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.

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.

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.

Structure-Relaxivity Mechanism of an Ultrasmall Ferrite Nanoparticle T1 MR Contrast Agent: The Impact of Dopants Controlled Crystalline Core and Surface Disordered Shell.

Ultrasmall ferrite nanoparticles (UFNPs) have emerged as powerful magnetic resonance imaging (MRI) T1 nanoprobe for noninvasive visualization of biological events. However, the structure-relaxivity relationship and regulatory mechanism of UFNPs remain elusive. Herein, we developed chemically engineered 3.8 nm ZnxFe3-xO4@ZnxMnyFe3-x-yO4 (denoted as ZnxF@ZnxMnyF) nanoparticles with precise dopants control in both crystalline core and disordered shell as a model system to assess the impact of dopants on the relaxometric properties of UFNPs. It is determined that the core-shell dopant architecture allows the optimal tuning of r1 relaxivity for Zn0.4F@Zn0.4Mn0.2F up to 20.22 mM-1 s-1, which is 5.2-fold and 6.5-fold larger than that of the original UFNPs and the clinically used Gd-DTPA. Moreover, the high-performing UFNPs nanoprobe, when conjugated with a targeting moiety AMD3100, enables the in vivo MRI detection of small lung metastasis with greatly enhanced sensitivity. Our results pave the way toward the chemical design of ultrasensitive T1 nanoprobe for advanced molecular imaging.

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.

The twisted structure of the rat Achilles tendon.

The rat is frequently used as a model to study the characteristics, aetiology and pathology of the Achilles tendon. However, though the structure of the human Achilles tendon has been extensively investigated, the anatomical structure of the rat Achilles tendon remains unclear, which impedes the ability to use rats to study Achilles tendinopathy. The purpose of this study was to reveal the structure of the rat Achilles tendon and to explore its similarities with the human Achilles tendon through an anatomical dissection of 80 rat Achilles tendons (40 female, 40 male). This study found that the subtendons of the rat Achilles tendon originating from the triceps surae muscle were twisted, and each subtendon also had its own torsion. The extent of these two types of torsion could be very different between rats. Alterations in this torsion may result in distinct stress fields in the Achilles tendon, which may play a critical role in the pathogenesis of Achilles tendinopathy. This study provides an important basis to support the use of rats as model animals to investigate the characteristics of the human Achilles tendon and Achilles tendinopathy.

Fabrication of a ß-cyclodextrin-based self-assembly containing a redox-responsive ferrocene.

The current research involves fabrication of a redox-responsive self-assembly system based on a ferrocene (Fc)-containing ß-cyclodextrin (ß-CD) derivative (ßCD-EG-Fc). ßCD-EG-Fc was synthesized, and its redox-sensitive self-assembly behavior was investigated using various techniques. On the basis of the intermolecular host-guest recognition between the ß-CD group and the Fc moiety, ßCD-EG-Fc primarily formed network-like structures and then vesicles following aging for a specified time. The formation of these structures was primarily driven by hydrogen bonding. Conversely, the oxidized molecules (ßCD-EG-Fc+) self-assembled into cationic vesicles with the absence of host-guest complexation. Upon controlling the oxidation and reduction of Fc/Fc+, reversible aggregate transformation was achieved. The current study resulted in a deeper understanding of ß-CD/Fc redox-responsive self-assemblies and contributed to the development of a single-component host-guest inclusion model.

Ultrasonication-Triggered Ubiquitous Assembly of Magnetic Janus Amphiphilic Nanoparticles in Cancer Theranostic Applications.

The ultrasonication-triggered interfacial assembly approach was developed to synthesize magnetic Janus amphiphilic nanoparticles (MJANPs) for cancer theranostic applications, where the biocompatible octadecylamine is used as a molecular linker to mediate the interactions between hydrophobic and hydrophilic nanoparticles across the oil-water interface. The obtained Co cluster-embedded Fe3O4 nanoparticles-graphene oxide (CCIO-GO) MJANPs exhibited superior magnetic heating efficiency and transverse relaxivity, 64 and 4 times higher than that of commercial superparamagnetic iron oxides, respectively. The methodology has been applicable to nanoparticles of various dimensions (5-100 nm), morphologies (sphere, ring, disk, and rod), and composition (metal oxides, noble metal and semiconductor compounds, etc.), thereby greatly enriching the array of MJANPs. In vivo theranostic applications using the tumor-bearing mice model further demonstrated the effectiveness of these MJANPs in high-resolution multimodality imaging and high-efficiency cancer therapeutics. The ubiquitous assembly approach developed in the current study pave the way for on-demand design of high-performance Janus amphiphilic nanoparticles for various clinical diagnoses and therapeutic applications.

Accurate identification of myocardial viability after myocardial infarction with novel manganese chelate-based MR imaging.

