Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation-inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drug-resistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.

Epilepsy significantly impacts global health, affecting about 65 million people worldwide, along with various animal species. The diagnostic processes of epilepsy are often hindered by the transient and unpredictable nature of seizures. Here we propose a multi-space alignment approach based on cross-species and cross-modality electroencephalogram (EEG) data to enhance the detection capabilities and understanding of epileptic seizures. By employing deep learning techniques, including domain adaptation and knowledge distillation, our framework aligns cross-species and cross-modality EEG signals to enhance the detection capability beyond traditional within-species and within-modality models. Experiments on multiple surfaces and intracranial EEG datasets of humans and canines demonstrated substantial improvements in detection accuracy, achieving over 90% AUC scores for cross-species and cross-modality seizure detection with extremely limited labeled data from the target species/modality. To our knowledge, this is the first study that demonstrates the effectiveness of integrating heterogeneous data from different species and modalities to improve EEG-based seizure detection performance. This is a pilot study that provides insights into the challenges and potential of multi-species and multi-modality data integration, offering an effective solution for future work to collect huge EEG data to train large brain models.

Resective surgery is an effective approach for long-term seizure control in drug-resistant focal epilepsy when the epileptic focus (EF) can be accurately delineated and removed. However, intraoperative mapping of EF with electrocorticography is laborious, time-consuming, and highly vulnerable to the effects of anesthesia. Here, we demonstrated that activated microglia can be reliable biomarkers for EF localization. Leveraging a newly developed ratiometric Raman nanosensor, ultraHOCls, we successfully visualize proinflammatory microglia in live epileptic mice, allowing for precise EF delineation without the interference of anesthesia. Compared to electrocorticography-guided surgery, ultraHOCl-guided surgery results in a substantial 61% reduction in total seizure burden in epileptic mouse models. Notably, ultraHOCls sprayed on freshly excised human brain tissues can effectively discriminate epileptic regions from non-epileptic tissues with high sensitivity (94.89%) and specificity (93.3%). This work provides an alternative strategy for delineating the EF intraoperatively, potentially revolutionizing surgery outcomes in epilepsy patients.

Epilepsy is a common neurological disorder characterized by a significant rate of disability. Accurate early diagnosis and precise localization of the epileptogenic zone are essential for timely intervention, seizure prevention, and personalized treatment. However, over 30% of patients with epilepsy exhibit negative results on electroencephalography and magnetic resonance imaging (MRI), which can lead to misdiagnosis and subsequent delays in treatment. Consequently, enhancing diagnostic methodologies is imperative for effective epilepsy management. The integration of nanomaterials with biomedicine has led to the development of diagnostic tools for epilepsy. Key advancements include nanomaterial-enhanced neural electrodes, contrast agents, and biochemical sensors. Nanomaterials improve the quality of electrophysiological signals and broaden the detection range of electrodes. In imaging, functionalized magnetic nanoparticles enhance MRI sensitivity, facilitating localization of the epileptogenic zone. NIR-II nanoprobes enable tracking of seizure-related biomarkers with deep tissue penetration. Furthermore, nanomaterials enhance the sensitivity of biochemical sensors for detecting epilepsy biomarkers, which is crucial for early detection. These advancements significantly increase diagnostic sensitivity and specificity. However, challenges remain, particularly regarding biosafety, quality control, and the scalability of fabrication processes. Overcoming these obstacles is essential for successful clinical translation. Artificial-intelligence-based big data analytics can facilitate the development of diagnostic tools by screening nanomaterials with specific properties. This approach may help to address current limitations and improve both effectiveness and safety. This review explores the application of nanomaterials in the diagnosis and detection of epilepsy, with the objective of inspiring innovative ideas and strategies to enhance diagnostic effectiveness.

Epilepsy is a prevalent chronic neurological disorder characterized by seizures resulting from an imbalance between excitatory and inhibitory neurons. While pharmacotherapy remains the standard treatment, traditional pharmacotherapy faces significant challenges, including poor brain penetration, high drug resistance rates, and providing only symptomatic relief, rather than addressing the underlying causes for a comprehensive cure. Recently, the neurovascular complex (NVC) has gained attention for its critical role in the development and progression of epilepsy. Simultaneously, various innovative bio-nanotechnology systems have emerged, specifically designed to enhance drug delivery across the brain and enable precise targeting within the lesion. Herein, this review begins by outlining the core NVC involved in epilepsy treatment, breaking it down into four key components: the blood-brain barrier (BBB), neurons, glial cells, and the microenvironment. The viability of targeting NVC to improve epilepsy therapy is analyzed. Next, innovative bio-nanotechnology systems, detailing their design principles, construction strategies, and preclinical evaluations in epilepsy therapy are highlighted. Finally, the prospects for next-generation nanotechnologies and the challenges that must be overcome for effective clinical translation are discussed. Overall, this review aims to guide the development of more efficient and precise bio-nano therapies, ultimately enhancing treatment outcomes for epilepsy patients.

