Drop to Gate Nasal Drops Attenuates Sepsis-Induced Cognitive Dysfunction.

Nasal administration can bypass the blood-brain barrier and directly deliver drugs to the brain, providing a non-invasive route for central nervous system (CNS) diseases. Inspired by the appearance that a gate can block the outside world and the characteristics of the sol-gel transition can form a "gate" in the nasal cavity, a Drop to Gate nasal drop (DGND) is designed to set a gate in nose, which achieves protecting role from the influence of nasal environment. The DGND demonstrates the efficiency and application prospect of delivering drugs to the brain through the N-to-B. The effective concentration of single administration is increased through the hydrophobic interaction between C8-GelMA and SRT1720 (SA), and then cross-linked under UV to form nanogel, which can respond to MMP in the inflammatory microenvironment of sepsis-induced cognitive dysfunction. Finally, the SA/nanogel is compounded into the thermogel, which can respond to the nasal cavity temperature to form DGND in situ, increasing the residence time and delivery efficiency of drugs in the nasal cavity. In vitro, the DGND alleviates lipopolysaccharides (LPS)-induced BV2 inflammation. In vivo, DGND effectively targets the nasal mucosa and deliver drugs to the brain, which activate Sirt1 to alleviate inflammation mediated by microglia and improve cognitive dysfunction in sepsis mice.

Prevented Cell Clusters' Migration Via Microdot Biomaterials for Inhibiting Scar Adhesion.

Cluster-like collective cell migration of fibroblasts is one of the main factors of adhesion in injured tissues. In this research, a microdot biomaterial system is constructed using α-helical polypeptide nanoparticles and anti-inflammatory micelles, which are prepared by ring-opening polymerization of α-amino acids-N-carboxylic anhydrides (NCAs) and lactide, respectively. The microdot biomaterial system slowly releases functionalized polypeptides targeting mitochondria and promoting the influx of extracellular calcium ions under the inflammatory environment, thus inhibiting the expression of N-cadherin mediating cell-cell interaction, and promoting apoptosis of cluster fibroblasts, synergistically inhibiting the migration of fibroblast clusters at the site of tendon injury. Meanwhile, the anti-inflammatory micelles are celecoxib (Cex) solubilized by PEG/polyester, which can improve the inflammatory microenvironment at the injury site for a long time. In vitro, the microdot biomaterial system can effectively inhibit the migration of the cluster fibroblasts by inhibiting the expression of N-cadherin between cell-cell and promoting apoptosis. In vivo, the microdot biomaterial system can promote apoptosis while achieving long-acting anti-inflammation effects, and reduce the expression of vimentin and α-smooth muscle actin (α-SMA) in fibroblasts. Thus, this microdot biomaterial system provides new ideas for the prevention and treatment of tendon adhesion by inhibiting the cluster migration of fibroblasts.

Periodic static compression of micro-strain pattern regulates endochondral bone formation.

Introduction: Developmental engineering based on endochondral ossification has been proposed as a potential strategy for repairing of critical bone defects. Bone development is driven by growth plate-mediated endochondral ossification. Under physiological conditions, growth plate chondrocytes undergo compressive forces characterized by micro-mechanics, but the regulatory effect of micro-mechanical loading on endochondral bone formation has not been investigated. Methods: In this study, a periodic static compression (PSC) model characterized by micro-strain (with 0.5% strain) was designed to clarify the effects of biochemical/mechanical cues on endochondral bone formation. Hydrogel scaffolds loaded with bone marrow mesenchymal stem cells (BMSCs) were incubated in proliferation medium or chondrogenic medium, and PSC was performed continuously for 14 or 28 days. Subsequently, the scaffold pretreated for 28 days was implanted into rat femoral muscle pouches and femoral condylar defect sites. The chondrogenesis and bone defect repair were evaluated 4 or 10 weeks post-operation. Results: The results showed that PSC stimulation for 14 days significantly increased the number of COL II positive cells in proliferation medium. However, the chondrogenic efficiency of BMSCs was significantly improved in chondrogenic medium, with or without PSC application. The induced chondrocytes (ichondrocytes) spontaneously underwent hypertrophy and maturation, but long-term mechanical stimulation (loading for 28 days) significantly inhibited hypertrophy and mineralization in ichondrocytes. In the heterotopic ossification model, no chondrocytes were found and no significant difference in terms of mineral deposition in each group; However, 4 weeks after implantation into the femoral defect site, all scaffolds that were subjected to biochemical/mechanical cues, either solely or synergistically, showed typical chondrocytes and endochondral bone formation. In addition, simultaneous biochemical induction/mechanical loading significantly accelerated the bone regeneration. Discussion: Our findings suggest that microstrain mechanics, biochemical cues, and in vivo microenvironment synergistically regulate the differentiation fate of BMSCs. Meanwhile, this study shows the potential of micro-strain mechanics in the treatment of critical bone defects.

