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.

Targeted Repair of Spinal Cord Injury Based on miRNA-124-3p-Loaded Mesoporous Silica Camouflaged by Stem Cell Membrane Modified with Rabies Virus Glycoprotein.

Spinal cord injury (SCI) has no effective treatment modalities. It faces a significant global therapeutical challenge, given its features of poor axon regeneration, progressive local inflammation, and inefficient systemic drug delivery due to the blood-spinal cord barrier (BSCB). To address these challenges, a new nano complex that achieves targeted drug delivery to the damaged spinal cord is proposed, which contains a mesoporous silica nanoparticle core loaded with microRNA and a cloaking layer of human umbilical cord mesenchymal stem cell membrane modified with rabies virus glycoprotein (RVG). The nano complex more readily crosses the damaged BSCB with its exosome-resembling properties, including appropriate size and a low-immunogenic cell membrane disguise and accumulates in the injury center because of RVG, where it releases abundant microRNAs to elicit axon sprouting and rehabilitate the inflammatory microenvironment. Culturing with nano complexes promotes axonal growth in neurons and M2 polarization in microglia. Furthermore, it showed that SCI mice treated with this nano complex by tail vein injection display significant improvement in axon regrowth, microenvironment regulation, and functional restoration. The efficacy and biocompatibility of the targeted delivery of microRNA by nano complexes demonstrate their immense potential as a noninvasive treatment for SCI.

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.

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.

Nanomaterial-Enabled Photothermal Heating and Its Use for Cancer Therapy via Localized Hyperthermia.

Photothermal therapy (PTT), which employs nanoscale transducers delivered into a tumor to locally generate heat upon irradiation with near-infrared light, shows great potential in killing cancer cells through hyperthermia. The efficacy of such a treatment is determined by a number of factors, including the amount, distribution, and dissipation of the generated heat, as well as the type of cancer cell involved. The amount of heat generated is largely controlled by the number of transducers accumulated inside the tumor, the absorption coefficient and photothermal conversion efficiency of the transducer, and the irradiance of the light. The efficacy of treatment depends on the distribution of the transducers in the tumor and the penetration depth of the light. The vascularity and tissue thermal conduction both affect the dissipation of heat and thereby the distribution of temperature. The successful implementation of PTT in the clinic setting critically depends on techniques for real-time monitoring and management of temperature.

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.

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.

Template-Directed Synthesis of Colloidal Hollow Particles: Mind the Material Used for the Template.

The dissolution of a polymeric solid typically starts with the absorption of solvent molecules, followed by swelling and volume expansion. Only when the extent of swelling reaches a threshold can the polymer chains be disentangled and then dissolved into the solvent. When the polymeric solid is encapsulated in a rigid shell, the swelling process will be impeded. Despite the widespread use of this process, it is rarely discussed in the literature how the polymeric solid is dissolved from the core for the generation of colloidal hollow particles. Recent studies have started to shed light on the mechanistic details involved in the formation of hollow particles through a template-directed process. Depending on the nature of the material used for the template, the removal of the template may involve different mechanisms and pathways, leading to the formation of distinct products. Here, a number of examples are used to illustrate this important phenomenon that is largely neglected in the literature. This article also discusses how the swelling of a polymeric template encapsulated in a rigid shell can be leveraged to fabricate new types of functional colloidal particles.

Delivery of miRNAs through Metal-Organic Framework Nanoparticles for Assisting Neural Stem Cell Therapy for Ischemic Stroke.

Stroke is the most common cause of disability globally. Neural stem cell (NSC) therapy, which can replace lost and damaged neurons, has been proposed as a potential treatment for stroke. The therapeutic efficacy of NSC therapy is hindered by the fact that only a small number of NSCs undergo neuronal differentiation. Neuron-specific miR-124, which promotes the differentiation of NSCs into mature neurons, can be combined with NSC therapy to cure ischemic stroke. However, the instability and poor internalization of miR-124 seriously hamper its broad clinical application. Herein, an innovative strategy involving delivery of miR-124 via a Ca-MOF@miR-124 nanodelivery system, which effectively prevents the degradation of miR-124 by nucleases and promotes the internalization of miR-124 by NSCs, is presented. The effect of accelerated neuronal directed differentiation of NSCs was assessed through in vitro cell experiments, and the clinical application potential of this nanodelivery system for the treatment of ischemic stroke was assessed through in vivo experiments involving the combination of NSC therapy and Ca-MOF@miR-124 nanoparticles. The results indicate that Ca-MOF@miR-124 nanoparticles can promote the differentiation of NSCs into mature neurons with electrophysiological function within 5 days. The differentiation rate of cells treated with Ca-MOF@miR-124 nanoparticles was at least 5 days faster than that of untreated cells. Moreover, Ca-MOF@miR-124 nanoparticles decreased the ischemic area to almost normal levels by day 7. The combination of Ca-MOF@miR-124 nanoparticles and NSC therapy will enhance the treatment of traumatic nerve injury and neurodegenerative diseases.