In magnetic resonance imaging (MRI), quantitative measurements of analytes are hindered by difficulties in distinguishing the MRI signals of activation of the probe by the analyte from those of the accumulation of the intact probe. Here we show that imaging sensitivity and quantitation can be enhanced by ratiometric MRI probes with a high relaxivity-ratio change (more than 2.5-fold at 7 T) via magnetic-susceptibility-dependent magnetic resonance tuning. Specifically, polymeric probes that incorporate paramagnetic Mn-porphyrin and superparamagnetic iron oxide nanoparticles inducing opposite changes in the longitudinal and transverse magnetic relaxivities responded to analyte concentration independently of probe concentration. In mice, the probes allowed for quantitative real-time dynamic imaging of H2O2, H2S or pH in subcutaneous tumours, in livers with drug-induced injury and in orthotropic gliomas. The ratiometric MRI probes may be advantageously used to obtain molecular insight into pathological processes and to circumvent interference from dynamic changes in probe concentration within the body while providing anatomical information.

Epilepsy is a common neurological disease characterized by distinct pathological changes in the epileptogenic zone. Antiseizure drugs (ASDs) are widely used as the primary treatment for epilepsy. To improve the efficiency of ASDs medication, stimuli-responsive nanoscale drug delivery systems (nanoDDSs), triggered by either endogenous or exogenous factors, have been developed and been considered as a noninvasive and spatial-temporal approach to epilepsy theranostics. In this review, we introduce the pathological variations observed in epileptic lesions such as dysregulated neurotransmitter systems, disrupted ion homeostasis, and dynamic inflammatory cytokine networks. Furthermore, we summarize the recent advances in functional nano-assemblies that could be activated by endogenous stimuli of pathological alterations or exogenous stimuli such as electricity, light, and other interventions. Finally, we discuss the remaining challenges and prospect the insight into perspective of future development in this field. In summary, this review aims to highlight the potential of stimuli-responsive nanoDDSs as precise, controllable and efficient strategies for addressing unresolved issues in epilepsy theranostics. STATEMENT OF SIGNIFICANCE: This review summarizes recent progress in pathological changes such as dysregulated neurotransmitter system, disrupted ion homeostasis and dynamic inflammatory cytokine network, and emphasizes endogenous/exogenous stimuli-responsive nanoscale platforms including neurotransmitter-, ion-, and other stimuli-responsive nanoDDSs, providing the prospects of smart nanoDDSs applications and discussing the challenges to offer generalized guideline for further development of epilepsy theranostics.

Surgery remains an essential treatment for managing drug-resistant focal epilepsy, but its accessibility and efficacy are limited in patients without distinct structural abnormalities on magnetic resonance imaging (MRI). Potassium ion (K+), a critical marker for seizure-associated neuronal signaling, shows significant promise for designing sensors targeting hidden epileptic foci. However, existing sensors cannot cross the blood-brain barrier and lack the ability to specifically enrich and amplify K+ signals in the brain with high temporal and spatial resolution. Here, an intravenously administered neuronal signal sorting and amplifying nanosensor (NSAN) is reported that combines real-time dynamic reversible K+ fluorescence imaging with high-resolution structural MRI, enabling electroencephalogram-concordant imaging of MRI-negative epileptic foci. Guided by NSANs, minimally invasive surgery is successfully performed in both intrahippocampal kainic acid (KA) epilepsy model with foci confined to the ipsilateral hippocampus, and intraperitoneal KA model where foci are randomly distributed, resulting in sustained seizure control and cognitive improvement. These findings highlight the NSAN as a transformative tool for visualizing hidden epileptic foci, thereby broadening eligibility for minimally invasive and precision surgical intervention.

As the brain's resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases and therapeutic responses. Although numerous probes are available for imaging pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an 18F-labeled PET tracer (QTFT) that targets the P2Y12, a receptor highly expressed on anti-inflammatory microglia. [18F]QTFT exhibited high binding affinity to the P2Y12 (14.43 nmol/L) and superior blood-brain barrier permeability compared to other candidates. Micro-PET imaging in IL-4-induced neuroinflammation models showed higher [18F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y12 antagonist. Furthermore, [18F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y12 in anti-inflammatory microglia. In a pilot clinical study, [18F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [18F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y12 overexpressed in anti-inflammatory microglia.

