Branch-Chain-Rich Diisopropyl Ether with Steric Hindrance Facilitates Stable Cycling of Lithium Batteries at - 20 °C.

Li metal batteries (LMBs) offer significant potential as high energy density alternatives; nevertheless, their performance is hindered by the slow desolvation process of electrolytes, particularly at low temperatures (LT), leading to low coulombic efficiency and limited cycle stability. Thus, it is essential to optimize the solvation structure thereby achieving a rapid desolvation process in LMBs at LT. Herein, we introduce branch chain-rich diisopropyl ether (DIPE) into a 2.5 M Li bis(fluorosulfonyl)imide dipropyl ether (DPE) electrolyte as a co-solvent for high-performance LMBs at - 20 °C. The incorporation of DIPE not only enhances the disorder within the electrolyte, but also induces a steric hindrance effect form DIPE's branch chain, excluding other solvent molecules from Li+ solvation sheath. Both of these factors contribute to the weak interactions between Li+ and solvent molecules, effectively reducing the desolvation energy of the electrolyte. Consequently, Li (50 µm)||LFP (mass loading ~ 10 mg cm-2) cells in DPE/DIPE based electrolyte demonstrate stable performance over 650 cycles at - 20 °C, delivering 87.2 mAh g-1, and over 255 cycles at 25 °C with 124.8 mAh g-1. DIPE broadens the electrolyte design from molecular structure considerations, offering a promising avenue for highly stable LMBs at LT.

Anti-Stress and Anti-ROS Effects of MnOx-Functionalized Thermosensitive Nanohydrogel Protect BMSCs for Intervertebral Disc Degeneration Repair.

Stem cell transplantation has been proven to be a promising strategy for intervertebral disc degeneration (IDD) repair. However, replicative senescence of bone marrow-derived mesenchymal stem cells (BMSCs), shear damage during direct injection, mechanical stress, and the reactive oxygen species (ROS)-rich microenvironment in degenerative intervertebral discs (IVDs) cause significant cellular damage and limit the therapeutic efficacy. Here, an injectable manganese oxide (MnOx)-functionalized thermosensitive nanohydrogel was proposed for BMSC transplantation for IDD therapy. The MnOx-functionalized thermosensitive nanohydrogel not only successfully protected BMSCs from shear force and mechanical stress before and after injection but also repaired the harsh high-ROS environment in degenerative IVDs, thus effectively increasing the viability of BMSCs and resident nucleus pulposus cells (NPCs). The MnOx-functionalized thermosensitive nanohydrogel provides mechanical protection for stem cells and helps to remove endogenous ROS, providing a promising stem cell delivery platform for the treatment of IDD. This article is protected by copyright. All rights reserved.

Ultrasmall Fe3O4 nanoparticles self-assembly induced dual-mode T1/T2-weighted magnetic resonance imaging and enhanced tumor synergetic theranostics.

Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective treatment, which endow the providential treatment and avoid the repeated medication with side effects. However, it is difficult to achieve the integrated strategy of MRI and therapeutic drug due to complicated synthesis route, low efficiency and potential biosafety issues. In this study, novel self-assembled ultrasmall Fe3O4 nanoclusters were developed for tumor-targeted dual-mode T1/T2-weighted magnetic resonance imaging (MRI) guided synergetic chemodynamic therapy (CDT) and chemotherapy. The self-assembled ultrasmall Fe3O4 nanoclusters synthesized by facilely modifying ultrasmall Fe3O4 nanoparticles with 2,3-dimercaptosuccinic acid (DMSA) molecule possess long-term stability and mass production ability. The proposed ultrasmall Fe3O4 nanoclusters shows excellent dual-mode T1 and T2 MRI capacities as well as favorable CDT ability due to the appropriate size effect and the abundant Fe ion on the surface of ultrasmall Fe3O4 nanoclusters. After conjugation with the tumor targeting ligand Arg-Gly-Asp (RGD) and chemotherapy drug doxorubicin (Dox), the functionalized Fe3O4 nanoclusters achieve enhanced tumor accumulation and retention effects and synergetic CDT and chemotherapy function, which serve as a powerful integrated theranostic platform for cancer treatment.