Accelerating Cell Migration along Radially Aligned Nanofibers through the Addition of Electrosprayed Nanoparticles in a Radial Density Gradient.

Scaffolds capable of promoting cell migration from the periphery towards the center along the radial direction hold promises for tissue regeneration. Here we report a simple and general method based on masked electrospray for the fabrication of such scaffolds by depositing collagen nanoparticles on radially-aligned nanofibers in a radial density gradient. Placed between the metallic needle and the collector, an aperture with tunable opening sizes serves as the mask. By increasing the size of the opening at a fixed speed, the electrosprayed particles take a radial density gradient that decreases from the center to the periphery. When deposited on a glass slide, the radial density gradient of collagen nanoparticles promotes the migration of fibroblasts from the periphery towards the center. By replacing the glass slide with a scaffold comprised of radially-aligned nanofibers, a synergetic effect arises to further accelerate cell migration along the radial direction. The synergistic effect can be attributed to a unique combination of the topographic cue arising from the aligned nanofibers and the haptotactic cue enabled by the graded nanoparticles. This work demonstrates a method to maximize cell migration from the periphery towards the center through a combination of topographic and haptotactic cues.

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.

The use of connective tissue growth factor mimics for flexor tendon repair.

Intrasynovial flexor tendon lacerations of the hand are clinically problematic, typically requiring operative repair and extensive rehabilitation. The small-molecule connective tissue growth factor (CTGF) mimics, oxotremorine M (Oxo-M) and 4-PPBP maleate (4-PPBP), have been shown to improve tendon healing in small animal models by stimulating the expansion and differentiation of perivascular CD146+ cells. To enhance intrasynovial flexor tendon healing, small-molecule CTGF mimics were delivered to repaired canine flexor tendons via porous sutures. In vitro studies demonstrated that Oxo-M and 4-PPBP retained their bioactivity and could be released from porous sutures in a sustained manner. However, in vivo delivery of the CTGF mimics did not improve intrasynovial tendon healing. Histologic analyses and expression of tenogenic, extracellular matrix, inflammation, and remodeling genes showed similar outcomes in treated and untreated repairs across two time points. Although in vitro experiments revealed that CTGF mimics stimulated robust responses in extrasynovial tendon cells, there was no response in intrasynovial tendon cells, explaining the lack of in vivo effects. The results of the current study indicate that therapeutic strategies for tendon repair must carefully consider the environment and cellular makeup of the particular tendon for improving the healing response.

Using computational methods to design patient-specific electrospun cardiac patches for pediatric heart failure.

Autologous cardiac cell therapy is a promising treatment for combating the right ventricular heart failure (RVHF) that can occur in patients with congenital heart disease (CHD). However, autologous cell therapies suffer from low cell retention following injection and patient-to-patient variability in cell quality. Here, we demonstrate how computational methods can be used to identify mechanisms of cardiac-derived c-Kit+ cell (CPC) reparative capacity and how biomaterials can be designed to improve cardiac patch performance by engaging these mechanisms. Computational modeling revealed the integrin subunit αV (ITGAV) as an important mediator of repair in CPCs with inherently low reparative capacity (CPCslow). We could engage ITGAV on the cell surface and improve reparative capacity by culturing CPCs on electrospun polycaprolactone (PCL) patches coated with fibronectin (PCL + FN). We tested CPCs from 4 different donors and found that only CPCslow with high ITGAV expression (patient 956) had improved anti-fibrotic and pro-angiogenic paracrine secretion on PCL + FN patches. Further, knockdown of ITGAV via siRNA led to loss of this improved paracrine secretion in patient 956 on PCL + FN patches. When implanted in rat model of RVHF, only PCL + FN + 956 patches were able to improve RV function, while PCL +956 patches did not. In total, we demonstrate how cardiac patches can be designed in a patient-specific manner to improve in vitro and in vivo outcomes.