Core-shell magnetic particles consisting of magnetic core and functional shells have aroused widespread attention in multidisciplinary fields spanning chemistry, materials science, physics, biomedicine, and bioengineering due to their distinctive magnetic properties, tunable interface features, and elaborately designed compositions. In recent decades, various surface engineering strategies have been developed to endow them desired properties (e.g., surface hydrophilicity, roughness, acidity, target recognition) for efficient applications in catalysis, optical modulation, environmental remediation, biomedicine, etc. Moreover, precise control over the shell structure features like thickness, porosity, crystallinity and compositions including metal oxides, carbon, silica, polymers, and metal-organic frameworks (MOFs) has been developed as the major method to exploit new functional materials. In this review, we highlight the synthesis methods, regulating strategies, interface engineering, and applications of core-shell magnetic particles over the past half-century. The fundamental methodologies for controllable synthesis of core-shell magnetic materials with diverse organic, inorganic, or hybrid compositions, surface morphology, and interface property are thoroughly elucidated and summarized. In addition, the influences of the synthesis conditions on the physicochemical properties (e.g., dispersibility, stability, stimulus-responsiveness, and surface functionality) are also discussed to provide constructive insight and guidelines for designing core-shell magnetic particles in specific applications. The brand-new concept of "core-shell assembly chemistry" holds great application potential in bioimaging, diagnosis, micro/nanorobots, and smart catalysis. Finally, the remaining challenges, future research directions and new applications for the core-shell magnetic particles are predicted and proposed.

In situ monitoring microRNA (miRNA) expression in vivo holds immense potential for directly visualizing the occurrence and progression of tumors. However, the significant barrier to developing a probe that can overcome the low abundance of miRNAs while providing an output signal with unlimited tissue penetration depth remains formidable. In this study, we developed a DNA machine-based magnetic resonance imaging nanoprobe (MRINP) for amplified detection of miR-21 in vivo. The MRINP was constructed with superparamagnetic Fe3O4 nanoparticles (NPs), paramagnetic Gd-DOTA complexes, and miR-21-activated DNA machines; the DNA machine was composed of hairpin DNAzyme (HD) strands serving as the DNAzyme walker and hairpin substrate (HS) strands serving as the track. Once uptake into tumor cells, the intracellular miR-21 specifically recognized and hybridized with the HD strand, restoring the activity of DNAzyme. Subsequently, the DNAzyme walker autonomously traveled on the surface of MRINP, and each step movement of the DNAzyme walker resulted in the cleavage of its substrate strands and the ensued release of the Gd-DOTA complex-labeled oligonucleotides, turning on the T1 signal of Gd-DOTA complexes for in situ imaging of miR-21 in tumor-bearing mice. This strategy would offer a promising approach for mapping tumor-specific biomarkers in vivo with unlimited penetration depth.

Nitric oxide (NO), a pivotal signalling molecule, plays multifaceted roles in physiological and pathological processes, including cardiovascular and immune functions, neurotransmission and cancer progression. Nevertheless, measuring NO in vivo is challenging due to its transient nature and the complexity of the biological environment. Here we describe NO-responsive magnetic probes made of crosslinked superparamagnetic iron oxide nanoparticles tethered to a NO-sensitive cleavable linker for highly sensitive and selective NO magnetic resonance imaging in vivo. These probes enable the detection of NO at concentrations as low as 0.147 μM, allowing for the imaging and quantification of NO in mouse tumour models, studying its effects on tumour progression and immunity and assessing the response of tumour-associated macrophages to cancer immunotherapeutic agents. Additionally, they facilitate concurrent anatomical and molecular imaging of organs, helping to identify pathological alterations in the liver. Overall, these probes represent promising non-invasive tools for investigating the dose-dependent conflicting role of NO in physiological and pathophysiological processes.

Over the past decade, precision medicine has garnered increasing attention, making significant strides in discovering new therapeutic drugs and mechanisms, resulting in notable achievements in symptom alleviation, pain reduction, and extended survival rates. However, the limited target specificity of primary drugs and inter-individual differences have often necessitated high-dosage strategies, leading to challenges such as restricted deep tissue penetration rates and systemic side effects. Material science advancements present a promising avenue for these issues. By leveraging the distinct internal features of diseased regions and the application of specific external stimuli, responsive materials can be tailored to achieve targeted delivery, controllable release, and specific biochemical reactions. This review aims to highlight the latest advancements in stimuli-responsive materials and their potential in precision medicine. Initially, we introduce disease-related internal stimuli and capable external stimuli, elucidating the reaction principles of responsive functional groups. Subsequently, we provide a detailed analysis of representative pre-clinical achievements of stimuli responsive materials across various clinical applications, including enhancements in the treatment of cancers, injury diseases, inflammatory diseases, infection diseases, and high-throughput microfluidic biosensors. Finally, we discuss some clinical challenges, such as off-target effects, long-term impacts of nano-materials, potential ethical concerns, and offer insights into future perspectives of stimuli-responsive materials.

This review highlights recent progress in utilizing iron oxide nanoparticles (IONPs) as a safer alternative to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). It consolidates findings from multiple studies, discussing current T1 contrast agents (CAs), the synthesis techniques for IONPs, the theoretical principles for designing IONP-based MRI CAs, and the key factors that impact their T1 contrast efficacy, such as nanoparticle size, morphology, surface modifications, valence states, and oxygen vacancies. Furthermore, we summarize current strategies to achieve IONP-based responsive CAs, including self-assembly/disassembly and distance adjustment. This review also evaluates the biocompatibility, organ accumulation, and clearance pathways of IONPs for clinical applications. Finally, the challenges associated with the clinical translation of IONP-based T1 CAs are included.