Dynamic Hybrid Module-Driven NK Cell Stimulation and Release for Tumor Immunotherapy.

Natural killer (NK) cells have become a powerful candidate for adoptive tumor immunotherapy, while their therapeutic efficacy in solid tumors remains unsatisfactory. Here, we developed a hybrid module with an injectable hydrogel and hydroxyapatite (HAp) nanobelts for the controlled delivery of NK cells to enhance the therapy of solid tumors. Surface-functionalized HAp nanobelts modified with agonistic antibodies against NKG2D and 4-1BB and cytokines IL-2 and IL-21 support survival and dynamic activation. Thus, the HAp-modified chitosan (CS) thermos-sensitive hydrogel not only improved the retention of NK cells for more than 20 days in vivo but also increased NK cell function by more than one-fold. The unique architecture of this biomaterial complex protects NK cells from the hostile tumor environment and improves antitumor efficacy. The generation of a transient inflammatory niche for NK cells through a biocompatible hydrogel reservoir may be a conversion pathway to prevent cancer recurrence of resectable tumors.

Generation of a Hydrophobic Protrusion on Nanoparticles to Improve the Membrane-Anchoring Ability and Cellular Internalization.

Controlling the nanoparticle-cell membrane interaction to achieve easy and fast membrane anchoring and cellular internalization is of great importance in a variety of biomedical applications. Here we report a simple and versatile strategy to maneuver the nanoparticle-cell membrane interaction by creating a tunable hydrophobic protrusion on Janus particles through swelling-induced symmetry breaking. When the Janus particle contacts cell membrane, the protrusion will induce membrane wrapping, leading the particles to docking to the membrane, followed by drawing the whole particles into the cell. The efficiencies of both membrane anchoring and cellular internalization can be promoted by optimizing the size of the protrusion. In vitro, the Janus particles can quickly anchor to the cell membrane in 1 h and be internalized within 24 h, regardless of the types of cells involved. In vivo, the Janus particles can effectively anchor to the brain and skin tissues to provide a high retention in these tissues after intracerebroventricular, intrahippocampal, or subcutaneous injection. This strategy involving the creation of a hydrophobic protrusion on Janus particles to tune the cell-membrane interaction holds great potential in nanoparticle-based biomedical applications.

Mnox Nanoenzyme Armed CAR-NK Cells Enhance Solid Tumor Immunotherapy by Alleviating the Immunosuppressive Microenvironment.

Adoptively transferred cells usually suffer from exhaustion, limited expansion, and poor infiltration, partially attributing to the complicated immunosuppressive microenvironment of solid tumors. Therefore, it is necessary to explore more effective strategies to improve the poor tumor microenvironment (TME) to efficaciously deliver and support extrinsic effector cells in vivo. Herein, an intelligent biodegradable hollow manganese dioxide nanoparticle (MnOX) that possesses peroxidase activity to catalyze excess H2O2 in the TME to produce oxygen and relieve the hypoxia of solid tumors is developed. MnOX nanoenzymes modified with CD56 antibody could specifically bind CAR-NK (chimeric antigen receptor modified natural killer) cells. It is demonstrated that CAR-NK cells incorporated with MnOX nanoenzymes effectively infiltrate into tumor tissues with an improved TME, which results in superior antitumor activity in solid tumor-bearing mice. The antibody connection between MnOX nanoenzymes and CAR-NK endows the lowest efficient dosage of MnOX. This study features a smart synergistic immunotherapy approach for solid tumors using MnOX nanoenzyme-armed CAR-NK cells, which would provide a valuable tool for immunocyte therapy in solid tumors.

Microfluidic Platforms for Real-Time In Situ Monitoring of Biomarkers for Cellular Processes.

