Progress in ultrasmall ferrite nanoparticles enhanced T1 magnetic resonance angiography.

Contrast-enhanced magnetic resonance angiography (CE-MRA) plays a critical role in diagnosing and monitoring various vascular diseases. Achieving high-sensitivity detection of vascular abnormalities in CE-MRA depends on the properties of contrast agents. In contrast to clinically used gadolinium-based contrast agents (GBCAs), the new generation of ultrasmall ferrite nanoparticles-based contrast agents have high relaxivity, long blood circulation time, easy surface functionalization, and high biocompatibility, hence showing promising prospects in CE-MRA. This review aims to comprehensively summarize the advancements in ultrasmall ferrite nanoparticles-enhanced MRA for detecting vascular diseases. Additionally, this review also discusses the future clinical translational potential of ultrasmall ferrite nanoparticles-based contrast agents for vascular imaging. By investigating the current status of research and clinical applications, this review attempts to outline the progress, challenges, and future directions of using ultrasmall ferrite nanoparticles to drive the field of CE-MRA into a new frontier of accuracy and diagnostic efficacy.

Intracellular magnetic hyperthermia reverses sorafenib resistance in hepatocellular carcinoma through its action on signaling pathways.

Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), unfortunately encounters resistance in most patients, leading to disease progression. Traditional approaches to counteract this resistance, particularly those targeting the RAF-MEK-ERK pathway, often face clinical feasibility limitations. Magnetic hyperthermia (MH), unlike conventional thermal therapies, emerges as a promising alternative. It uniquely combines magnetothermal effects with an increase in reactive oxygen species (ROS). This study found the potential of intracellular MH enhanced the efficacy of sorafenib, increased cellular sensitivity to sorafenib, and reversed sorafenib resistance by inhibiting the RAF-MEK-ERK pathway in an ROS-dependent manner in a sorafenib-resistant HCC cell. Further, in a sorafenib-resistant HCC mouse model, MH significantly sensitized tumors to sorafenib therapy, resulting in inhibited tumor growth and improved survival rates. This presents a promising strategy to overcome sorafenib resistance in HCC, potentially enhancing therapeutic outcomes for patients with this challenging condition.

Tailoring Zinc Ferrite Nanoparticle Surface Coating for Macrophage-Affinity Magnetic Resonance Imaging of Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease characterized by the formation of atherosclerotic plaques, while macrophages as key players in plaque progression and destabilization are promising targets for atherosclerotic plaque imaging. Contrast-enhanced magnetic resonance imaging (CE-MRI) has emerged as a powerful noninvasive imaging technique for the evaluation of atherosclerotic plaques within arterial walls. However, the visualization of macrophages within atherosclerotic plaques presents considerable challenges due to the intricate pathophysiology of the disease and the dynamic behavior of these cells. Biocompatible ferrite nanoparticles with diverse surface ligands possess the potential to exhibit distinct relaxivity and cellular affinity, enabling improved imaging capabilities for macrophages in atherosclerosis. In this work, we report macrophage-affinity nanoparticles for magnetic resonance imaging (MRI) of atherosclerosis via tailoring nanoparticle surface coating. The ultrasmall zinc ferrite nanoparticles (Zn0.4Fe2.6O4) as T1 contrast agents were synthesized and modified with dopamine, 3,4-dihydroxyhydrocinnamic acid, and phosphorylated polyethylene glycol to adjust their surface charges to be positively, negatively, and neutrally charged, respectively. In vitro MRI evaluation shows that the T1 relaxivity for different surface charged Zn0.4Fe2.6O4 nanoparticles was three higher than that of the clinically used Gd-DTPA. Furthermore, in vivo atherosclerotic plaque MR imaging indicates that positively charged Zn0.4Fe2.6O4 showed superior MRI efficacy on carotid atherosclerosis than the other two, which is ascribed to high affinity to macrophages of positively charged nanoparticles. This work provides improved diagnostic capability and a better understanding of the molecular imaging of atherosclerosis.

