking multiple mechanisms is a rationale to synergistically elevate therapeutic effect for effectively overcoming cancer chemo-resistance. Herein, we demonstrated a multifunctional nanoparticle (DDP-Ola@HR), which could simultaneously co-deliver DDP and Olaparib (Ola, DNA damage repair inhibitor) using targeted ligand cRGD peptide modified with heparin (HR) as nanocarrier, enabling the concurrent tackling of multiple resistance mechanisms to effectively inhibit the growth and metastasis of DDP-resistant ovarian cancer. In combination strategy, heparin could suppress the function of multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) to promote the intracellular accumulation of DDP and Ola by specifically binding with heparanase (HPSE) to down-regulate PI3K/AKT/mTOR signaling pathway, and simultaneously served as a carrier combined with Ola to synergistically enhance the anti-proliferation ability of DDP for resistant ovarian cancer, thus achieving great therapeutic efficacy. Our DDP-Ola@HR could provide a simple and multifunctional combination strategy to trigger an anticipated cascading effect, thus effectively overcoming the chemo-resistance of ovarian cancer.

Self-anti-angiogenesis nanoparticles enhance anti-metastatic-tumor efficacy of chemotherapeutics.

Beyond traditional endothelium-dependent vessel (EDV), vascular mimicry (VM) is another critical tumor angiogenesis that further forms in many malignant metastatic tumors. However, the existing anti-angiogenesis combined chemotherapeutics strategies are only efficient for the treatment of EDV-based subcutaneous tumors, but remain a great challenge for the treatment of in situ malignant metastatic tumor associated with EDV and VM. Here, we demonstrate a self-assembled nanoparticle (VE-DDP-Pro) featuring self-anti-EDV and -VM capacity enables to significantly enhance the treatment efficacy of cisplatin (DDP) against the growth and metastasis of ovarian cancer. The VE-DDP-Pro is constructed by patching DDP loaded cRGD-folate-heparin nanoparticles (VE) onto the surface of protamine (Pro) nanoparticle. We demonstrated the self-anti-angiogenesis capacity of VE-DDP-Pro was attributed to VE, which could significantly inhibit the formation of EDV and VM by regulating signaling pathway of MMP-2/VEGF, AKT/mTOR/MMP-2/Laminin and AKT/mTOR/EMT, facilitating chemotherapeutics to effectively suppress the development and metastasis of ovarian cancer. Thus, combing with the chemotherapeutics effectiveness of DDP, the VE-DDP-Pro can significantly enhance treatment efficacy and prolong median survival of mice with metastatic ovarian cancer. We believe our self-assembled nanoparticles integrating the anti-EDV and anti-VM capacity provide a new preclinical sight to enhance the efficacy of chemotherapeutics for the treatment malignant metastasis tumor.

Lemon-Derived Extracellular Vesicles Nanodrugs Enable to Efficiently Overcome Cancer Multidrug Resistance by Endocytosis-Triggered Energy Dissipation and Energy Production Reduction.

Multidrug resistance remains a great challenge for cancer chemotherapy. Herein, a biomimetic drug delivery system based on lemon-derived extracellular vesicles (EVs) nanodrugs (marked with heparin-cRGD-EVs-doxorubicin (HRED)) is demonstrated, achieving highly efficient overcoming cancer multidrug resistance. The HRED is fabricated by modifying functional heparin-cRGD (HR) onto the surface of EVs and then by loading with doxorubicin (DOX). The obtained HRED enable to effectively enter DOX-resistant cancer cells by caveolin-mediated endocytosis (main), macropinocytosis (secondary), and clathrin-mediated endocytosis (last), exhibiting excellent cellular uptake capacity. The diversified endocytosis capacity of HRED can efficiently dissipate intracellular energy and meanwhile trigger downstream production reduction of adenosine triphosphate (ATP), leading to a significant reduction of drug efflux. Consequently, they show excellent anti-proliferation capacities to DOX-resistant ovarian cancer, ensuring the efficiently overcoming ovarian cancer multidrug resistance in vivo. The authors believe this strategy provides a new strategy by endocytosis triggered-energy dissipation and ATP production reduction to design drug delivery system for overcoming cancer multidrug resistance.

Reconstructable Uterus-Derived Materials for Uterus Recovery toward Efficient Live Births.

Uterine factor infertility is increasingly common in modern society and has severely affected human life and health. However, the existing biomaterial scaffold-mediated systems remain limited in efficient uterus recovery, leading to low pregnancy rate and live births. Here, reconstructable uterus-derived materials (RUMs) are demonstrated by combining uterus-derived extracellular matrix and seeded chorionic villi mesenchymal stem cells for uterus recovery, achieving highly efficient live births in rats with severe uterine injury. The RUMs can be designed into different states (such as, liquid RUMs and solid RUMs) and shapes (such as, cuboid, triangular-prism, and cube) in terms of requirements. The RUMs can effectively prevent intrauterine adhesion, and promote endometrial regeneration and muscle collagen reconstruction, as well as, accelerate wound healing by constructing a physical barrier and secreting cytokines, allowing efficient uterus recovery. The injured uterus nearly achieves complete recovery after treating with the RUMs and has normal pregnancies for supporting fetal development and live births, similar to the normal rats. The study provides a regenerative medicine therapeutics for uterine factor infertility.