Magnetic resonance imaging contrast agents can enhance diagnostic precision but often face limitations such as short imaging windows, low tissue specificity, suboptimal contrast enhancement, or potential toxicity, which affect resolution and long-term monitoring. Here, we present a protein contrast agent based on lanmodulin, engineered with a single-point mutation at position 108 from N to D to yield maximum gadolinium binding sites. After loading with Gd3+ ions, the resulting protein complex, LanND-Gd, exhibits efficient renal clearance, high relaxivity, and prolonged renal retention compared to commercial agents. LanND-Gd enables high-performance visualization of whole-body structures and brain vasculature in male mice at a resolution finer than one hundred micrometers. In male ischemia mouse models, LanND-Gd also improves kidney dysfunction monitoring while minimizing risks of neural toxicity or immunogenic reactions. This protein-based contrast agent offers superior image quality, improved biocompatibility, and extended imaging timeframes, promising significant advancements in magnetic resonance-based diagnostics and patient outcomes.

Implantable neural electrodes are crucial in neurological diagnosis and therapy because of their ultra-high spatial resolution, but they are constrained by high impedance and insufficient charge injection capacity, resulting in noise that often obscures valuable signals. Emerging nanotechnologies are powerful tools to improve sensitivity and biocompatibility. Herein, we developed quantized 2D MoS2 electrodes by incorporating bioactive MoS2 nanosheets onto bare electrodes, achieving sensitive, compatible recording. The 2D materials can create tiny nanowells, which behaved as quantized charge storage units and thus improved sensitivity. The key sensitivity indicators, impedance and cathode charge storage capacity, showed a multifold increase. The 17.7-fold improvement in catalytic activity of MoS2 electrodes facilitated effective current transmission and reduced inflammatory response. In vivo recording showed that the sensitivity of local field potentials increased throughout frequency range and peaked at a 4.7-fold in β rhythm. This work provides a general strategy for achieving effective diagnoses of neurological disorders.

Molecular imaging holds the potential for noninvasive and accurate grading of liver fibrosis. It is limited by the lack of biomarkers that strongly correlate with liver fibrosis grade. Here, we discover the grading potential of fibroblast activation protein alpha (FAPα) for liver fibrosis through transcriptional analysis and biological assays on clinical liver samples. The protein and mRNA expression of FAPα are linearly correlated with fibrosis grade (R2 = 0.89 and 0.91, respectively). A FAPα-responsive MRI molecular nanoprobe is prepared for quantitatively grading liver fibrosis. The nanoprobe is composed of superparamagnetic amorphous iron nanoparticles (AFeNPs) and paramagnetic gadoteric acid (Gd-DOTA) connected by FAPα-responsive peptide chains (ASGPAGPA). As liver fibrosis worsens, the increased FAPα cut off more ASGPAGPA, restoring a higher T1-MRI signal of Gd-DOTA. Otherwise, the signal remains quenched due to the distance-dependent magnetic resonance tuning (MRET) effect between AFeNPs and Gd-DOTA. The nanoprobe identifies F1, F2, F3, and F4 fibrosis, with area under the curve of 99.8%, 66.7%, 70.4%, and 96.3% in patients' samples, respectively. This strategy exhibits potential in utilizing molecular imaging for the early detection and grading of liver fibrosis in the clinic.

The study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model.

The epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/β-catenin/GSK 3β signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated.

The results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/β-catenin/GSK 3β signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects.

S-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB.

Epilepsy is a common yet complex neurological disorder. Historically, antiseizure medications (ASMs) have faced challenges in crossing the blood-brain barrier (BBB) and targeting the epileptogenic zone, creating a bottleneck in seizure management. Certain nanomaterials can facilitate drug penetration through the BBB and enable stimulus-responsive drug release, thereby enhancing targeted and efficient drug utilization while reducing adverse reactions in other brain tissues and peripherally. This article reviews the current researches on stimulus-responsive nanosystems applicable in antiepileptic therapy, as well as nanotechnology applications that improve the brain delivery of ASMs.