Bimetallic Janus Nanocrystals: Syntheses and Applications.

Bimetallic Janus nanocrystals have received considerable interest in recent years owing to their unique properties and niche applications. The side-by-side distribution of two distinct metals provides a flexible platform for tailoring the optical and catalytic properties of nanocrystals. First, a brief introduction to the structural features of bimetallic Janus nanocrystals, followed by an extensive discussion of the synthetic approaches, is given. The strategies and experimental controls for achieving the Janus structure, as well as the mechanistic understandings, are specifically discussed. Then, a number of intriguing properties and applications enabled by the Janus nanocrystals are highlighted. Finally, this article is concluded with future directions and outlooks with respect to both syntheses and applications of this new class of functional nanomaterials.

Biomimetic Scaffolds with a Mineral Gradient and Funnel-Shaped Channels for Spatially Controllable Osteogenesis.

A facile method is described herein for generating a mineral gradient in a biodegradable polymer scaffold. The gradient is achieved by swelling a composite film made of polycaprolactone (PCL) and hydroxyapatite (HAp) nanoparticles with a PCL solution. During the swelling process, the solvent and PCL polymer chains diffuse into the composite film, generating a gradient in HAp density at their interface. The thickness of the mineral gradient can be tuned by varying the extent of swelling to match the length scale of the natural tendon-to-bone attachment (20-60 µm). When patterned with an array of funnel-shaped channels, the mineral gradient presents stem cells with spatial gradations in both biochemical cues (e.g., osteoinductivity and conductivity associated with the HAp nanoparticles) and mechanical cues (e.g., substrate stiffness) to stimulate their differentiation into a graded distribution of cell phenotypes. This new class of biomimetic scaffolds holds great promise for facilitating the regeneration of the injured tendon-to-bone attachment by stimulating the formation of a functionally graded interface.

Polydopamine Nanobottles with Photothermal Capability for Controlled Release and Related Applications.

Nanobottles refer to colloidal particles featuring a hollow body connected to a single opening on the surface. This unique feature makes them ideal carriers for the encapsulation and controlled release of various types of cargos. Here a facile route to the fabrication of uniform nanobottles made of polydopamine by leveraging swelling-induced pressure is reported. When polystyrene spheres are coated with polydopamine and then incubated with a toluene/water emulsion, the polystyrene will be swollen to automatically poke a single hole in the shell because of the pressure inside the shell. After quenching the swelling with ethanol and then removing all the polystyrene with tetrahydrofuran, polydopamine nanobottles are obtained. The dimensions of the hollow body are determined by the polystyrene template, while the size of the opening can be tuned by varying the shell thickness. Through the opening, different types of cargos, including small molecules and biomacromolecules, can be easily loaded with a thermoresponsive material into the cavity. The cargos can be released in a controllable manner through direct heating or polydopamine-enabled photothermal heating. In a proof-of-concept experiment, the polydopamine nanobottles are used for temperature-controlled release of thrombin to trigger the formation of fibrin gels in situ.

Swelling-Induced Symmetry Breaking: A Versatile Approach to the Scalable Production of Colloidal Particles with a Janus Structure.

Janus particles are widely sought for applications related to colloidal assembly, stabilization of emulsions, and development of active colloids, among others. Here we report a versatile route to the fabrication of well-controlled Janus particles by simply breaking the symmetry of spherical particles with swelling. When a polystyrene (PS) sphere covered by a rigid shell made of silica or polydopamine is exposed to a good solvent for PS, a gradually increased pressure will be created inside the shell. If the pressure becomes high enough to poke a hole in the shell, the spherical symmetry will break while pushing out the swollen PS through the opening to generate a Janus particle comprised of two distinct components. One of the components is made of PS and its size is controlled by the extent of swelling. The other component is comprised of the rigid shell and remaining PS, with its overall diameter determined by the original PS sphere and the rigid shell. This solution-based route holds promises for the scalable production of complex Janus particles with a variety of compositions and in large quantities.