Intracellular Magnetic Hyperthermia Enables Concurrent Down-Regulation of CD47 and SIRPα To Potentiate Antitumor Immunity.

Harnessing the potential of tumor-associated macrophages (TAMs) to engulf tumor cells offers promising avenues for cancer therapy. Targeting phagocytosis checkpoints, particularly the CD47-signal regulatory protein α (SIRPα) axis, is crucial for modulating TAM activity. However, single checkpoint inhibition has shown a limited efficacy. In this study, we demonstrate that ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-mediated magnetic hyperthermia effectively suppresses the expression of CD47 protein on Hepa1-6 tumor cells and SIRPα receptor on macrophages, which disrupts CD47-SIRPα interaction. FVIO-mediated magnetic hyperthermia also induces immunogenic cell death and polarizes TAMs toward M1 phenotype. These changes collectively bolster the phagocytic ability of macrophages to eliminate tumor cells. Furthermore, FVIO-mediated magnetic hyperthermia concurrently escalates cytotoxic T lymphocyte levels and diminishes regulatory T cell levels. Our findings reveal that magnetic hyperthermia offers a novel approach for dual down-regulation of CD47 and SIRPα, reshaping the tumor microenvironment to stimulate immune responses, culminating in significant antitumor activity.

Design, synthesis and antibacterial activity of novel 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives.

Based on the observed biological activity of 1,2,4-triazin-5-one derivatives and their cyclic analogues, a novel series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives that contain ester moiety compounds 3a-3g, carboxylic acid moiety compounds 4a-4g and piperazine amide moiety compounds 5a-5k at position-3 of the thiazolotriazinone scaffold were synthesized. The intermolecular cyclization occurred regioselectively at N2-position of 1,2,4-triazine ring was characterized by X-ray single-crystal diffraction analysis. The in vitro biological activities of the target compounds were assayed against some bacterial strains. Compared with ciprofloxacin, compounds 3g and 4g exhibited more excellent antibacterial activity, especially the activity against Staphylococcus aureus and Escherichia coli, showing that the fluorine at the para position of the benzyl group would be the best choice. In addition, compounds 4e-4g with carboxylic acid moiety can enhance the antibacterial activity. Compounds 5g-5k containing bulky 1-(substituted phenyl)piperazine moiety were found with slightly less biological activity. Similar to ciprofloxacin, the docking result of target compounds with DNA topoisomerase II indicates the carboxyl group of the target compounds with carboxylic acid moiety has a crucial salt bridge interaction with Mg2+ in the protein.

Zn-Shik-PEG nanoparticles alleviate inflammation and multi-organ damage in sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by excessive formation of reactive oxygen species (ROS) and dysregulated inflammatory response. Previous studies have reported that shikonin (Shik) possess prominent anti-inflammatory and antioxidant effects and holds promise as a potential therapeutic drug for sepsis. However, the poor water solubility and the relatively high toxicity of shikonin hamper its clinical application. To address this challenge, we constructed Zn2+-shikonin nanoparticles, hereafter Zn-Shik-PEG NPs, based on an organic-inorganic hybridization strategy of metal-polyphenol coordination to improve the aqueous solubility and biosafety of shikonin. Mechanistic studies suggest that Zn-Shik-PEG NPs could effectively clear intracellular ROS via regulating the Nrf2/HO-1 pathway, meanwhile Zn-Shik-PEG NPs could inhibit NLRP3 inflammasome-mediated activation of inflammation and apoptosis by regulating the AMPK/SIRT1 pathway. As a result, the Zn-Shik-PEG NPs demonstrated excellent therapeutic efficacies in lipopolysaccharide (LPS) as well as cecal ligation puncture (CLP) induced sepsis model. These findings suggest that Zn-Shik-PEG NPs may have therapeutic potential for the treatment of other ROS-associated and inflammatory diseases.