Fluorescence sensing is crucial to studying biological processes and diagnosing diseases, especially in the second near-infrared (NIR-II) window with reduced background signals. However, it's still a great challenge to construct "off-on" sensors when the sensing wavelength extends into the NIR-II region to obtain higher imaging contrast, mainly due to the difficult synthesis of spectral overlapped quencher. Here, we present a new fluorescence quenching strategy, which utilizes steric hindrance quencher (SHQ) to tune the molecular packing state of fluorophores and suppress the emission signal. Density functional theory (DFT) calculations further reveal that large SHQs can competitively pack with fluorophores and prevent their self-aggregation. Based on this quenching mechanism, a novel activatable "off-on" sensing method is achieved via bio-analyte responsive invalidation of SHQ, namely the Steric Hindrance Invalidation geNerated Emission (SHINE) strategy. As a proof of concept, the ClO--sensitive SHQ lead to the bright NIR-II signal release in epileptic mouse hippocampus under the skull and high photon scattering brain tissue, providing the real-time visualization of ClO- generation process in living epileptic mice.

Implanted neural electrodes have been widely used to treat brain diseases that require high sensitivity and biocompatibility at the tissue-electrode interface. However, currently used clinical electrodes cannot meet both these requirements simultaneously, which hinders the effective recording of electronic signals. Herein, nanozyme-based neural electrodes incorporating bioinspired atomically precise clusters are developed as a general strategy with a heterogeneous design for multiscale and ultrasensitive neural recording via quantum transport and biocatalytic processes. Owing to the dual high-speed electronic and ionic currents at the electrode-tissue interface, the impedance of nanozyme electrodes is 26 times lower than that of state-of-the-art metal electrodes, and the acquisition sensitivity for the local field potential is ≈10 times higher than that of clinical PtIr electrodes, enabling a signal-to-noise ratio (SNR) of up to 14.7 dB for single-neuron recordings in rats. The electrodes provide more than 100-fold higher antioxidant and multi-enzyme-like activities, which effectively decrease 67% of the neuronal injury area by inhibiting glial proliferation and allowing sensitive and stable neural recording. Moreover, nanozyme electrodes can considerably improve the SNR of seizures in acute epileptic rats and are expected to achieve precise localization of seizure foci in clinical settings.

Epilepsy refers to a disabling neurological disorder featured by the long-term and unpredictable occurrence of seizures owing to abnormal excessive neuronal electrical activity and is closely linked to unresolved inflammation, oxidative stress, and hypoxia. The difficulty of accurate localization and targeted drug delivery to the lesion hinders the effective treatment of this disease. The locally activated inflammatory cells in the epileptogenic region offer a new opportunity for drug delivery to the lesion. In this work, CD163-positive macrophages in the epileptogenic region were first harnessed as Trojan horses after being hijacked by targeted albumin manganese dioxide nanoparticles, which effectively penetrated the brain endothelial barrier and delivered multifunctional nanomedicines to the epileptic foci. Hence, accumulative nanoparticles empowered the visualization of the epileptogenic lesion through microenvironment-responsive MR T1-weight imaging of manganese dioxide. Besides, these manganese-based nanomaterials played a pivotal role in shielding neurons from cell apoptosis mediated by oxidative stress and hypoxia. Taken together, the present study provides an up-to-date approach for integrated diagnosis and treatment of epilepsy and other hypoxia-associated inflammatory diseases. STATEMENT OF SIGNIFICANCE: The therapeutic effects of antiepileptic drugs (AEDs) are hindered by insufficient drug accumulation in the epileptic site. Herein, we report an efficient strategy to use locally activated macrophages as carriers to deliver multifunctional nanoparticles to the brain lesion. As MR-responsive T1 contrast agents, multifunctional BMC nanoparticles can be harnessed to accurately localize the epileptogenic region with high sensitivity and specificity. Meanwhile, catalytic nanoparticles BMC can synergistically scavenge ROS, generate O2 and regulate neuroinflammation for the protection of neurons in the brain.

The alpha-synuclein (α-syn) oligomers hold a central role in the pathology of Parkinson's disease (PD). Achieving accurate detection of α-syn oligomers in vivo presents a promising avenue for early and accurate diagnosis of PD. Magnetic resonance imaging (MRI), with non-invasion and exceptional tissue penetration, offers a potent tool for visualizing α-syn oligomers in vivo. Nonetheless, ensuring diagnostic specificity remains a formidable challenge. Herein, a novel MRI probe (ASOSN) is introduced, which encompasses highly sensitive antiferromagnetic nanoparticles functionalized with single-chain fragment variable antibodies, endowing it with the capacity for discerning recognition and binding to α-syn oligomers and triggering a switchable T1-T2 MRI signal. Significantly, ASOSN possesses the unique capability to accurately discriminate α-syn oligomers from neuroinflammation in vivo. Moreover, ASOSN facilitates the non-invasive and precise visualizing of endogenous α-syn oligomers in living systems. This innovative design heralds the development of a non-invasive visualization strategy for α-syn oligomers, marking a pivotal advancement for early and accurate diagnosis of PD.

