DNA-Mediated Magnetic-Dimer Assembly for Fault-Free Ultra-High-Field Magnetic Resonance Imaging of Tumors.

Ultra-high-field (UHF) magnetic resonance imaging (MRI) stands as a pivotal cornerstone in biomedical imaging, yet the challenge of false imaging persists, constraining its full potential. Despite the development of dual-mode contrast agents improving conventional MRI, their effectiveness in UHF remains suboptimal due to the high magnetic moment, resulting in diminished T1 relaxivity and excessively enhanced T2 relaxivity. Herein, we report a DNA-mediated magnetic-dimer assembly (DMA) of iron oxide nanoparticles that harnesses UHF-tailored nanomagnetism for fault-free UHF-MRI. DMA exhibits a dually enhanced longitudinal relaxivity of 4.42 mM-1·s-1 and transverse relaxivity of 26.23 mM-1·s-1 at 9 T, demonstrating a typical T1-T2 dual-mode UHF-MRI contrast agent. Importantly, DMA leverages T1-T2 dual-modality image fusion to achieve artifact-free breast cancer visualization, effectively filtering interference from hundred-micrometer-level false-positive signals with unprecedented precision. The UHF-tailored T1-T2 dual-mode DMA contrast agents hold promise for elevating the accuracy of MR imaging in disease diagnosis.

Ligand-Induced Atomically Segregation-Tunable Alloy Nanoprobes for Enhanced Magnetic Resonance Imaging.

Bimetallic iron-noble metal alloy nanoparticles have emerged as promising contrast agents for magnetic resonance imaging (MRI) due to their biocompatibility and facile control over the element distribution. However, the inherent surface energy discrepancy between iron and noble metal often leads to Fe atom segregation within the nanoparticle, resulting in limited iron-water molecule interactions and, consequently, diminished relaxometric performance. In this study, we present the development of a class of ligand-induced atomically segregation-tunable alloy nanoprobes (STAN) composed of bimetallic iron-gold nanoparticles. By manipulating the oxidation state of Fe on the particle surface through varying molar ratios of oleic acid and oleylamine ligands, we successfully achieve surface Fe enrichment. Under the application of a 9 T MRI system, the optimized STAN formulation, characterized by a surface Fe content of 60.1 at %, exhibits an impressive r1 value of 2.28 mM-1·s-1, along with a low r2/r1 ratio of 6.2. This exceptional performance allows for the clear visualization of hepatic tumors as small as 0.7 mm in diameter in vivo, highlighting the immense potential of STAN as a next-generation contrast agent for highly sensitive MR imaging.

Structural Defect-Enabled Magnetic Neutrality Nanoprobes for Ultra-High-Field Magnetic Resonance Imaging of Isolated Tumor Cells in Vivo.

The identification of metastasis "seeds," isolated tumor cells (ITCs), is of paramount importance for the prognosis and tailored treatment of metastatic diseases. The conventional approach to clinical ITCs diagnosis through invasive biopsies is encumbered by the inherent risks of overdiagnosis and overtreatment. This underscores the pressing need for noninvasive ITCs detection methods that provide histopathological-level insights. Recent advancements in ultra-high-field (UHF) magnetic resonance imaging (MRI) have ignited hope for the revelation of minute lesions, including the elusive ITCs. Nevertheless, currently available MRI contrast agents are susceptible to magnetization-induced strong T2-decaying effects under UHF conditions, which compromises T1 MRI capability and further impedes the precise imaging of small lesions. Herein, this study reports a structural defect-enabled magnetic neutrality nanoprobe (MNN) distinguished by its paramagnetic properties featuring an exceptionally low magnetic susceptibility through atomic modulation, rendering it almost nonmagnetic. This unique characteristic effectively mitigates T2-decaying effect while concurrently enhancing UHF T1 contrast. Under 9 T MRI, the MNN demonstrates an unprecedentedly low r2/r1 value (≈1.06), enabling noninvasive visualization of ITCs with an exceptional detection threshold of ≈0.16 mm. These high-performance MNNs unveil the domain of hitherto undetectable minute lesions, representing a significant advancement in UHF-MRI for diagnostic purposes and fostering comprehensive metastasis research.