Reversal of HMGA1-Mediated Immunosuppression Synergizes with Immunogenic Magnetothermodynamic for Improved Hepatocellular Carcinoma Therapy.

Magnetothermodynamic (MTD) therapy can activate antitumor immune responses by inducing potent immunogenic tumor cell death. However, tumor development is often accompanied by multifarious immunosuppressive mechanisms that can counter the efficacy of immunogenic MTD therapy. High-mobility group protein A1 (HMGA1) is overexpressed within hepatocellular carcinoma tissues and plays a crucial function in the generation of immunosuppressive effects. The reversal of HMGA1-mediated immunosuppression could enhance immunogenic tumor cell death-induced immune responses. A ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-based nanovehicle was developed, which is capable of efficiently mediating an alternating magnetic field for immunogenic tumor cell death induction, while concurrently delivering HMGA1 small interfering (si)RNA (siHMGA1) to the cytoplasm of hepatocellular carcinoma Hepa 1-6 cells for HMGA1 pathway interference. Using siHMGA1-FVIO-mediated MTD therapy, the proliferation of hepatocellular carcinoma Hepa 1-6 tumors was inhibited, and the survival of a mouse model was improved. We also demonstrated that siHMGA1-FVIO-mediated MTD achieved synergistic antitumor effects in a subcutaneous hepatocellular carcinoma Hepa 1-6 and H22 tumor model by promoting dendritic cell maturation, enhancing antigen-presenting molecule expression (both major histocompatibility complexes I and II), improving tumor-infiltrating T lymphocyte numbers, and decreasing immunosuppressive myeloid-derived suppressor cells, interleukin-10, and transforming growth factor-ß expression. The nanoparticle system outlined in this paper has the potential to target HMGA1 and, in combination with MTD-induced immunotherapy, is a promising approach for hepatocellular carcinoma treatment.

Magnetic nanomaterials-mediated neuromodulation.

Researchers have leveraged magnetic nanomaterials (MNMs) to explore neural circuits and treat neurological diseases via an approach known as MNMs-mediated neuromodulation. Here, the magneto-responsive effects of MNMs to an external magnetic field are manipulated to activate or inhibit neuronal cell activity. In this way, MNMs can serve as a nano-mediator, by converting electromagnetic energy into heat, mechanical force/torque, and an electrical field at nanoscale. These physicochemical effects can stimulate ion channels and activate precise signaling pathways involved in neuromodulation. In this review, we outline the various ion channels and MNMs that have been applied to MNMs-mediated neuromodulation. We highlight the recent advances made in this technique and its potential applications, and then discuss the current challenges and future directions of MNMs-mediated neuromodulation. Our aim is to reveal the potential of MNMs to treat neurological diseases in the clinical setting. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

A hepatocyte-targeting nanoparticle for enhanced hepatobiliary magnetic resonance imaging.

Hepatobiliary magnetic resonance imaging (MRI) can inform the diagnosis of liver tumours in patients with liver cirrhosis and hepatitis. However, its clinical utility has been hampered by the lack of sensitive and specific contrast agents, partly because hepatocyte-specific nanoparticles, regardless of their surface ligands, are readily sequestered by Kupffer cells. Here we show, in rabbits, pigs and macaques, that the performance of hepatobiliary MRI can be enhanced by an ultrasmall nanoparticle composed of a manganese ferrite core (3 nm in diameter) and poly(ethylene glycol)-ethoxy-benzyl surface ligands binding to hepatocyte-specific transmembrane metal and anion transporters. The nanoparticle facilitated faster, more sensitive and higher-resolution hepatobiliary MRI than the clinically used contrast agent gadoxetate disodium, a substantial enhancement in the detection rate (92% versus 48%) of early-stage liver tumours in rabbits, and a more accurate assessment of biliary obstruction in macaques. The nanoparticle's performance and biocompatibility support the further translational development of liver-specific MRI contrast agents.

Engineering magnetic nano-manipulators for boosting cancer immunotherapy.

