Cu2+ -Chelatable and ROS-Scavenging MXenzyme as NIR-II-Triggered Blood-Brain Barrier-Crossing Nanocatalyst against Alzheimer's Disease.

Transition-metal dyshomeostasis has been identified as a critical pathogenic factor for the aggregates of amyloid-beta (Aß) peptide, which is associated with the onset and progression of Alzheimer's disease (AD). Excessive transition-metal ions, especially copper ion (Cu2+ ), catalyze the formation of reactive oxygen species (ROS), triggering neuroinflammation and neuronal cell apoptosis. Therefore, developing a robust chelating agent can not only efficiently bind toxic Cu2+ , but also simultaneously scavenge the over-generated ROS that is urgently needed for AD treatment. In this work, a 2D niobium carbide (Nb2 C) MXene-based nano-chelator is constructed and its performance in suppressing Cu2+ -induced accumulation of aggregated Aß peptide and acting as a nanozyme (MXenzyme) with powerful antioxidant property to scavenge excess cellular ROS is explored, and the intrinsic mechanism is revealed by computational simulation. Importantly, the benign photothermal effect of Nb2 C MXenzyme demonstrates the facilitated permeability of the blood-brain barrier under near-infrared laser irradiation, conquering limitations of the most conventional anti-AD therapeutic agents. This work not only demonstrates a favorable strategy for combating AD by engineering Nb2 C MXenzyme-based neuroprotective nano-chelator, but also paves a distinct insight for extending the biomedical applications of MXenes in treating transition-metal dyshomeostasis-and ROS-mediated central nervous system diseases.

Targeted nanotheranostics for the treatment of epilepsy through in vivo hijacking of locally activated macrophages.

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.

Construction of Pepstatin A-Conjugated ultrasmall SPIONs for targeted positive MR imaging of epilepsy-overexpressed P-glycoprotein.

Surgical resection of the epileptogenic region is typically regarded to be practical and efficient for complete elimination of intractable seizures, which cannot be simply controlled by anti-epileptic drugs alone. To achieve a precision removal of the epileptogenic region and even a surgical cure, molecular imaging of epilepsy markers is highly essential for non-invasive accurate detection of the epileptogenic region. In this work, a peptide-targeted nanoprobe, based on ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs), PA-USPIONs, was elaborately constructed to enable highly selective delivery and sensitive T1-weighted positive magnetic resonance (MR) imaging of the epileptogenic region. Especially, Pepstatin A (PA), a small peptide which can specifically target to P-glycoprotein (P-gp) overexpressed at the epileptogenic region in a kainic acid (KA)-induced mice model of seizures, was conjugated onto the surface of PEGylated USPIONs. It has been demonstrated that the as-constructed PA-USPIONs nanoprobes have favorable T1 contrast enhancement and high r1 relaxivity compared with the clinically used T1-MR contrast agent (Gd-DTPA) by systematic in vitro and vivo assessments. Importantly, the toxicity evaluation, especially to brains, was assessed by the histological as well as hematological examinations, demonstrating that the fabricated PA-USPIONs nanoprobes are featured with excellent biocompatibility, guaranteeing the further potential clinical application. This first report on the development of USPIONs as T1-weighted MR contrast agents for active targeting of the epileptogenic region holds the high potential for precise resection of the according lesion in order to achieve therapeutic, often curative purposes.

Dual-targeting and excretable ultrasmall SPIONs for T1-weighted positive MR imaging of intracranial glioblastoma cells by targeting the lipoprotein receptor-related protein.

A precise delineation of the intracranial glioblastoma boundary is urgently required for pre-surgical operations, due to the tumor-inherent infiltrative character of a tumor and the difficulty to completely remove the tumor. Magnetic resonance (MR) imaging is the leading clinical diagnostic tool for brain tumors, where a safe MR contrast agent that targets cancer biomarkers is critical for non-invasive and accurate brain tumor detection. In this work, a multifunctional targeted nanoprobe composed of PEGylated ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs), with surface conjugated Angiopep-2, was successfully constructed by a stepwise reaction. The nanoprobe efficiently crossed the blood-brain barrier (BBB), targeted the glioblastoma and then generated positive contrast enhancement for T1-weighted MR imaging. Angiopep-2 was herein selected as a targeting ligand to construct the dual-targeting nanoprobes for MR imaging of brain tumors, because it can specifically combine to the low-density lipoprotein receptor-related protein (LRP), which is overexpressed in both BBB and glioblastoma cells. The targeting capability and, in particular, the biocompatibility/excretion of these ANG-modified MRI nanoprobes were systematically evaluated not only at the intracellular level in vitro, but also on tumor xenografts in vivo. This first report on ANG-engineered USPIONs as T1-weighted positive MR contrast agents for intracranial targeted glioblastoma imaging, provides a promising application potential for these SPION-based ultrasmall nanoprobes, not only for efficient pre-operative tumor diagnosis, but also for the targeted surgical resection of intracranial glioblastomas.

Engineered superparamagnetic iron oxide nanoparticles (SPIONs) for dual-modality imaging of intracranial glioblastoma via EGFRvIII targeting.

In this work, a peptide-modified, biodegradable, nontoxic, brain-tumor-targeting nanoprobe based on superparamagnetic iron oxide nanoparticles (SPIONs) (which have been commonly used as T 2-weighted magnetic resonance (MR) contrast agents) was successfully synthesized and applied for accurate molecular MR imaging and sensitive optical imaging. PEPHC1, a short peptide which can specifically bind to epidermal growth factor receptor variant III (EGFRvIII) that is overexpressed in glioblastoma, was conjugated with SPIONs to construct the nanoprobe. Both in vitro and in vivo MR and optical imaging demonstrated that the as-constructed nanoprobe was effective and sensitive for tumor targeting with desirable biosafety. Given its desirable properties such as a 100 nm diameter (capable of penetration of the blood-brain barrier) and bimodal imaging capability, this novel and versatile multimodal nanoprobe could bring a new perspective for elucidating intracranial glioblastoma preoperative diagnosis and the accuracy of tumor resection.