Antibiotic Zwitterionic Nanogel Membrane: from Molecular Dynamics Simulation to Structure Manipulation.

Membrane separation has been considered as one of the most revolutionary technologies for the removal of oils, dyes, or other pollutants from wastewater. However, most membranes still face great challenges in water permeability, antifouling property, and even antibiotic ability. Possessing a pathogen-repellent surface is of great significance as it can enable membranes to minimize the presence of active viral pathogens. Herein, we demonstrate a distinct design with a molecular dynamics simulation-guided experiment for the surface domination of antibiotic zwitterionic nanogel membranes. The zwitterionic nanoparticle gel (ZNG)/Cu2+/glutaraldehyde (GA) synergy system is first simulated by introducing a ZNG into a preset CuCl2 brine solution and into a GA ethanol solution, in which the nanogel is observed to initially swell and subsequently shrink with the increase of GA concentration, leading to the membrane surface structure transition. Then, the corresponding experiments are performed under strict conditions, and the results suggest the surface structure transition from nanoparticles to network nanoflowers, which are consistent with the simulated results. The obtained network structure membrane with superhydrophilic and underwater superoleophobic abilities can significantly enhance the water permeability as high as almost 40% with its original rejection rate in comparison with unoptimizable ZNG-PVDF (polyvinylidene difluoride) membranes. Moreover, the obtained membrane achieves additional excellent antibiofouling capacity with the antibiotic efficiency exceeding 99.3%, manifesting remarkable potential for disinfection applications. By comparison, the conventional antibiotic methods generally improve the membrane's antibiotic property solely but can hardly improve the other properties of the membrane. That is to say, our simulation combined with the experimental strategy significantly improved the zwitterionic membrane property in this work, which provides a new perspective on the design of high-performance functional materials.

A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

Interfacial Polymerization: From Chemistry to Functional Materials.

Interfacial polymerization, where a chemical reaction is confined at the liquid-liquid or liquid-air interface, exhibits a strong advantage for the controllable fabrication of films, capsules, and fibers for use as separation membranes and electrode materials. Recent developments in technology and polymer chemistry have brought new vigor to interfacial polymerization. Here, we consider the history of interfacial polymerization in terms of the polymerization types: interfacial polycondensation, interfacial polyaddition, interfacial oxidative polymerization, interfacial polycoordination, interfacial supramolecular polymerization, and some others. The accordingly emerging functional materials are highlighted, as well as the challenges and opportunities brought by new technologies for interfacial polymerization. Interfacial polymerization will no doubt keep on developing and producing a series of fascinating functional materials.

Recent Progress of Microfluidic Devices for Hemodialysis.

Microfluidic hemodialysis techniques have recently attracted great attention in the treatment of kidney disease due to their advantages of portability and wearability as well as their great potential for replacing clinical hospital-centered blood purification with continuous in-home hemodialysis. This Review summarizes the recent progress in microfluidic devices for hemodialysis. First, the history of kidney-inspired hemodialysis is introduced. Then, recent achievements in the preparation of microfluidic devices and hemodialysis nanoporous membrane materials are presented and categorized. Subsequently, attention is drawn to the recent progress of nanoporous membrane-based microfluidic devices for hemodialysis. Finally, the challenges and opportunities of hemodialysis microfluidic devices in the future are also discussed. This Review is expected to provide a comprehensive guide for the design of hemodialysis microfluidic devices that are closely related to clinical applications.

Photo-Irresponsive Molecule-Amplified Cell Release on Photoresponsive Nanostructured Surfaces.

Cell manipulation has raised extensive concern owing to its underlying applications in numerous biological situations such as cell-matrix interaction, tissue engineering, and cell-based diagnosis. Generally, light is considered as a superior candidate for manipulating cells (e.g., cell release) due to their high spatiotemporal precision and non-invasion. However, it remains a big challenge to release cells with high efficiency due to their potential limitation of the light-triggered wettability transition on photoresponsive surfaces. In this study, we report a photoresponsive spiropyran-coated nanostructured surface that enables highly efficient release of cancer cells, amplified by the introduction of a photo-irresponsive molecule. On one hand, structural recognition stems from topological interaction between nanofractal surfaces and the protrusions of cancer cells. On the other, molecular recognition can be amplified by a photo-irresponsive and hydrophilic molecule by reducing the steric hindrance of photoresponsive components and resisting nonspecific cell adhesion. Therefore, this study may afford a novel avenue for developing advanced smart materials for high-quality biological analysis and clinical diagnosis.

Bioinspired Microfluidic Device by Integrating a Porous Membrane and Heterostructured Nanoporous Particles for Biomolecule Cleaning.