Four-dimensional hydrogel dressing adaptable to the urethral microenvironment for scarless urethral reconstruction.

The harsh urethral microenvironment (UME) after trauma severely hinders the current hydrogel-based urethral repair. In fact, four-dimensional (4D) consideration to mimic time-dependent physiological processes is essential for scarless urethral reconstruction, which requires balancing extracellular matrix (ECM) deposition and remodeling at different healing stages. In this study, we develop a UME-adaptable 4D hydrogel dressing to sequentially provide an early-vascularized microenvironment and later-antifibrogenic microenvironment for scarless urethral reconstruction. With the combination of dynamic boronic ester crosslinking and covalent photopolymerization, the resultant gelatin methacryloyl phenylboronic acid/cis-diol-crosslinked (GMPD) hydrogels exhibit mussel-mimetic viscoelasticity, satisfactory adhesion, and acid-reinforced stability, which can adapt to harsh UME. In addition, a temporally on-demand regulatory (TOR) technical platform is introduced into GMPD hydrogels to create a time-dependent 4D microenvironment. As a result, physiological urethral recovery is successfully mimicked by means of an early-vascularized microenvironment to promote wound healing by activating the vascular endothelial growth factor (VEGF) signaling pathway, as well as a later-antifibrogenic microenvironment to prevent hypertrophic scar formation by timing transforming growth factor-ß (TGFß) signaling pathway inhibition. Both in vitro molecular mechanisms of the physiological healing process and in vivo scarless urethral reconstruction in a rabbit model are effectively verified, providing a promising alternative for urethral injury treatment.

Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy.

The response rate of pancreatic cancer to chemotherapy or immunotherapy pancreatic cancer is low. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for irresectable pancreatic cancers, the immunosuppressive tumour microenvironment that characterizes this tumour type enables tumour recurrence. Thus, strengthening endogenous adaptive antitumour immunity is critical for improving the outcome of ablation therapy and post-ablation immune therapy. Here we present a hydrogel microsphere vaccine that amplifies post-ablation anti-cancer immune response via releasing its cargo of FLT3L and CD40L at the relatively lower pH of the tumour bed. The vaccine facilitates migration of the tumour-resident type 1 conventional dendritic cells (cDC1) to the tumour-draining lymph nodes (TdLN), thus initiating the cDC1-mediated antigen cross-presentation cascade, resulting in enhanced endogenous CD8+ T cell response. We show in an orthotopic pancreatic cancer model in male mice that the hydrogel microsphere vaccine transforms the immunologically cold tumour microenvironment into hot in a safe and efficient manner, thus significantly increasing survival and inhibiting the growth of distant metastases.

Mechanical Signal-Tailored Hydrogel Microspheres Recruit and Train Stem Cells for Precise Differentiation.