Ligand-Mediated Magnetism-Conversion Nanoprobes for Activatable Ultra-High Field Magnetic Resonance Imaging.

Ultra-high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low-field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand-mediated magnetism-conversion nanoprobe (MCNP) composed of 3-mercaptopropionic acid ligand-coated silver-gadolinium bimetallic nanoparticles. The MCNP exhibits a pH-dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH-activatable UHF MRI. Under neutral pH, the thiolate (-S- ) ligands lead to short τ'm and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (-SH) ligands, resulting in prolonged τ'm and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH-sensitive changes in Ag-S binding affinity of the MCNP lead to a remarkable (>10-fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next-generation UHF-tailored smart MRI contrast agent.

A Cancer Cell Selective Replication Stress Nano Amplifier Promotes Replication Fork Catastrophe to Overcome Radioresistance.

Replication stress (RS) induced by DNA damage plays a significant role in conferring the anticancer effects of radiotherapy and is tightly associated with radioresistance of cancer cells. Amplification of RS represents an effective approach to improving the efficacy of radiotherapy, although the development of selective RS amplifiers remains an unexplored frontier. We herein present an RS nano amplifier (RSNA) consisting of a catalytic FePt nanoparticle loaded with the chemotherapeutic doxorubicin (DOX), which selectively exacerbates RS in cancer cells by promoting replication fork (RF) catastrophe. RSNA converts the excessive reactive oxygen species (ROS) in cancer cells into oxygen, enhancing the DNA-damaging effects of radiotherapy to create more template lesions that impede RF progression in coalition with DOX. After radiation, ROS scavenging by RSNA accelerates RF progression through damaged template strands, increasing the frequency of RF collapse into double-strand breaks. Moreover, pretreatment with RSNA accumulates cancer cells in the S phase, exposing more RFs to radiation-induced RS. These effects of RSNA convergently maximize RS in cancer cells, effectively overcoming the radioresistance of cancer cells without affecting normal cells. Our study demonstrates the feasibility of selectively amplifying RS to boost radiotherapy.

Fabrication of magnetic nanoprobes for ultrahigh-field magnetic resonance imaging.

Ultrahigh-field magnetic resonance imaging (UHF-MRI) has been attracting tremendous attention in biomedical imaging owing to its high signal-to-noise ratio, superior spatial resolution, and fast imaging speed. However, at UHF-MRI, there is a lack of proper imaging probes that can impart superior imaging sensitivity of disease lesions because conventional contrast agents generally produce pronounced susceptibility artifacts and induce very strong T2 decay effects, thus hindering satisfactory imaging performance. This review focused on the recent development of high-performance nanoprobes that can improve the sensitivity and specificity of UHF-MRI. Firstly, the contrast enhancement mechanism of nanoprobes at UHF-MRI has been elucidated. In particular, the strategies for modulating nanoprobe performance, including size effects, metal alloying and magnetic-dopant effects, surface effects, and stimuli-response regulation, have been comprehensively discussed. Furthermore, we illustrate the remarkable advances in the design of UHF-MRI nanoprobes for medical diagnosis, such as early-stage primary tumor and metastasis imaging, angiography, and dynamic monitoring of biosignaling factors in vivo. Finally, we provide a summary and outlook on the development of cutting-edge UHF-MRI nanoprobes for advanced biomedical imaging.

A K+-sensitive AND-gate dual-mode probe for simultaneous tumor imaging and malignancy identification.