Cancer remains a threat to human health. However, if tumors can be detected in the early stage, then the effectiveness of cancer treatment could be significantly improved. Therefore, it is worthwhile to develop more sensitive and accurate cancer diagnostic methods. Herein, we demonstrated an azo reductase (AzoR)-activated magnetic resonance tuning (MRET) probe with a "switch-on" property for specific and sensitive tumor imaging in vivo. Specifically, Gd-labeled DNA1 (DNA1-Gd) and cyclodextrin-coated magnetic nanoparticles (MNP-CD) were employed as enhancer and quencher of MRET, respectively, while DNA2, an azobenzene (Azo) group-modified aptamer (AS1411), served as a linker between enhancer and quencher to construct the MRET probe of MNP@DNA(1-2)-Gd. In tumor tissues with high-level AzoR, the T1-weighted magnetic resonance signal of the MRET probe could be restored by intelligently regulating the switch from "OFF" to "ON" after activation with AzoR, thus accurately indicating the location of the tumor accurately. Moreover, the tumor with a 4 times smaller size than that of the normal tumor model could be imaged based on the proposed MRET probe. The as-proposed MRET-based magnetic resonance imaging strategy not only achieves tumor imaging accurately but also shows promise for early diagnosis of tumors, which might improve patients' survival rates and provide an opportunity for image-guided biomedical applications in the future.

The chemical, physical and biological effects of chiral nanomaterials have inspired general interest and demonstrated important advantages in fundamental science. Here, chiral iron oxide supraparticles (Fe3 O4 SPs) modified by chiral penicillamine (Pen) molecules with g-factor of ≈2 × 10-3 at 415 nm are fabricated, and these SPs act as high-quality magnetic resonance imaging (MRI) contrast agents. Therein, the transverse relaxation efficiency and T2 -MRI results demonstrated chiral Fe3 O4 SPs have a r2 relaxivity of 157.39 ± 2.34 mM-1 ·S-1 for D-Fe3 O4 SPs and 136.21 ± 1.26 mM-1 ·S-1 for L-Fe3 O4 SPs due to enhanced electronic transition dipole moment for D-Fe3 O4 SPs compared with L-Fe3 O4 SPs. The in vivo MRI results show that D-Fe3 O4 SPs exhibit two-fold lower contrast ratio than L-Fe3 O4 SPs, which enhances targeted enrichment in tumor tissue, such as prostate cancer, melanoma and brain glioma tumors. Notably, it is found that D-Fe3 O4 SPs have 7.7-fold higher affinity for the tumor cell surface receptor cluster-of-differentiation 47 (CD47) than L-Fe3 O4 SPs. These findings uncover that chiral Fe3 O4 SPs act as a highly effective MRI contrast agent for targeting and imaging broad tumors, thus accelerating the practical application of chiral nanomaterials and deepening the understanding of chirality in biological and non-biological environments.

The aging of the population is an increasingly serious issue, and many age-related illnesses are on the rise. These illnesses pose a serious threat to the health and safety of elderly individuals and create a serious economic and social burden. Despite substantial research into the pathogenesis of these diseases, their etiology and pathogenesis remain unclear. In recent decades, rodent models have been used in attempts to elucidate these disorders, but such models fail to simulate the full range of symptoms. Nonhuman primates (NHPs) are the most ideal neuroscientific models for studying the human brain and are more functionally similar to humans because of their high genetic similarities and phenotypic characteristics in comparison with humans. Here, we review the literature examining typical NHP brain disease models, focusing on NHP models of common diseases such as dementia, Parkinson's disease, and epilepsy. We also explore the application of electroencephalography (EEG), magnetic resonance imaging (MRI), and optogenetic study methods on NHPs and neural circuits associated with cognitive impairment.

Traditional diagnosis relies on identifying anatomical abnormality, which offers a stage for various anatomical imaging techniques, such as X-ray computed tomography (CT), ultrasonic imaging, and magnetic resonance imaging (MRI). The good capacity of providing anatomical details, especially for soft tissues, popularizes the clinical use of MRI. However, as the understanding of various diseases reaches the molecular level, it is gradually accepted that molecular anomaly often precedes anatomical abnormality. Therefore, molecular imaging, which is aimed at gathering various molecular information in organisms via imaging, starts to gain momentum. Unfortunately, traditional MRI is not capable of molecular imaging. As a result, there is an urgent demand for probes that enable MRI to "see" molecules. A promising design strategy for these probes is to elicit a signal change triggered by the presence of molecular targets, i.e. activation. Benefiting from the rapid development of nanotechnology, a number of nanoparticle-based activatable MRI probes have been developed for molecular imaging. This review summarizes recent advances of activatable MRI nanoprobes for imaging pathological characteristics of cancer, inflammation, and neurodegenerative diseases, with a focus on the design strategies and applications of these probes. In addition, the prospects and challenges of activatable MRI nanoprobes are also discussed.