The aberrant mechanical microenvironment in degenerated tissues induces misdirection of cell fate, making it challenging to achieve efficient endogenous regeneration. Herein, a hydrogel microsphere-based synthetic niche with integrated cell recruitment and targeted cell differentiation properties via mechanotransduction is constructed . Through the incorporation of microfluidics and photo-polymerization strategies, fibronectin (Fn) modified methacrylated gelatin (GelMA) microspheres are prepared with the independently tunable elastic modulus (1-10Kpa) and ligand density (2 and 10 µg mL-1 ), allowing a wide range of cytoskeleton modulation to trigger the corresponding mechanobiological signaling. The combination of the soft matrix (2Kpa) and low ligand density (2 µg mL-1 ) can support the nucleus pulposus (NP)-like differentiation of intervertebral disc (IVD) progenitor/stem cells by translocating Yes-associated protein (YAP), without the addition of inducible biochemical factors. Meanwhile, platelet-derived growth factor-BB (PDGF-BB) is loaded onto Fn-GelMA microspheres (PDGF@Fn-GelMA) via the heparin-binding domain of Fn to initiate endogenous cell recruitment. In in vivo experiments, hydrogel microsphere-niche maintained the IVD structure and stimulated matrix synthesis. Overall, this synthetic niche with cell recruiting and mechanical training capabilities offered a promising strategy for endogenous tissue regeneration.

Motion lubrication suppressed mechanical activation via hydrated fibrous gene patch for tendon healing.

Mechanical activation of fibroblasts, caused by friction and transforming growth factor-ß1 recognition, is one of the main causes of tissue adhesions. In this study, we developed a lubricated gene-hydrogel patch, which provides both a motion lubrication microenvironment and gene therapy. The patch's outer layer is composed of polyethylene glycol polyester hydrogel. The hydrogel forms hydrogen bonds with water molecules to create the motion lubrication layer, and it also serves as a gene delivery library for long-term gene silencing. Under the motion lubricated microenvironment, extracellular signal-regulated kinase-small interfering RNA can silence fibroblasts and enhance the blocking effect against fibroblast activation. In vitro, the proposed patch effectively inhibits fibroblast activation and reduces the coefficient of friction. In vivo, this patch reduces the expression of vimentin and α-smooth muscle actin in fibroblasts. Therefore, the lubricated gene-hydrogel patch can inhibit the mechanical activation of fibroblasts to promote tendon healing.

Injectable heat-sensitive nanocomposite hydrogel for regulating gene expression in the treatment of alcohol-induced osteonecrosis of the femoral head.

For repairing lesions, it is important to recover physiological and cellular activities. Gene therapy can restore these activities by regulating the expression of genes in lesion cells; however, in chronic diseases, such as alcohol-induced osteonecrosis of the femoral head (ONFH), gene therapy has failed to provide long-term effects. In this study, we developed a heat-sensitive nanocomposite hydrogel system with a secondary nanostructure that can regulate gene expression and achieve long-term gene regulation in lesion cells. This nanocomposite hydrogel exists in a liquid state at 25 °C and is injectable. Once injected into the body, the hydrogel can undergo solidification induced by body heat, thereby gaining the ability to be retained in the body for a prolonged time period. With the gradual degradation of the hydrogel in vivo, the internal secondary nanostructures are continuously released. These nanoparticles carry plasmids and siRNA into lesion stem cells to promote the expression of B-cell lymphoma 2 (inhibiting the apoptosis of stem cells) and inhibit the secretion of peroxisome proliferators-activated receptors γ (PPARγ, inhibiting the adipogenic differentiation of stem cells). Finally, the physiological activity of the stem cells in the ONFH area was restored and ONFH repair was promoted. In vivo experiments demonstrated that this nanocomposite hydrogel can be indwelled for a long time, thereby providing long-term treatment effects. As a result, bone reconstruction occurs in the ONFH area, thus enabling the treatment of alcohol-induced ONFH. Our nanocomposite hydrogel provides a novel treatment option for alcohol-related diseases and may serve as a useful biomaterial for other gene therapy applications.

Regulated extravascular microenvironment via reversible thermosensitive hydrogel for inhibiting calcium influx and vasospasm.

Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature, leading to tissue necrosis. The timely discovery and synchronized treatment become pivotal. In this study, a reversible, intelligent, responsive thermosensitive hydrogel system is constructed employing both the gel-sol transition and the sol-gel transition. The "reversible thermosensitive (RTS)" hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvironment by inhibiting extracellular calcium influx. After accurate implantation and following in situ gelation, the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue temperature drops to the predetermined transition temperature. Subsequent restoration of the blood supply alleviates further tissue injury. Before the temperature drops, the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm. The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells, mice mesenteric arterial rings, and vascular ultrasonic Doppler detection. Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change. Therefore, this RTS hydrogel holds therapeutic potential for diseases requiring timely detection of temperature change.