Cellular processes are mechanisms carried out at the cellular level that are aimed at guaranteeing the stability of the organism they comprise. The investigation of cellular processes is key to understanding cell fate, understanding pathogenic mechanisms, and developing new therapeutic technologies. Microfluidic platforms are thought to be the most powerful tools among all methodologies for investigating cellular processes because they can integrate almost all types of the existing intracellular and extracellular biomarker-sensing methods and observation approaches for cell behavior, combined with precisely controlled cell culture, manipulation, stimulation, and analysis. Most importantly, microfluidic platforms can realize real-time in situ detection of secreted proteins, exosomes, and other biomarkers produced during cell physiological processes, thereby providing the possibility to draw the whole picture for a cellular process. Owing to their advantages of high throughput, low sample consumption, and precise cell control, microfluidic platforms with real-time in situ monitoring characteristics are widely being used in cell analysis, disease diagnosis, pharmaceutical research, and biological production. This review focuses on the basic concepts, recent progress, and application prospects of microfluidic platforms for real-time in situ monitoring of biomarkers in cellular processes.

Insight into interface electronic structure of ZnIn2S4/TiO2 heterostructure for enhanced photoelectrochemical glycerol oxidation.

Developing a high-efficiency photoelectrochemical (PEC) electrode for the glycerol oxidation reaction (GOR) is important for producing valuable products. The PEC performance could be enhanced by rationally designing heterostructures with inhibited recombination of charge carriers. Nevertheless, the interface electronic structure of heterostructures has not been comprehensively analyzed. In this work, the PEC GOR performance of ZnIn2S4/TiO2 heterostructure photoanode showed 1.7 folds enhancement than that of pure TiO2 photoanode at 1.23 V vs. RHE. The ZnIn2S4/TiO2 heterostructure was simulated by constructing ZnIn2S4 on the TiO2 single crystal, which was beneficial for investigating the interface electronic structure of heterostructure. Single-particle spectroscopy demonstrated a significantly increased lifetime of charge carriers. Combined with the in-situ X-ray photoelectron spectroscopy, Kelvin probe force microscopy, work function, and electron paramagnetic resonance, the interface electronic structure of the ZnIn2S4/TiO2 heterostructure was proposed with a Z-scheme mechanism. This work provides a comprehensive strategy for analyzing the interface electronic structure of heterostructures.

CD44 and HAP-Conjugated hADSCs as Living Materials for Targeted Tumor Therapy and Bone Regeneration.

Combining targeted tumor therapy with tissue regeneration represents a promising strategy for synergistic tumor therapy. In this study, a multifunctional living material is constructed with human-derived adipose stem cells (hADSCs) and antibody-modified hydroxyapatite nanorods (nHAP) for targeted drug delivery and bone regeneration following surgery. The living material delivers the therapeutics to the tumor site efficiently based on the strength of the inherent tumor tropism of hADSCs. The bioconjugation of nHAP with hADSCs via specific antibody modification is found to be biocompatible, even when loaded with the chemotherapeutic drug doxorubicin (Dox). The endocytosis of nHAP stimulates the osteogenic differentiation of hADSCs, promoting bone tissue regeneration. Moreover, the antibody-modified nHAP-hADSC conjugate exhibits targeted tumor delivery, which is further facilitated by pH-triggered release of Dox, inducing apoptosis of tumor cells with low toxicity to healthy tissues. Therefore, the present study provides a general strategy for engineering living materials to achieve targeted tumor therapy and bone tissue regeneration after surgery, which can be extended to other disease types.

Trimanganese Tetroxide Nanozyme protects Cartilage against Degeneration by Reducing Oxidative Stress in Osteoarthritis.

Osteoarthritis, a chronic degenerative cartilage disease, is the leading cause of movement disorders among humans. Although the specific pathogenesis and associated mechanisms remain unclear, oxidative stress-induced metabolic imbalance in chondrocytes plays a crucial role in the occurrence and development of osteoarthritis. In this study, a trimanganese tetroxide (Mn3 O4 ) nanozyme with superoxide dismutase (SOD)-like and catalase (CAT)-like activities is designed to reduce oxidative stress-induced damage and its therapeutic effect is investigated. In vitro, Mn3 O4 nanozymes are confirmed to reprogram both the imbalance of metabolism in chondrocytes and the uncontrolled inflammatory response stimulated by hydrogen peroxide. In vivo, a cross-linked chondroitin sulfate (CS) hydrogel is designed as a substrate for Mn3 O4 nanozymes to treat osteoarthritis in mouse models. As a result, even in the early stage of OA (4 weeks), the therapeutic effect of the Mn3 O4 @CS hydrogel is observed in both cartilage metabolism and inflammation. Moreover, the Mn3 O4 @CS hydrogel maintained its therapeutic effects for at least 7 days, thus revealing a broad scope for future clinical applications. In conclusion, these results suggest that the Mn3 O4 @CS hydrogel is a potentially effective therapeutic treatment for osteoarthritis, and a novel therapeutic strategy for osteoarthritis based on nanozymes is proposed.