We developed a novel manganese (Mn2+ ) chelate for magnetic resonance imaging (MRI) assessment of myocardial viability in acute and chronic myocardial infarct (MI) models, and compared it with Gadolinium-based delay enhancement MRI (Gd3+ -DEMRI) and histology. MI was induced in 14 rabbits by permanent occlusion of the left circumflex coronary artery. Gd3+ -DEMRI and Mn2+ chelate-based delayed enhancement MRI (Mn2+ chelate-DEMRI) were performed at 7 days (acute MI, n = 8) or 8 weeks (chronic MI, n = 6) after surgery with sequential injection of 0.15 mmol/kg Gd3+ and Mn2+ chelate. The biodistribution of Mn2+ in tissues and blood was measured at 1.5 and 24 h. Blood pressure, heart rate (HR), left ventricular (LV) function, and infarct fraction (IF) were analyzed, and IF was compared with the histology. The Mn2+ chelate group maintained a stable hemodynamic status during experiment. For acute and chronic MI, all rabbits survived without significant differences in HR or LV function before and after injection of Mn2+ chelate or Gd3+ (p > 0.05). Mn2+ chelate mainly accumulated in the kidney, liver, spleen, and heart at 1.5 h, with low tissue uptake and urine residue at 24 h after injection. In the acute MI group, there was no significant difference in IF between Mn2+ chelate-DEMRI and histology (22.92 ± 2.21% vs. 21.79 ± 2.25%, respectively, p = 0.87), while Gd3+ -DEMRI overestimated IF, as compared with histology (24.54 ± 1.73%, p = 0.04). In the chronic MI group, there was no significant difference in IF between the Mn2+ chelate-DEMRI, Gd3+ -DEMRI, and histology (29.50 ± 11.39%, 29.95 ± 9.40%, and 29.00 ± 10.44%, respectively, p > 0.05), and all three were well correlated (r = 0.92-0.96, p < 0.01). We conclude that the use of Mn2+ chelate-DEMRI is reliable for MI visualization and identifies acute MI more accurately than Gd3+ -DEMRI.

Enzyme-Nanowire Mesocrystal Hybrid Materials with an Extremely High Biocatalytic Activity.

The laccase-Cu2O-nanowire mesocrystal hybrid materials were developed with a superior catalytic activity inspired by natural biocatalysis processes in living cells that highly resemble the metal ions activation and the well-organized spatial structure of the natural rough endoplasmic reticulum. The enzyme and nanobiocatalyst activities of the obtained hybrid material exhibited an approximate 10-fold and 2.2-fold increase than the free enzyme, surpassing the currently available nanobiocatalysts. The comprehensive catalytic performance of the hybrid materials has been further demonstrated using a prototype continuous-flow reactor for the bioremediation of 2,4-dichlorophenol-contaminated water, which showed a high degradation efficiency and remarkable reusability. These new highly efficient nanobiocatalysts are expected to be used for diverse applications in biotechnology, biosensing, and environmental remediation.

Ultrasensitive (Co)polymers Based on Poly(methacrylamide) Structure with Fining-Tunable pH Responsive Value.

Novel pH responsive copolymers with tertiary amine groups were prepared by free radical polymerization with 2-(dialkylamino)ethyl methacrylate monomers. These polymers were pH sensitive with the ability to be responsively fine-tuned in aqueous solution, which was proven through titration, transmittance measurements, and proton nuclear magnetic resonance spectroscopy. The polymers were soluble in water at low pH values, induced by electrostatic repulsion between amine groups, and aggregated above their pKa value due to the hydrophobic effect of the alkyls. The pH responsive values were precisely tuned from 7.4 to 4.8 by increasing the hydrophobic monomer ratio. Our work provides a novel approach for the development of ultrasensitive pH-responsive polymers for application in biomedical materials.

Label-Free Visualization of Carbapenemase Activity in Living Bacteria.

Evaluating enzyme activity intracellularly on natural substrates is a significant experimental challenge in biomedical research. We report a label-free method for real-time monitoring of the catalytic behavior of class A, B, and D carbapenemases in live bacteria based on measurement of heat changes. By this means, novel biphasic kinetics for class D OXA-48 with imipenem as substrate is revealed, providing a new approach to detect OXA-48-like producers. This in-cell calorimetry approach offers major advantages in the rapid screening (10 min) of carbapenemase-producing Enterobacteriaceae from 142 clinical bacterial isolates, with superior sensitivity (97 %) and excellent specificity (100 %) compared to conventional methods. As a general, label-free method for the study of living cells, this protocol has potential for application to a wider range and variety of cellular components and physiological processes.

Redox-responsive self-assembly of ß-cyclodextrin and ferrocene double-headed amphiphilic molecules.

We present a redox-responsive self-assembly based on a unimolecular platform. Three double-headed amphiphilic molecules composed of ß-cyclodextrin (ß-CD) and ferrocene (Fc) each with an alkyl chain as a linker (ßCD-Cm-Fc, m = 2, 6, and 10) were synthesized, and their self-assembly behaviors were investigated. The molecules self-assembled into polydisperse micelles that transformed into vesicles upon oxidization of the Fc moieties to Fc+. 2D 1H NMR results suggest that although the three molecules formed aggregates with similar morphologies, their molecular configurations were different because of the different lengths of the alkyl chains. When the linker was a C2 chain, no host-guest complexes were formed, whereas host-guest recognition was detected for linker lengths of C6 and C10. For the oxidized state samples, there were no host-guest interactions for linker lengths of C2 and C6, whereas the alkyl chain was locked in the cavity of ß-CD by host-guest inclusion for the molecule with a C10 linker. Moreover, reversible redox-responsive self-assemblies based on the three ß-CD derivatives with a terminal Fc were successfully achieved. Our results enrich the field of ß-CD/Fc reversible self-assembly systems, and provide a possible unimolecular host-guest complexation model in host-guest chemistry.