Biomaterial-based delivery of nucleic acids for tissue regeneration.

Gene therapy is a promising novel method of tissue regeneration by stimulating or inhibiting key signaling pathways. However, their therapeutic applications in vivo are largely limited by several physiological obstacles, such as degradation of nucleases, impermeability of cell membranes, and transport to the desired intracellular compartments. Biomaterial-based gene delivery systems can overcome the problems of stability and local drug delivery, and can temporarily control the overexpression of therapeutic genes, leading to the local production of physiologically relevant levels of regulatory factors. But the gene delivery of biomaterials for tissue regeneration relies on multi-factor design. This review aims to outline the impact of gene delivery methods, therapeutic genes and biomaterials selection on this strategy, emphatically introduce the latest developments in the design of gene delivery vehicles based on biomaterials, summarize the mechanism of nucleic acid for tissue regeneration, and explore the strategies of nucleic acid delivery vehicles for various tissue regeneration.

Injectable Thermogel Generated by the "Block Blend" Strategy as a Biomaterial for Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection is an established method for the removal of early cancers and large lesions from the gastrointestinal tract but is faced with the risk of perforation. To decrease this risk, a submucosal fluid cushion (SFC) is needed clinically by submucosal injection of saline and so on to lift and separate the lesion from the muscular layer. Some materials have been tried as the SFC so far with disadvantages. Here, we proposed a thermogel generated by the "block blend" strategy as an SFC. This system was composed of two amphiphilic block copolymers in water, so it was called a "block blend". We synthesized two non-thermogellable copolymers poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) and blended them in water to achieve a sol-gel transition upon heating in both pure water and physiological saline. We explored the internal structure of the resultant thermogel with transmission electron microscopy, three-dimensional light scattering, 13C NMR, fluorescence resonance energy transfer, and rheological measurements, which indicated a percolated micelle network. The biosafety of the synthesized copolymer was preliminarily confirmed in vitro. The main necessary functions as an SFC, namely, injectability of a sol and the maintained mucosal elevation as a gel after injection, were verified ex vivo. This study has revealed the internal structure of the block blend thermogel and illustrated its potential application as a biomaterial. This work might be stimulating for investigations and applications of intelligent materials with both injectability and thermogellability of tunable phase-transition temperatures.

Sustained Release Strategy Designed for Lixisenatide Delivery to Synchronously Treat Diabetes and Associated Complications.

Diabetes and its complications have become a global challenge of public health. Herein, we aimed to develop a long-acting delivery system of lixisenatide (Lixi), a glucose-dependent antidiabetic peptide, based on an injectable hydrogel for the synchronous treatment of type 2 diabetes mellitus (T2DM) and associated complications. Two triblock copolymers, poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) and poly(d,l-lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(d,l-lactic acid-co-glycolic acid) possessing temperature-induced sol-gel transitions, were synthesized by us. Compared to the two single-component hydrogels, their 1/1 mixture hydrogel not only maintained the temperature-induced gelation but also exhibited a steadier degradation profile in vivo. Both in vitro and in vivo release studies demonstrated that the mixture hydrogel provided the sustained release of Lixi for up to 9 days, which was attributed to balanced electrostatic interactions between the positive charges in the peptide and the negative charges in the polymer carrier. The hypoglycemic efficacy of Lixi delivered from the mixture hydrogel after a single subcutaneous injection into diabetic db/db mice was comparable to that of twice-daily administrations of Lixi solution for up to 9 days. Furthermore, three successive administrations of the abovementioned gel system within a month significantly increased the plasma insulin level, lowered glycosylated hemoglobin, and improved the pancreatic function of the animals. These results were superior or equivalent to those of twice-daily injections of Lixi solution for 30 days, but the number of injections was markedly reduced from 60 to 3. Finally, an improvement in hyperlipidemia, augmentation of nerve fiber density, and enhancement of motor nerve conduction velocity in the gel formulation-treated db/db mice indicated that the sustained delivery of Lixi arrested and even ameliorated diabetic complications. These findings suggested that the Lixi-loaded mixture hydrogel has great potential for the treatment of T2DM with significant improvements in the health and quality of life of patients.