Imaging plays an integral role in diagnostics and treatment monitoring for conditions affecting the brain; enhanced brain imaging capabilities will improve upon both while increasing the general understanding of how the brain works. T₁-weighted magnetic resonance imaging is the preferred modality for brain imaging. Commercially available contrast agents, which are often required to render readable brain images, have considerable toxicity concerns. In recent years, much progress has been made in developing new contrast agents based on the magnetic features of gadolinium, iron, or magnesium. Nanotechnological approaches for these systems allow for the protected integration of potentially harmful metals with added benefits like reduced dosage and improved transport. Polymeric enhancement of each design further improves biocompatibility while allowing for specific brain targeting. This review outlines research on polymeric nanomedicine designs for T₁-weighted contrast agents that have been evaluated for performance in the brain.

Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. In this study, using the principle of distance-dependent magnetic resonance tuning, we constructed a telomerase-activated magnetic resonance imaging probe (TAMP) by connecting superparamagnetic ferroferric oxide nanoparticles (SPFONs) and paramagnetic Gd-DOTA (Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complexes via telomerase-responsive DNA motifs. Upon telomerase-catalyzed extension of the primer in TAMP, Gd-DOTA-conjugated oligonucleotides can be liberated from the surface of SPFONs through a DNA strand displacement reaction, restoring the T₁ signal of the Gd-DOTA for a direct readout of the telomerase activity. Here we show that, by tracking telomerase activity, this probe provides consistent monitoring of tumor growth kinetics during progression and in response to drug treatment and enables in situ screening of telomerase inhibitors in whole-animal models. This study provides an alternative toolkit for cancer diagnosis, treatment response assessment, and anticancer drug screening.

Accurate identification of the resectable epileptic lesion is a precondition of operative intervention to drug-resistant epilepsy (DRE) patients. However, even when multiple diagnostic modalities are combined, epileptic foci cannot be accurately identified in ∼30% of DRE patients. Inflammation-associated low-density lipoprotein receptor-related protein-1 (LRP1) has been validated to be a surrogate target for imaging epileptic foci. Here, we reported an LRP1-targeted dual-mode probe that is capable of providing comprehensive epilepsy information preoperatively with SPECT imaging while intraoperatively delineating epileptic margins in a sensitive high-contrast manner with surface-enhanced resonance Raman scattering (SERRS) imaging. Notably, a novel and universal strategy for constructing self-assembled monolayer (SAM)-based Raman reporters was proposed for boosting the sensitivity, stability, reproducibility, and quantifiability of the SERRS signal. The probe showed high efficacy to penetrate the blood-brain barrier. SPECT imaging showed the probe could delineate the epileptic foci clearly with a high target-to-background ratio (4.11 ± 0.71, 2 h). Further, with the assistance of the probe, attenuated seizure frequency in the epileptic mouse models was achieved by using SPECT together with Raman images before and during operation, respectively. Overall, this work highlights a new strategy to develop a SPECT/SERRS dual-mode probe for comprehensive epilepsy surgery that can overcome the brain shift by the co-registration of preoperative SPECT and SERRS intraoperative images.

Excising epileptic foci (EF) is the most efficient approach for treating drug-resistant epilepsy (DRE). However, owing to the vast heterogeneity of epilepsies, EF in one-third of patients cannot be accurately located, even after exhausting all current diagnostic strategies. Therefore, identifying biomarkers that truly represent the status of epilepsy and fabricating probes with high targeting specificity are prerequisites for identifying the "concealed" EF. However, no systematic summary of this topic has been published. Herein, the potential biomarkers of EF are first summarized and classified into three categories: functional, molecular, and structural aberrances during epileptogenesis, a procedure of nonepileptic brain biasing toward epileptic tissue. The materials used to fabricate these imaging probes and their performance in defining the EF in preclinical and clinical studies are highlighted. Finally, perspectives for developing the next generation of probes and their challenges in clinical translation are discussed. In general, this review can be helpful in guiding the development of imaging probes defining EF with improved accuracy and holds promise for increasing the number of DRE patients who are eligible for surgical intervention.

Optically monitoring hypochlorous acid (HClO) in living body favors diagnosis and study of inflammatory diseases. However, this has been hampered by limited strategies to develop highly fluorogenic tools in the deep-penetration near-infrared spectrum. Herein, a near-infrared aza-BODIPY-bisferrocene triad Fc₂ -CBDP that unexpectedly achieves an exceptionally sensitive and selective fluorescence turn-on (>220-fold) response toward HClO through single-ferrocene oxidation and boron-alkynyl hydrolysis cascade is reported. Mechanism insight shows that Fc₂ -CBDP features "enhanced charge transfer"-caused quenching due to intramolecular bisferrocene electronic coupling, which is decoupled in the reaction with HClO. The utility of Fc₂ -CBDP for intracellular HClO imaging is evaluated and, more importantly, in vivo high-contrast deep-tissue imaging of lymphatic inflammation and colitis is realized. This work provides new insights into both HClO and ferrocene chemistry, and extends the reach of fluorogenic strategies in the near-infrared biosensing.