Mimicking the structures and functions of biological systems is considered as a promising approach to construct artificial materials, which have great potential in energy, the environment, and health. Here, we demonstrate a conceptually distinct design by synergistically combining a kidney-inspired porous membrane and natural sponge-inspired heterostructured nanoporous particles to fabricate a bioinspired biomolecule cleaning device, achieving highly efficient biomolecule cleaning spanning from small molecules to macromolecules. The bioinspired biomolecule cleaning device is a two-layer microfluidic device that integrates a polyamide porous membrane and heterostructured nanoporous poly(acrylic acid)-poly(styrene divinylbenzene) particles. The former as a filtration membrane isolates the upper sample liquid and the latter fixed onto the bottom of the underlying channel acts as an active sorbent, particularly enhancing the clearance of macromolecules. As a proof-of-concept, we demonstrate that typical molecules, including urea, creatinine, lysozyme, and ß2-microglobulin, can be efficiently cleaned from simulant liquid and even whole blood. This study provides a method to fabricate a bioinspired biomolecule cleaning device for highly efficient biomolecule cleaning. We believe that our bioinspired synergistic design may expand to other fields for the fabrication of integrated functional devices, creating opportunities in a wide variety of applications.

An interfacially polymerized self-healing organo/hydro copolymer with shape memory.

Organo/hydro copolymer materials have recently received significant attention in the fields of energy, environment and healthcare. Herein, we report the fabrication of a robust organo/hydro copolymer with rapid self-healing and shape memory by emulsion interfacial polymerization. The emulsion interfacial polymerization allowed the formation of a crosslinked organo/hydro copolymer with hydrogen-bonded networks, significantly enhancing the mechanical properties; the proposed organo/hydro copolymer substantially outperformed most of the synthetic self-healing polymers based on hydrogen bonding interactions. We showed that the interfacially polymerized organo/hydro copolymer exhibited good self-healing capacity, i.e. achieved self-healing in less than 2 h, with a healing efficiency of 95.6%. Moreover, it presented shape memory, with a complete shape memory time less than 5 min.

pH-Regulated Heterostructure Porous Particles Enable Similarly Sized Protein Separation.

Porous particles are frequently used for various healthcare applications that involve protein separation processes. However, conventional porous particles, either homogeneous particles or those subjected to surface modification with a layer of specific molecules, often encounter bottlenecks in separating proteins with similar size. Here, it is reported that heterostructure-enabled separation particles (HESP), synthesized by a double emulsion interfacial polymerization process, can effectively and rapidly separate similarly sized proteins. Double emulsion interfacial polymerization endows the HESP with a nanoscale carboxylic layer outside the particles and inside the pores, allowing pH-regulated selective adsorption of proteins. Thus, by optimizing the environmental pH, proteins with similar size can be effectively and rapidly separated. These HESP are expected to show potential in widespread applications ranging from biomolecule adsorption, encapsulation, and separation to controlled release and other biomedical fields.

Polyoxometalate-based microcrystal arrays patterned on air-grid superwettable surface.

Surface patterning of polyoxometalates (POMs) is an important step to gain functional materials and devices. However, some special requirements such as complex operation steps or strict synthesis environment greatly limit their further applications. Herein, we have employed a simple and universal strategy for patterning POM-based microcrystal arrays on air-grid superwettable surfaces. The size and distribution of POM crystals were precisely adjusted by varying the pillar parameter of superwettable surface and concentration of POM mother liquid. We envision that this POM patterning method may bring valuable insights for designing POM-based functional materials and devices.

Interfacially Polymerized Particles with Heterostructured Nanopores for Glycopeptide Separation.

Porous polymer materials are extensively used for biomolecule separation. However, conventional homogeneous porous polymer materials cannot efficiently separate specific low-abundance biomolecules from complex samples. Here, particles fabricated by emulsion interfacial polymerization featuring heterostructured nanopores with tunable size are reported, which can be used to realize low-abundance glycopeptide (GP) separation from complex biofluids. The heterostructured surface inside the nanopores allows solvent-dependent local adsorption of biomolecules onto hydrophilic or hydrophobic regions. Low-abundance hydrophilic GPs in complex biofluids can be efficiently separated via the hydrophilic region of nanopores in low-polarity solvent after the hydrophobic region removes high-abundance hydrophobic proteins and non-glycopeptides in high-polarity solvent. It is expected that these particles with heterostructured nanopores can be used for separation of nucleic acids, saccharides, and proteins, and downstream clinical diagnosis.

A general strategy to synthesize chemically and topologically anisotropic Janus particles.

Emulsion polymerization is the most widely used synthetic technique for fabricating polymeric particles. The interfacial tension generated with this technique limits the ability to tune the topology and chemistry of the resultant particles. We demonstrate a general emulsion interfacial polymerization approach that involves introduction of additional anchoring molecules surrounding the microdroplets to synthesize a large variety of Janus particles with controllable topological and chemical anisotropy. This strategy is based on interfacial polymerization mediated by an anchoring effect at the interface of microdroplets. Along the interface of the microdroplets, the diverse topology and surface chemistry features of the Janus particles can be precisely tuned by regulating the monomer type and concentration as well as polymerization time. This method is applicable to a wide variety of monomers, including positively charged, neutrally charged, and negatively charged monomers, thereby enriching the community of Janus particles.