Although molecular imaging probes have the potential to non-invasively diagnose a tumor, imaging probes that can detect a tumor and simultaneously identify tumor malignancy remain elusive. Here, we demonstrate a potassium ion (K+) sensitive dual-mode nanoprobe (KDMN) for non-invasive tumor imaging and malignancy identification, which operates via a cascaded 'AND' logic gate controlled by inputs of magnetic resonance imaging (MRI) and fluorescence imaging (FI) signals. We encapsulate commercial K+ indicators into the hollow cavities of magnetic mesoporous silica nanoparticles, which are subsequently coated with a K+-selective membrane that exclusively permits the passage of K+ while excluding other cations. The KDMN can readily accumulate in tumors and enhance the MRI contrast after systemic administration. Spatial information of the tumor lesion is thus accessible via MRI and forms the first layer of the 'AND' gate. Meanwhile, the KDMN selectively captures K+ and prevents interference from other cations, triggering a K+-activated FI signal as the second layer of the 'AND' gate in the case of a malignant tumor with a high extracellular K+ level. This dual-mode imaging approach effectively eliminates false positive or negative diagnostic results and allows for non-invasive imaging of tumor malignancy with high sensitivity and accuracy.

A Sub-Nanostructural Transformable Nanozyme for Tumor Photocatalytic Therapy.

The structural change-mediated catalytic activity regulation plays a significant role in the biological functions of natural enzymes. However, there is virtually no artificial nanozyme reported that can achieve natural enzyme-like stringent spatiotemporal structure-based catalytic activity regulation. Here, we report a sub-nanostructural transformable gold@ceria (STGC-PEG) nanozyme that performs tunable catalytic activities via near-infrared (NIR) light-mediated sub-nanostructural transformation. The gold core in STGC-PEG can generate energetic hot electrons upon NIR irradiation, wherein an internal sub-nanostructural transformation is initiated by the conversion between CeO2 and electron-rich state of CeO2-x, and active oxygen vacancies generation via the hot-electron injection. Interestingly, the sub-nanostructural transformation of STGC-PEG enhances peroxidase-like activity and unprecedentedly activates plasmon-promoted oxidase-like activity, allowing highly efficient low-power NIR light (50 mW cm-2)-activated photocatalytic therapy of tumors. Our atomic-level design and fabrication provide a platform to precisely regulate the catalytic activities of nanozymes via a light-mediated sub-nanostructural transformation, approaching natural enzyme-like activity control in complex living systems.

Artificially engineered antiferromagnetic nanoprobes for ultra-sensitive histopathological level magnetic resonance imaging.

Histopathological level imaging in a non-invasive manner is important for clinical diagnosis, which has been a tremendous challenge for current imaging modalities. Recent development of ultra-high-field (UHF) magnetic resonance imaging (MRI) represents a large step toward this goal. Nevertheless, there is a lack of proper contrast agents that can provide superior imaging sensitivity at UHF for disease detection, because conventional contrast agents generally induce T2 decaying effects that are too strong and thus limit the imaging performance. Herein, by rationally engineering the size, spin alignment, and magnetic moment of the nanoparticles, we develop an UHF MRI-tailored ultra-sensitive antiferromagnetic nanoparticle probe (AFNP), which possesses exceptionally small magnetisation to minimize T2 decaying effect. Under the applied magnetic field of 9 T with mice dedicated hardware, the nanoprobe exhibits the ultralow r2/r1 value (~1.93), enabling the sensitive detection of microscopic primary tumours (<0.60 mm) and micrometastases (down to 0.20 mm) in mice. The sensitivity and accuracy of AFNP-enhanced UHF MRI are comparable to those of the histopathological examination, enabling the development of non-invasive visualization of previously undetectable biological entities critical to medical diagnosis and therapy.

An Ultrahigh-Field-Tailored T1 -T2 Dual-Mode MRI Contrast Agent for High-Performance Vascular Imaging.

The assessment of vascular anatomy and functions using magnetic resonance imaging (MRI) is critical for medical diagnosis, whereas the commonly used low-field MRI system (≤3 T) suffers from low spatial resolution. Ultrahigh field (UHF) MRI (≥7 T), with significantly improved resolution and signal-to-noise ratio, shows great potential to provide high-resolution vasculature images. However, practical applications of UHF MRI technology for vascular imaging are currently limited by the low sensitivity and accuracy of single-mode (T1 or T2 ) contrast agents. Herein, a UHF-tailored T1 -T2 dual-mode iron oxide nanoparticle-based contrast agent (UDIOC) with extremely small core size and ultracompact hydrophilic surface modification, exhibiting dually enhanced T1 -T2 contrast effect under the 7 T magnetic field, is reported. The UDIOC enables clear visualization of microvasculature as small as ≈140 µm in diameter under UHF MRI, extending the detection limit of the 7 T MR angiography. Moreover, by virtue of high-resolution UHF MRI and a simple double-checking process, UDIOC-based dual-mode dynamic contrast-enhanced MRI is successfully applied to detect tumor vascular permeability with extremely high sensitivity and accuracy, providing a novel paradigm for the precise medical diagnosis of vascular-related diseases.