Mesoporous Silica Promotes Osteogenesis of Human Adipose-Derived Stem Cells Identified by a High-Throughput Microfluidic Chip Assay.

Silicon-derived biomaterials are conducive to regulating the fate of osteo-related stem cells, while their effects on the osteogenic differentiation of human adipose-derived stem cells (hADSCs) remain inconclusive. Mesoporous silica (mSiO2) is synthesized in a facile route that exhibited the capability of promoting osteogenic differentiation of hADSCs. The metabolism of SiO2 in cells is proposed according to the colocalization fluorescence analysis between lysosomes and nanoparticles. The released silicon elements promote osteogenic differentiation. The detection of secretory proteins through numerous parallel experiments performed via a microfluidic chip confirms the positive effect of SiO2 on the osteogenic differentiation of hADSCs. Moreover, constructed with superparamagnetic iron oxide (Fe3O4), the magnetic nanoparticles (MNPs) of Fe3O4@mSiO2 endow the cells with magnetic resonance imaging (MRI) properties. The MNP-regulated osteogenic differentiation of autologous adipose-derived stem cells provides considerable clinical application prospects for stem cell therapy of bone tissue repair with an effective reduction in immune rejection.

Ferroelectric Domain Reversal Dynamics in LiNbO3 Optical Superlattice Investigated with a Real-Time Monitoring System.

The optical superlattice structure derived from a periodic poling process endows ferroelectric crystals with tunable optical property regulation, which has become one of the most efficient strategies for fabricating high-efficiency optical devices. Achieving a precise superlattice structure has been the main barrier for preparation of specific optical applications due to the unclear dynamics of domain structure regulation. Herein, a real-time monitoring system for the in situ observation of periodic poling of lithium niobate is established to investigate ferroelectric domain reversal dynamics. The formation of reversed domain nuclei, growth, and expansion of the domain are monitored, which is highly related to domain growth dynamics. The nucleation and growth of domain are discussed combined with the monition of domain reversal and the variation of local electric field distribution along with finite element analysis. An electrode configuration with multiholes is proposed to use the local electric field more efficiently and controllably, which could achieve a higher domain nucleus density with high uniformity. Two-mm-thick periodically poled LiNbO3 crystals with high quality are achieved. A nonlinear light conversion from 1064.2 to 3402.4 nm is realized by the single-resonance optical parameter oscillator with a nonlinear optical efficiency up to 26.2%.

Gold Nanostrip Array-Mediated Wireless Electrical Stimulation for Accelerating Functional Neuronal Differentiation.

Neural stem cell (NSC)-based therapy holds great promise for the treatment of neurodegenerative diseases. Presently, however, it is hindered by poor functional neuronal differentiation. Electrical stimulation is considered one of the most effective ways to promote neuronal differentiation of NSCs. In addition to surgically implanted electrodes, traditional electrical stimulation includes wires connected to the external power supply, and an additional surgery is required to remove the electrodes or wires following stimulation, which may cause secondary injuries and infections. Herein, a novel method is reported for generation of wireless electrical signals on an Au nanostrip array by leveraging the effect of electromagnetic induction under a rotating magnetic field. The intensity of the generated electrical signals depends on the rotation speed and magnetic field strength. The Au nanostrip array-mediated electric stimulation promotes NSC differentiation into mature neurons within 5 days, at the mRNA, protein, and function levels. The rate of differentiation is faster by at least 5 days than that in cells without treatment. The Au nanostrip array-based wireless device also accelerates neuronal differentiation of NSCs in vivo. The novel method to accelerate the neuronal differentiation of NSCs has the advantages of wireless, timely, localized and precise controllability, and noninvasive power supplementation.

Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.