A pH-responsive wormlike micellar system of a noncovalent interaction-based surfactant with a tunable molecular structure.

Responsive wormlike micelles are very useful in a number of applications, whereas it is still challenging to create dramatic viscosity changes in wormlike micellar systems. Here we developed a pH-responsive wormlike micellar system based on a noncovalent constructed surfactant, which is formed by the complexation of N-erucamidopropyl-N,N-dimethylamine (UC22AMPM) and citric acid at the molar ratio of 3 : 1 (EACA). The phase behavior, aggregate microstructure and viscoelasticity of EACA solutions were investigated by macroscopic appearance observation, rheological and cryo-TEM measurements. It was found that the phase behavior of EACA solutions undergoes transition from transparent viscoelastic fluids to opalescent solutions and then phase separation with white floaters upon increasing the pH. Upon increasing the pH from 2.03 to 6.17, the viscosity of wormlike micelles in the transparent solutions continuously increased and reached ∼683 000 mPa s at pH 6.17. As the pH was adjusted to 7.31, the opalescent solution shows a water-like flowing behaviour and the η0 rapidly declines to ∼1 mPa s. Thus, dramatic viscosity changes of about 6 magnitudes can be triggered by varying the pH values without any deterioration of the EACA system. This drastic variation in rheological behavior is attributed to the pH dependent interaction between UC22AMPM and citric acid. Furthermore, the dependence on concentration and temperature of the rheological behavior of EACA solutions was also studied to assist in obtaining the desired pH-responsive viscosity changes.

Amphiphilic BODIPY derivatives: the solvophobic effect on their photophysical properties and bioimaging in living cells.

Three novel amphiphilic BODIPY derivatives were prepared and their photophysical properties in THF/water mixtures with varying fractions of water were investigated. BDP-1 could self-assemble into different vesicle architectures in aqueous solution, while BDP-2 and BDP-3 with more hydrophilic abilities formed spherical and worm-like micelles. The BODIPY derivatives could be absorbed by HeLa cells and showed no apparent toxicity during the course of the test. In particular, unlike traditional amines or morpholinyl functionalized lysosome fluorescent probes, BDP-1 nanovesicles without targeted groups exhibit red emission and show effective lysosome biological imaging. Co-staining experiments with lysosome specific trackers further confirmed the disassembly of BDP-1 nanovesicles in lysosomes. This research provides a new avenue of using probes without targeting the structural unit to stain special organelles and shows potential applications in cell imaging fields.

Phase behavior and microstructures in a mixture of anionic Gemini and cationic surfactants.

We report in this work the phase behavior and microstructures in a mixture of an anionic Gemini surfactant, sodium dilauramino cystine (SDLC), and a conventional cationic surfactant, dodecyl trimethyl ammonium chloride (DTAC). Observation of the appearance shows that the phase behavior of the SDLC-DTAC mixed cationic surfactant system transforms from an isotropic homogeneous phase to an aqueous surfactant two-phase system (ASTP) and then to an anisotropic homogeneous phase with the continuous addition of DTAC. The corresponding aggregate microstructures are investigated by rheology, dynamic light scattering, transmission electron microscopy and polarization microscopy. It has been found that a wormlike micelle, in the isotropic homogeneous phase, occurs linear to the branch growth. The aggregate microstructures in the ASTP lower and upper phases are branched wormlike micelles and vesicles, respectively. The micelle transformed into a vesicle upon varying the phase volume percentage until a lamellar liquid crystal formed in the anisotropic homogeneous phase. The macroscopic phase behavior and microscopic aggregate structure are related to the understanding of the possible mechanisms for the above phenomena.

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.

Functional nanotransducer-mediated wireless neural modulation techniques.

Functional nanomaterials have emerged as versatile nanotransducers for wireless neural modulation because of their minimal invasion and high spatiotemporal resolution. The nanotransducers can convert external excitation sources (e.g. NIR light, x-rays, and magnetic fields) to visible light (or local heat) to activate optogenetic opsins and thermosensitive ion channels for neuromodulation. The present review provides insights into the fundamentals of the mostly used functional nanomaterials in wireless neuromodulation including upconversion nanoparticles, nanoscintillators, and magnetic nanoparticles. We further discussed the recent developments in design strategies of functional nanomaterials with enhanced energy conversion performance that have greatly expanded the field of neuromodulation. We summarized the applications of functional nanomaterials-mediated wireless neuromodulation techniques, including exciting/silencing neurons, modulating brain activity, controlling motor behaviors, and regulating peripheral organ function in mice. Finally, we discussed some key considerations in functional nanotransducer-mediated wireless neuromodulation along with the current challenges and future directions.

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.