Artificially Engineered Cubic Iron Oxide Nanoparticle as a High-Performance Magnetic Particle Imaging Tracer for Stem Cell Tracking.

Stem cell therapies are increasingly recognized as the future direction of regenerative medicine, but the biological fate of the administrated stem cells remains a major concern for clinical translation, which calls for an approach to efficiently monitoring the stem cell behaviors in vivo. Magnetic particle imaging (MPI) is an emerging technology for cell tracking; however, its utility has been largely restricted due to the lack of optimal magnetic nanoparticle tracers. Herein, by controlled engineering of the size and shape of magnetic nanoparticles tailored to MPI physics theory, a specialized MPI tracer, based on cubic iron oxide nanoparticles with an edge length of 22 nm (CIONs-22), is developed. Due to the inherent lower proportion of disordered surface spins, CIONs-22 exhibit significantly larger saturation magnetization than that of spherical ones, while they possess similar saturation magnetization but smaller coercivity compared to larger-sized CIONs. These magnetic properties of CIONs-22 warrant high sensitivity and resolution of MPI. With their efficient cellular uptake, CIONs-22 exhibit superior MPI performance for stem cell labeling and tracking compared to the commercialized tracer Vivotrax. By virtue of these advantages, CIONs-22 enable real-time and prolonged monitoring of the spatiotemporal trajectory of stem cells transplanted to hindlimb ischemia mice, which demonstrates the great potential of CIONs-22 as MPI tracers to advance stem cell therapies.

Dynamically Reversible Iron Oxide Nanoparticle Assemblies for Targeted Amplification of T1-Weighted Magnetic Resonance Imaging of Tumors.

Smart magnetic resonance (MR) contrast agents, by which MR contrast can be selectively enhanced under acidic tumor microenvironment, are anticipated to significantly improve the diagnostic accuracy. Here, we report pH-sensitive iron oxide nanoparticle assemblies (IONAs) that are cross-linked by small-molecular aldehyde derivative ligands. The dynamic formation and cleavage of hydrazone linkages in neutral and acidic environments, respectively, allow the reversible response of the nanoassemblies to pH variations. At neutral pH, IONAs are structurally robust due to the cross-linking by the strong hydrazone bonds. In acidic tumor microenvironment, the hydrazone bonds are cleaved so that the IONAs are quickly disassembled into a large number of hydrophilic extremely small-sized iron oxide nanoparticles (ESIONs). As a result, significantly enhanced T1MR contrast is achieved, as confirmed by the measurement of r1 values at different pH conditions. Such acidity-targeting MR signal amplification by the pH-sensitive IONAs was further validated in vivo, demonstrating a novel T1 magnetic resonance imaging (MRI) strategy for highly sensitive imaging of acidic tumors.

Smart Organic-Inorganic Nanogels for Activatable Theranostics.

Intelligent polymeric nanogels, with the rationally designed stimuli-responsive drug delivery and controlled drug release, have attracted considerable attention as an ideal nanoplatform for activatable therapy. On the other hand, functional inorganic nanomaterials are widely used as medical imaging agents due to their unique magnetic or optical properties. The construction of stimuli-responsive polymeric nanogels incorporating with functional inorganic nanomaterials inherits the excellent properties of both polymers and inorganic nanomaterials, consequently, the resulted organic-inorganic hybrid nanogels naturally exhibit stimuli-responsive multi-functionalities for both imaging and therapy. In this review, we summarize the recent advances of stimuli-responsive organic-inorganic hybrid nanogels. Firstly, we discuss the physical and chemical methods thus far developed for the integration of polymeric nanogels and inorganic nanomaterials, and then we show the typical examples of activatable theranostic applications using organic-inorganic hybrid nanogels. In the end, the existing challenges and future directions are briefly discussed.