Glioblastoma (GBM) is one of the most fatal central nervous system tumors and lacks effective or sufficient therapies. Ferroptosis is a newly discovered method of programmed cell death and opens a new direction for GBM treatment. However, poor blood-brain barrier (BBB) penetration, reduced tumor targeting ability, and potential compensatory mechanisms hinder the effectiveness of ferroptosis agents during GBM treatment. Here, a novel composite therapeutic platform combining the magnetic targeting features and drug delivery properties of magnetic nanoparticles with the BBB penetration abilities and siRNA encapsulation properties of engineered exosomes for GBM therapy is presented. This platform can be enriched in the brain under local magnetic localization and angiopep-2 peptide-modified engineered exosomes can trigger transcytosis, allowing the particles to cross the BBB and target GBM cells by recognizing the LRP-1 receptor. Synergistic ferroptosis therapy of GBM is achieved by the combined triple actions of the disintegration of dihydroorotate dehydrogenase and the glutathione peroxidase 4 ferroptosis defense axis with Fe3 O4 nanoparticle-mediated Fe2+ release. Thus, the present findings show that this system can serve as a promising platform for the treatment of glioblastoma.

Osteogenic Property Regulation of Stem Cells by a Hydroxyapatite 3D-Hybrid Scaffold With Cancellous Bone Structure.

Cancellous bone plays an indispensable role in the skeletal system due to its various functions and high porosity. In this work, chitosan and hydroxyapatite nanowires (CS@HAP NWs) hybrid nanostructured scaffolds with suitable mechanical properties, high porosity and a fine porous structure were prepared to simulate the 3-dimensional structure of cancellous bone. The 3D-hybrid scaffolds promote cell adhesion and the migration of human adipose-derived stem cells (hADSCs) inside the scaffolds. The cavities in the scaffolds provide space for the hADSCs proliferation and differentiation. Moreover, the various contents of HAP and the induced mechanical property changes regulate the differentiation of hADSCs toward osteoblasts. Overall, cellular fate regulation of hADSCs via rationally engineered HAP-based hybrid scaffolds is a facile and effective approach for bone tissue engineering.

Surface specifically modified NK-92 cells with CD56 antibody conjugated superparamagnetic Fe3O4 nanoparticles for magnetic targeting immunotherapy of solid tumors.

Although there has been significant progress in the development of tumor immunotherapies, many challenges still exist for the treatment of solid tumors. Natural killer (NK) cells possess broad-spectrum cytotoxicity against tumors, but their limited migration and infiltration abilities restrict their application in solid tumor therapies. Here, we combined a facile and efficient magnetic-targeting strategy with NK cell-based therapy to develop a novel immunotherapy approach for treating solid tumors. Anti-CD56 antibodies were conjugated with Fe3O4 nanoparticles, which could specifically bind with NK-92 cells endowing them with a magnetic field driven targeting ability. These NK-Fe3O4 biohybrid nanoparticles were able to facilitate directional migration to the tumor site in vivo under external magnetic field guidance and efficiently inhibit tumor growth. These functionalized NK cells represent a novel approach for solid tumor therapy and may provide a promising modality for cancer interventions in the future.

Regulation of stem cell fate using nanostructure-mediated physical signals.

One of the major issues in tissue engineering is regulation of stem cell differentiation toward specific lineages. Unlike biological and chemical signals, physical signals with adjustable properties can be applied to stem cells in a timely and localized manner, thus making them a hot topic for research in the fields of biomaterials, tissue engineering, and cell biology. According to the signals sensed by cells, physical signals used for regulating stem cell fate can be classified into six categories: mechanical, light, thermal, electrical, acoustic, and magnetic. In most cases, external macroscopic physical fields cannot be used to modulate stem cell fate, as only the localized physical signals accepted by the surface receptors can regulate stem cell differentiation via nanoscale fibrin polysaccharide fibers. However, surface receptors related to certain kinds of physical signals are still unknown. Recently, significant progress has been made in the development of functional materials for energy conversion. Consequently, localized physical fields can be produced by absorbing energy from an external physical field and subsequently releasing another type of localized energy through functional nanostructures. Based on the above concepts, we propose a methodology that can be utilized for stem cell engineering and for the regulation of stem cell fate via nanostructure-mediated physical signals. In this review, the combined effect of various approaches and mechanisms of physical signals provides a perspective on stem cell fate promotion by nanostructure-mediated physical signals. We expect that this review will aid the development of remote-controlled and wireless platforms to physically guide stem cell differentiation both in vitro and in vivo, using optimized stimulation parameters and mechanistic investigations while driving the progress of research in the fields of materials science, cell biology, and clinical research.