Cancer immunotherapy has shown promising therapeutic results in the clinic, albeit only in a limited number of cancer types, and its efficacy remains less than satisfactory. Nanoparticle-based approaches have been shown to increase the response to immunotherapies to address this limitation. In particular, magnetic nanoparticles (MNPs) as a powerful manipulator are an appealing option for comprehensively regulating the immune system in vivo due to their unique magnetically responsive properties and high biocompatibility. This review focuses on assessing the potential applications of MNPs in enhancing tumor accumulation of immunotherapeutic agents and immunogenicity, improving immune cell infiltration, and creating an immunotherapy-sensitive environment. We summarize recent progress in the application of MNP-based manipulators to augment the efficacy of immunotherapy, by MNPs and their multiple magnetically responsive effects under different types of external magnetic field. Furthermore, we highlight the mechanisms underlying the promotion of antitumor immunity, including magnetically actuated delivery and controlled release of immunotherapeutic agents, tracking and visualization of immune response in real time, and magnetic regulation of innate/adaptive immune cells. Finally, we consider perspectives and challenges in MNP-based immunotherapy.

Biocompatible Iron Oxide Nanoring-Labeled Mesenchymal Stem Cells: An Innovative Magnetothermal Approach for Cell Tracking and Targeted Stroke Therapy.

Labeling stem cells with magnetic nanoparticles is a promising technique for in vivo tracking and magnetic targeting of transplanted stem cells, which is critical for improving the therapeutic efficacy of cell therapy. However, conventional endocytic labeling with relatively poor labeling efficiency and a short labeling lifetime has hindered the implementation of these innovative enhancements in stem-cell-mediated regenerative medicine. Herein, we describe an advanced magnetothermal approach to label mesenchymal stem cells (MSCs) efficiently by local induction of heat-enhanced membrane permeability for magnetic resonance imaging (MRI) tracking and targeted therapy of stroke, where biocompatible γ-phase, ferrimagnetic vortex-domain iron oxide nanorings (γ-FVIOs) with superior magnetoresponsive properties were used as a tracer. This approach facilitates a safe and efficient labeling of γ-FVIOs as high as 150 pg of Fe per cell without affecting the MSCs proliferation and differentiation, which is 3.44-fold higher than that by endocytosis labeling. Such a high labeling efficiency not only enables the ultrasensitive magnetic resonance imaging (MRI) detection of sub-10 cells and long-term tracking of transplanted MSCs over 10 weeks but also endows transplanted MSCs with a magnetic manipulation ability in vivo. A proof-of-concept study using a rat stroke model showed that the labeled MSCs facilitated MRI tracking and magnetic targeting for efficient replacement therapy with a significantly reduced dosage of 5 × 104 transplanted cells. The findings in this study have demonstrated the great potential of the magnetothermal approach as an efficient labeling technique for future clinical usage.

Magnetic hyperthermia induces effective and genuine immunogenic tumor cell death with respect to exogenous heating.

Immunogenic cell death (ICD) can improve the therapeutic effects of cancer immunotherapy by initiating adaptive immune responses. Unlike the exogenous hyperthermia modality in clinics, magnetic hyperthermia (MH) is characterized by an iron oxide nano-agent acting as a heating source and the effects induced by heating acting at the intracellular region. However, the immunological effects of endogenous heating generated during MH and exogenous heating, and the difference in damage-associated molecular pattern (DAMP) emissions correlating with the ICD are unclear; whether MH elicits genuine ICD remains unknown. Herein, we have identified 10 distinct DAMP correlates of ICD induced by intracellular MH, and found that only heat shock proteins 70/90 were expressed after water bath heating (exogenous hyperthermia) in human triple-negative breast cancer (TNBC) MDA-MB-231 cells, murine TNBC 4T1 cells, and surgically resected specimens of ductal breast cancer from patients. In vivo vaccination assays were performed in immunocompetent BALB/c mice. The results demonstrated that MH with endogenous heating could stimulate the genuine ICD on 4T1 cells and achieved optimal therapeutic effects on 4T1 tumors, whereas exogenous heating under the same conditions failed to elicit these effects. These findings with regard to the MH induced genuine ICD with high efficiency are critical for the development of safe and effective therapeutics to amplify the therapeutic responses of cancer immunotherapy.