Dynamic supraparticles for the treatment of age-related diseases.

Age-related diseases (ARDs) are arising as a major threat to public health in our fast-aging society. Current development of nanomedicine has sparked much optimism toward ARDs management by improving drug delivery and controlled drug release. However, effective treatments for ARDs, such as cancer and Alzheimer's diseases (AD), are still lacking, due to the complicated pathological features of ARDs including multifactorial pathogenesis, intricate disease microenvironment, and dynamic symptom manifestation. Recently, dynamic supraparticles (DS), which are reversibly self-assembled functional nanoparticles, have provided a novel strategy for combating ARDs. Besides the intrinsic advantages of nanomedicine including multifunctional and multitarget, DS are capable of dynamic structural reconfiguration upon certain stimulation, creating another layer of maneuverability that allows programmed response to the spatiotemporal alterations of ARDs during progression and treatment. In this review, we will overview the challenges faced by ARDs management, and discuss the unique opportunities brought by DS. Then, we will summarize the designed synthesis of DS for ARDs treatment. Finally, we will dissect the therapeutic targets in ARDs that can be exploited by DS, and present the encouraging advances in this field. Hopefully, this review will bridge our knowledge of the design principle of DS and ARDs management, which may inspire the future development of potent theranostic agents to improve the healthcare.

Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis.

Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma.

Tau-Targeted Multifunctional Nanocomposite for Combinational Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) remains an incurable disease and lacks efficient diagnostic methods. Most AD treatments have focused on amyloid-ß (Aß) targeted therapy; however, it is time to consider the alternative theranostics due to accumulated findings of weak correlation between Aß deposition and cognition, as well as the failures of Phase III clinical trial on Aß targeted therapy. Recent studies have shown that the tau pathway is closely associated with clinical development of AD symptoms, which might be a potential therapeutic target. We herein construct a methylene blue (MB, a tau aggregation inhibitor) loaded nanocomposite (CeNC/IONC/MSN-T807), which not only possesses high binding affinity to hyperphosphorylated tau but also inhibits multiple key pathways of tau-associated AD pathogenesis. We demonstrate that these nanocomposites can relieve the AD symptoms by mitigating mitochondrial oxidative stress, suppressing tau hyperphosphorylation, and preventing neuronal death both in vitro and in vivo. The memory deficits of AD rats are significantly rescued upon treatment with MB loaded CeNC/IONC/MSN-T807. Our results indicate that hyperphosphorylated tau-targeted multifunctional nanocomposites could be a promising therapeutic candidate for Alzheimer's disease.

Squamosamide derivative FLZ inhibits TNF-α-induced ICAM-1 expression via down-regulation of the NF-κB signaling pathway in ARPE-19 cells.

Dysfunction of the retinal pigment epithelium (RPE) resulting from chronic inflammation is implicated in the pathogenesis of age-related macular degeneration (AMD). It has been reported that tumor necrosis factor-α (TNF-α) could induce intercellular adhesion molecule-1 (ICAM-1) expression in RPE cells. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant anti-inflammatory activity. However, the effects of FLZ on TNF-α-induced ICAM-1 expression in RPE cells remain unknown. Therefore, in the present study, we evaluated the effects of FLZ on TNF-α-induced ICAM-1 expression in RPE cells. We found that FLZ prevented TNF-α-induced ICAM-1 expression and the ability of monocytes to adhere to ARPE-19 cells induced by TNF-α. Furthermore, FLZ inhibited TNF-α-induced NF-κB p65 expression, as well as phosphorylation of IκBα in ARPE-19 cells. Taken together, these results suggest that FLZ inhibited TNF-α-induced ICAM-1 expression through blocking NF-κB signaling pathway in ARPE-19 cells. Thus, FLZ could be used for designing novel therapeutic agents against AMD.