3D-printed titanium implant combined with interleukin 4 regulates ordered macrophage polarization to promote bone regeneration and angiogenesis.

AIMS: The use of 3D-printed titanium implant (DT) can effectively guide bone regeneration. DT triggers a continuous host immune reaction, including macrophage type 1 polarization, that resists osseointegration. Interleukin 4 (IL4) is a specific cytokine modulating osteogenic capability that switches macrophage polarization type 1 to type 2, and this switch favours bone regeneration. METHODS: IL4 at concentrations of 0, 30, and 100 ng/ml was used at day 3 to create a biomimetic environment for bone marrow mesenchymal stromal cell (BMMSC) osteogenesis and macrophage polarization on the DT. The osteogenic and immune responses of BMMSCs and macrophages were evaluated respectively. RESULTS: DT plus 30 ng/ml of IL4 (DT + 30 IL4) from day 3 to day 7 significantly (p < 0.01) enhanced macrophage type 2 polarization and BMMSC osteogenesis compared with the other groups. Local injection of IL4 enhanced new bone formation surrounding the DT. CONCLUSION: DT + 30 IL4 may switch macrophage polarization at the appropriate timepoints to promote bone regeneration. Cite this article: Bone Joint Res 2021;10(7):411-424.

Wireless Localized Electrical Stimulation Generated by an Ultrasound-Driven Piezoelectric Discharge Regulates Proinflammatory Macrophage Polarization.

Proinflammatory (M1) macrophages play a vital role in antitumor immunity, and regulation of proinflammatory macrophage polarization is critical for immunotherapy. The polarization of macrophages can be regulated by biological or chemical stimulation, but investigations of the regulatory effect of physical stimulation are limited. Herein, regulating macrophage polarization with localized electrical signals derived from a piezoelectric ß-phase poly(vinylidene fluoride) (ß-PVDF) film in a wireless mode is proposed. Charges released on the surface of the ß-PVDF film driven by ultrasonic irradiation can significantly enhance the M1 polarization of macrophages. Mechanistic investigation confirms that electrical potentials rather than reactive oxygen species and mechanical forces enable Ca2+ influx through voltage-gated channels and establishment of the Ca2+-CAMK2A-NF-κB axis to promote the proinflammatory macrophage response during ultrasound treatment. Piezoelectric material-mediated electrical signal-activated proinflammatory macrophages significantly inhibit tumor cell proliferation. A method for electrogenetic regulation of immune cells as well as a powerful tool for engineering macrophages for immunotherapy is provided here.

Hydroxyapatite Nanorods Function as Safe and Effective Growth Factors Regulating Neural Differentiation and Neuron Development.

Neural stem cell (NSC) transplantation is one of the most promising therapeutic strategies for neurodegenerative diseases. However, the slow spontaneous differentiation of NSCs often hampers their application in neural repair. Although some biological growth factors accelerate the differentiation of NSCs, their high cost, short half-life, and unpredictable behavior in vivo, as well as the complexity of the operation, hinder their clinical use. In this study, it is demonstrated that hydroxyapatite (HAp), the main component of bone, in the form of nanorods, can regulate the neural differentiation of NSCs and maturation of the newly differentiated cells. Culturing NSCs with HAp nanorods leads to the differentiation of NSCs into mature neurons that exhibit well-defined electrophysiological behavior within 5 days. The state of these neurons is much better than when culturing the cells without HAp nanorods, which undergo a 2-week differentiation process. Furthermore, RNA-sequencing data reveal that the neuroactive ligand-receptor interaction pathway is dominant in the enriched differentiated neuronal population. Hence, inorganic growth factors like HAp act as a feasible, effective, safe, and practical tool for regulating the differentiation of NSCs and can potentially be used in the treatment of neurodegenerative diseases.