The Metal Ion Release of Manganese Ferrite Nanoparticles: Kinetics, Effects on Magnetic Resonance Relaxivities, and Toxicity.

Mn2+ release is particularly important for biological application of manganese-based nanomaterials. However, the Mn2+ release profiles of the manganese ferrite nanoparticles are under clarification. Here, we synthesized 3, 10, and 18 nm manganese ferrite nanoparticles (MFNPs) as model systems to study the Mn2+ release behavior, size, and pH-dependent kinetics. The Mn2+ release kinetic study showed that the first-order kinetic model was suitable for 3 and 10 nm MFNPs, while the Higuchi model was suitable for 18 nm MFNPs in a neutral PBS buffer (pH 7.4). In an acidic PBS buffer (pH 4.8), the Mn2+ release from all sizes of MFNPs follows first-order kinetics, which is possible due to the reaction between MFNPs and H+. The influence of Mn2+ release was evaluated by comparing the variations of magnetic resonance (MR) relaxation and magnetic properties before and after Mn2+ release of MFNPs. The results showed that the saturation magnetization (Ms), longitudinal relaxivity (r1), and transverse relaxivity (r2) values declined due to Mn2+ release, while the ratio of r2/r1 increased slightly, showing that all sizes of MFNPs exhibited the same MR mode as the synthesized MFNPs. More importantly, the release kinetics were employed to estimate the toxicity of the released Mn2+in vivo. The potential toxicity is acceptable for MFNP administration since the calculated amount of Mn2+ is in the range of safe doses.

In vivo MRI tracking and therapeutic efficacy of transplanted mesenchymal stem cells labeled with ferrimagnetic vortex iron oxide nanorings for liver fibrosis repair.

Mesenchymal stem cells (MSCs) have showed promising effects in the treatment of liver fibrosis. Long-term and noninvasive in vivo tracking of transplanted MSCs is essential for understanding the therapeutic mechanism of MSCs during the therapy of liver fibrosis. In this study, we report the development of a ferrimagnetic vortex iron oxide nanoring (FVIO)-based nanotracer for the long-term visualization of transplanted human MSCs (hMSCs) by magnetic resonance imaging (MRI). The FVIOs were prepared by a hydrothermal reaction followed by hydrogen reduction. To endow the FVIOs with biocompatibility, polyethylene glycol amine (mPEG-NH2) was covalently coupled on the surface of FVIOs, forming FVIO@PEG nanotracers with high contrast enhancement and intracellular uptake. The hMSCs labeled with FVIO@PEG nanotracers exhibited enhanced MRI contrast than those labeled with a commercial contrast agent, and could be continuously monitored by MRI in liver fibrosis mice for 28 days after transplantation, clearly clarifying the migration behavior of hMSCs in vivo. Moreover, we explored the therapeutic mechanism of the FVIO@PEG labeled hMSCs in the amelioration of liver fibrosis, including the reduction in inflammation and oxidative stress, the inhibition of hepatic fibrosis-caused histopathological damage, as well as the down-regulation of the expression of relevant cytokines. The results obtained in this work may deepen our understanding of the behavior and role of hMSCs in the treatment of liver fibrosis, which is key to the clinical application of stem cells in the therapy of liver diseases.

Recent Strategies to Combat Biofilms Using Antimicrobial Agents and Therapeutic Approaches.