Acetal-linked PEGylated paclitaxel prodrugs forming free-paclitaxel-loaded pH-responsive micelles with high drug loading capacity and improved drug delivery.

Endosomal pH-responsive micellar nanoparticles were prepared by self-assembly of an amphiphilic poly(ethylene glycol)-acetal-paclitaxel (PEG-acetal-PTX) prodrug, and free PTX could be encapsulated in the hydrophobic core of the nanoparticles. These nanoparticles exhibited excellent storage stability for over 6months under normal conditions, but disassembled quickly in response to faintly acidic environment. Incorporating physical encapsulation and chemical conjugation, the PTX concentration in the nanoparticles solution could reach as high as 3665µg/mL, accompanying with a high drug loading capacity of 60.3%. Additionally, benefitting from the difference in drug release mechanism and rate between encapsulated PTX and conjugated PTX, a programmed drug release behavior was observed, which may result in higher intracellular drug concentration and longer action time. CCK-8 assays showed that the nanoparticles demonstrated superior antitumor activity than free PTX against both HeLa and MDA-MB-231 cells. These prodrug-based nanomedicines have a great potential in developing translational PTX formulations for cancer therapy.

Selective Dual-Channel Imaging on Cyanostyryl-Modified Azulene Systems with Unimolecularly Tunable Visible-Near Infrared Luminescence.

Although organic light-emitting molecules have received a growing attention and applicability in modern bioimaging science, the design and control of complex photoluminescent properties in unimolecularly selective imaging remains a challenging topic. Considering that tunable multipathway imaging can be advantagedly connected with treatment processes in therapy, the integration of an azulene and a cyanostyryl moiety into one skeleton is carried out for the generation of in situ stimuli-responsive luminescent materials, with the aim to achieve tunable and effective emissions in distinct channels through smart molecular design on a single-molecular platform. This strategy takes advantage of 1) the Z/E isomerization of the cyanostyryl unit that can vary the push-pull effect of the substitution on azulene, accompanied by altering absorption and emission of individual excited states, and 2) an optimized excited-state regulation for opening a near infrared emissive channel and making up for a controllable dual-pathway luminescent system together with the utilization of visible emission. As exemplified by a demonstration of manipulating the luminescence at the cell level, the materials exhibit a superior application potential for unimolecularly selective imaging, labeling and probing events.

Dopamine-assisted fixation of drug-loaded polymeric multilayers to osteoarticular implants for tuberculosis therapy.

Currently, the major issues in the treatment of osteoarticular tuberculosis (TB) after implant placement are low drug concentration at the infected focus and drug resistance resulting from the long-term chemotherapy. The application of drug-loaded polymeric multilayers on implantable devices offers a promising solution to the problems. Herein, a poly(ethylene glycol)-based hydrogel film embedded with isoniazid (INH)-loaded alginate microparticles was fixed to Ti implants via adhesive polydopamine, subsequently capped by poly(lactic-co-glycolic acid) membranes for the sustained and localized delivery of the anti-TB drug. The antibacterial efficacy of the released INH was confirmed by a 4.5 ± 0.8 cm inhibition zone formed in the fourth week after inoculation of Mycobacterium tuberculosis. The INH-loaded Ti implants showed no toxicity to the osteoblast cell and provided a consistent drug release for nearly one week in vitro. The release profile in vivo showed a high local concentration and low systemic exposure. The local INH concentration could be kept higher than its minimum inhibitory concentration over a period of 8 weeks, which proves that it is a promising strategy to improve the severe osteoarticular TB treatment.

Fabrication of pH-Responsive Nanoparticles with an AIE Feature for Imaging Intracellular Drug Delivery.