To develop a functionalized PEG-PLA nanoparticle system containing ketoconazole (KCZ) to overcome the overactivity of pregnane X receptor (PXR) for the treatment of drug-resistant epilepsy (DRE).

KCZ was developed as a therapy strategy for DRE limited by its lethal hepatotoxicity and minute brain concentration. KCZ-incorporated nanoparticles modified with angiopep-2 (NPs/KCZ) could reduce adverse effects of KCZ and achieve epileptic foci-targeted drug delivery.

NPs/KCZ was prepared by thin-film hydration method and characterized in vitro and in vivo. The efficacy evaluation of NPs/KCZ was evaluated in a kainic acid (KA)-induced mice model of epilepsy with carbamazepine (CBZ) treatment.

The mean particle size and Zeta potential of NPs/KCZ were 17.84 ± 0.33 nm and - 2.28 ± 0.12 mV, respectively. The drug-loading (DL%) of KCZ in nanoparticles was 8.96 ± 0.12 % and the entrapment efficiency (EE%) was 98.56 ± 0.02 %. The critical value of critical micelle concentration was 10^-3.3 mg/ml. No obvious cytotoxicity was found in vitro. The behavioral and electrographic seizure activities were obviously attenuated in NPs/KCZ+CBZ group. The CBZ concentration of brain tissues in mice treated with NPs/KCZ+CBZ was significantly increased than those treated with CBZ alone (P = 0.0028). A significantly decreased expression level of PXR and its downstream proteins was observed in NPs/KCZ+CBZ group compared with that in the control and CBZ group (All P < 0.05).

Our results showed that NPs/KCZ achieved the epileptic foci-targeted delivery of KCZ and ameliorated the efficacy of CBZ on DRE by attenuating the overactivity of PXR.

As a non-invasive imaging monitoring method, molecular imaging can provide the location and expression level of disease signature biomolecules in vivo, leading to early diagnosis of relevant diseases, improved treatment strategies, and accurate assessment of treating efficacy. In recent years, a variety of nanosized imaging probes have been developed and intensively investigated in fundamental/translational research and clinical practice. Meanwhile, as an interdisciplinary discipline, this field combines many subjects of chemistry, medicine, biology, radiology, and material science, etc. The successful molecular imaging not only requires advanced imaging equipment, but also the synthesis of efficient imaging probes. However, limited summary has been reported for recent advances of nanoprobes. In this paper, we summarized the recent progress of three common and main types of nanosized molecular imaging probes, including ultrasound (US) imaging nanoprobes, magnetic resonance imaging (MRI) nanoprobes, and computed tomography (CT) imaging nanoprobes. The applications of molecular imaging nanoprobes were discussed in details. Finally, we provided an outlook on the development of next generation molecular imaging nanoprobes.

Magnetic resonance imaging (MRI) is one of the most important techniques in the diagnosis of many diseases including cancers, where contrast agents (CAs) are usually necessary to improve its precision and sensitivity. Previous MRI CAs are confined to the signal-to-noise ratio (SNR) elevation of lesions for precisely localizing lesions. As nanobiotechnology advances, some new MRI CAs or nanobiotechnology-enabled MRI modes have been established to vary the longitudinal or transverse relaxation of CAs, which are harnessed to detect lesion targets, monitor disease evolution, predict or evaluate curative effect, etc. These distinct cases provide unexpected insights into the correlation of the design principles of these nanobiotechnologies and corresponding MRI CAs with their potential applications. In this review, first, we briefly present the principles, classifications and applications of conventional MRI CAs, and then elucidate the recent advances in relaxation tuning via the development of various nanobiotechnologies with emphasis on the design strategies of nanobiotechnology and the corresponding MRI CAs to target the tumor microenvironment (TME) and biological targets or activities in tumors or other diseases. In addition, we exemplified the advantages of these strategies in disease theranostics and explored their potential application fields. Finally, we analyzed the present limitations, potential solutions and future development direction of MRI after its combination with nanobiotechnology.

Neural electrodes have been widely used to monitor neurological disorders and have a major impact on neuroscience, whereas traditional electrodes are limited to their inherent high impedance, which makes them insensitive to weak signals during recording neural signals. Herein, we developed a neural electrode based on the graphene/Ag van der Waals heterostructure for improving the detection sensitivity and signal-to-noise ratio (SNR). The impedance of the graphene/Ag electrode is reduced to 161.4 ± 13.4 MΩ μm², while the cathode charge-storage capacity (CSCc) reaches 24.2 ± 1.9 mC cm^-2, which is 6.3 and 48.4 times higher than those of the commercial Ag electrodes, respectively. Density functional theory (DFT) results find that the Ag-graphene interface has more doped electronic states, providing faster electron transfer and enhanced interfacial transport. In vivo detection sensitivity and SNR of graphene/Ag electrodes are significantly improved. The current work provides a feasible solution for designing brain electrodes to monitor neural signals more sensitively and accurately.