Biofilms are intricate bacterial assemblages that attach to diverse surfaces using an extracellular polymeric substance that protects them from the host immune system and conventional antibiotics. Biofilms cause chronic infections that result in millions of deaths around the world every year. Since the antibiotic tolerance mechanism in biofilm is different than that of the planktonic cells due to its multicellular structure, the currently available antibiotics are inadequate to treat biofilm-associated infections which have led to an immense need to find newer treatment options. Over the years, various novel antibiofilm compounds able to fight biofilms have been discovered. In this review, we have focused on the recent and intensively researched therapeutic techniques and antibiofilm agents used for biofilm treatment and grouped them according to their type and mode of action. We also discuss some therapeutic approaches that have the potential for future advancement.

Design of Magnetic Nanoplatforms for Cancer Theranostics.

Cancer is the top cause of death globally. Developing smart nanomedicines that are capable of diagnosis and therapy (theranostics) in one-nanoparticle systems are highly desirable for improving cancer treatment outcomes. The magnetic nanoplatforms are the ideal system for cancer theranostics, because of their diverse physiochemical properties and biological effects. In particular, a biocompatible iron oxide nanoparticle based magnetic nanoplatform can exhibit multiple magnetic-responsive behaviors under an external magnetic field and realize the integration of diagnosis (magnetic resonance imaging, ultrasonic imaging, photoacoustic imaging, etc.) and therapy (magnetic hyperthermia, photothermal therapy, controlled drug delivery and release, etc.) in vivo. Furthermore, due to considerable variation among tumors and individual patients, it is a requirement to design iron oxide nanoplatforms by the coordination of diverse functionalities for efficient and individualized theranostics. In this article, we will present an up-to-date overview on iron oxide nanoplatforms, including both iron oxide nanomaterials and those that can respond to an externally applied magnetic field, with an emphasis on their applications in cancer theranostics.

Magnetoresponsive nanozyme: magnetic stimulation on the nanozyme activity of iron oxide nanoparticles.

The iron oxide nanoparticles (IONPs) that combine the nanozyme activity and magnetothermal properties have attracted significant interest for various biomedical applications. However, the effect of magnetic stimulation in fine-tuning the nanozyme activities remains unclear. Here, we have constructed a series of IONPs with different magneto-thermal conversion abilities, and systematically study the effect of magnetic field stimulation on the peroxidase (POD) activity of IONPs. The results show that POD activity is effectively amplified via an in situ alternating magnetic field (AMF) stimulation with no solution temperature rise, and the degree of activity enhancement is closely related to the magnetic heating ability of the IONPs, confirming the origin of activity enhancement arises from the local magnetothermal effect. As the first report to prove magnetothermal regulation on nanozyme activity and to shed lights on the underlying correlation between activity enhancement and the intrinsic specific absorption rate (SAR), this work is expected to provide important support for future design of new magnetoresponsive nanozymes in various practical applications.

Synthesizing the First Phase of Dynamic Sequences of Breast MRI for Enhanced Lesion Identification.

OBJECTIVE: To develop a deep learning model for synthesizing the first phases of dynamic (FP-Dyn) sequences to supplement the lack of information in unenhanced breast MRI examinations. METHODS: In total, 97 patients with breast MRI images were collected as the training set (n = 45), the validation set (n = 31), and the test set (n = 21), respectively. An enhance border lifelike synthesize (EDLS) model was developed in the training set and used to synthesize the FP-Dyn images from the T1WI images in the validation set. The peak signal-to-noise ratio (PSNR), structural similarity (SSIM), mean square error (MSE) and mean absolute error (MAE) of the synthesized images were measured. Moreover, three radiologists subjectively assessed image quality, respectively. The diagnostic value of the synthesized FP-Dyn sequences was further evaluated in the test set. RESULTS: The image synthesis performance in the EDLS model was superior to that in conventional models from the results of PSNR, SSIM, MSE, and MAE. Subjective results displayed a remarkable visual consistency between the synthesized and original FP-Dyn images. Moreover, by using a combination of synthesized FP-Dyn sequence and an unenhanced protocol, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI were 100%, 72.73%, 76.92%, and 100%, respectively, which had a similar diagnostic value to full MRI protocols. CONCLUSIONS: The EDLS model could synthesize the realistic FP-Dyn sequence to supplement the lack of enhanced images. Compared with full MRI examinations, it thus provides a new approach for reducing examination time and cost, and avoids the use of contrast agents without influencing diagnostic accuracy.