Here we have demonstrated a facile method for construction of self-assembled nanoparticles with excellent fluorescent properties by the synergetic combination of unique AIE effects and tadpole-shaped polymers. The introduction of acid-sensitive Schiff base bonds furnished the polymeric vesicles and micelles with unique pH responsiveness that can possess maximal drug-release controllability inside tumor cells upon changes in physical and chemical environments, but present good stability under physiological conditions. Having benefited from the efficient fluorescence resonance energy transfer (FRET), the DOX-loaded fluorescent aggregates were employed for intracellular imaging and self-localization in surveillance of systemic DOX delivery. Cytotoxicity assay of the DOX-loaded aggregates indicated a fast internalization and a high cellular proliferation inhibition to MCF-7 cells while the PEG-POSS-(TPE)7 nanoparticles displayed no cytotoxicity, exhibiting excellent biocompatibility and biological imaging properties. These results indicated that these biodegradable nanoparticles, as a class of effective pH-responsive and visible nanocarriers, have the potential to improve smart drug delivery and enhance the antitumor efficacy for biomedical applications.

Facile Construction of pH- and Redox-Responsive Micelles from a Biodegradable Poly(ß-hydroxyl amine) for Drug Delivery.

Here we demonstrate a type of pH and reduction dual-sensitive biodegradable micelles, which were self-assembled by a cationic polymer in an aqueous solution. Due to tumor cells or tissues showing low pH and high reduction concentration, these micelles possessed specific tumor targetability and maximal drug-release controllability inside tumor cells upon changes in physical and chemical environments, but presented good stability at physiological conditions. CCK-8 assay showed that the DOX-loaded micelles had a similar cytotoxicity for MCF-7 tumor cells as free DOX, and blank micelles had a very low cytotoxicity to the cells. Fluorescent microscopy observation revealed that the drug-loaded micelles could be quickly internalized by endosomes to inhibit cancer cell growth. These results indicated these biodegradable micelles, as a novel and effective pH- and redox-responsive nanocarrier, have a potential to improve drug delivery and enhance the antitumor efficacy.

Fabrication and effect on regulating vSMC phenotype of a biomimetic tunica media scaffold.

An ideal vascular tissue engineering scaffold should imitate physical and biochemical cues in native vessels for guiding cell growth, differentiation and tissue formation. The tunica media provides a key structure and function support for native vessels. In this study, a film-like MNP-TGF/bFGF-PLGA scaffold that simulated physical and biochemical cues of tunica media in native vessels was fabricated by soft lithography combined with solution casting and phase separation technique. The scaffold had dual surface topographies of parallel arranged microgrooves and nanofiber structures, and interconnected pores to be able to deliver nutrient and eliminate metabolized products. The TGF-ß1 and bFGF immobilized on the scaffold by silica nanoparticle binding and plasma treatment technique could maintain continuous release for 10 and 7 days, respectively. The synergy effect of the dual surface topography and released growth factors endowed the MNP-TGF/bFGF-PLGA scaffold with good capacity on regulating vascular smooth muscle cell (vSMC) phenotype. Importantly, the scaffold possessed good mechanical properties and could easily be rolled into a multilayer cylindrical tube as a promising biomimic vascular tissue engineering scaffold.

Uniform PEGylated PLGA Microcapsules with Embedded Fe3O4 Nanoparticles for US/MR Dual-Modality Imaging.

Well-designed agents for enhanced multimodal imaging have attracted great interests in recent years. In this work, we adopted a premix membrane emulsification (PME) method to prepare uniform PEGylated poly(lactic-co-glycolic acid) (PLGA) microcapsules (MCs) with superparamagnetic Fe3O4 nanoparticles (NPs) embedded in the shell (Fe3O4@PEG-PLGA MCs) for ultrasound (US)/magnetic resonance (MR) bimodal imaging. Compared to Fe3O4@PLGA MCs without PEGylation, Fe3O4@PEG-PLGA MCs could more stably and homogeneously disperse in physiological solutions. In vitro and in vivo trials demonstrated that Fe3O4@PEG-PLGA MCs (∼3.7 µm) with very narrow size distribution (PDI=0.03) could function as efficient dual-modality contrast agents to simultaneously enhance US and MR imaging performance greatly. In vitro cell toxicity and careful histological examinations illustrated no appreciable cytotoxicity and embolism of Fe3O4@PEG-PLGA MCs to mice even at high dose. The uniform composite MCs developed here can act as clinical bimodal contrast agents to improve hybrid US/MR imaging contrast, which is promising for accurate diagnosis and real-time monitoring of difficult and complicated diseases.