The Dynamic Interactions between Nanoparticles and Macrophages Impact Their Fate in Brain Tumors.

Functional nanomaterials such as iron oxide nanoparticles have been extensively explored for the diagnosis and treatment of central nervous system diseases. However, an insufficient understanding of the comprehensive nanomaterial-biological interactions in the brain hinders the nanomaterials from meeting the medical requirements for translational research. Here, FDA-approved ferumoxytol, an iron oxide nanoparticle, is chosen as the model nanomaterial for a systematic study of the dynamic interactions between ferumoxytol and immune cells, including microglia and macrophages, in the brain tumors. Strikingly, up to 90% of intratumorally injected ferumoxytol nanoparticles are recognized and phagocytized by tumor-associated microglia and macrophages. The dynamic trafficking progress of ferumoxytol in microglia and macrophages, including scavenger receptor-mediated endocytosis, lysosomal internalization, and extracellular vesicle-dominated excretion, is further studied. Importantly, the results demonstrate that extracellular vesicle-encapsulated nanoparticles could be gradually eliminated from the brain along with cerebrospinal fluid circulation over 21 days. Moreover, ferumoxytol exhibits no obvious long-term neurological toxicity after its injection. The study suggests that the dynamic biointeractions of nanoparticles with immune cells in the brain exert a key rate-limiting impact on the efficiency of targeting tumor cells and their in vivo fate and thus provide a deeper understanding of the nanomaterials in the brain for clinical applications.

Design and Preparation of "corn-like" SPIONs@DFK-SBP-M13 Assembly for Improvement of Effective Internalization.

PURPOSE: Superparamagnetic iron oxide nanoparticles (SPIONs) have exhibited preeminent diagnosis and treatment performances, but their low internalization severely limits predesigned functions. The low cell internalization is now an urgent bottleneck problem for almost all nanomaterials. To achieve more internalization of SPIONS, recombinant M13 phage was designed for targeted delivery and smart release. METHODS: M13 phages were designed to co-express exogenous SPARC binding peptide (SBP) and cathepsin B cleavage peptide (DFK), formed recombinant DFK-SBP-M13. 3.37± 0.06 nm of SPIONs were modified by 3, 4-dihydroxyhydrocinnamic acid (DHCA) to gain 10.80 ± 0.21 nm of DHCA-coated SPIONs, i.e., DHCA@SPIONs. Upon adjusting the proportions of DHCA@SPIONs and DFK-SBP-M13, the multi-carboxyl SPIONs assembled onto recombinant M13 phages via covalent bonding. The assemblies were co-cultured with MDA-MB-231 cells to interpret their internalization and smart release. RESULTS: The "corn-like" SPIONs@DFK-SBP-M13 (261.47±3.30 nm) assemblies have not been reported previously. The assembly was stable, dispersible, superparamagnetic and biocompatible. After co-cultivation with MDA-MB-231 cells, the SPIONs@DFK-SBP-M13 assemblies quickly bond to the cell surface and are internalized. The enrichment rate of SPIONs@DFK-SBP-M13 assembly was 13.9 times higher than free SPIONs at 0.5 h, and intracellular Fe content was 3.6 times higher at 1 h. Furthermore, the DFK peptides favored cathepsin B to cleave SPIONs from the M13 templates resulting in release of SPIONs inside cells. CONCLUSION: The novel SPIONs@DFK-SBP-M13 assembly can rapidly deliver SPIONs to the targeted sites and enabled smart release. The combination of genetic recombination and nanotechnology is beneficial for designing and optimizing some new nanomaterials with special functions to achieve wider applications.