Covalent organic framework based cytoprotective therapy after ischemic stroke.

Cytoprotection has emerged as an effective therapeutic strategy for mitigating brain injury following acute ischemic stroke (AIS). The sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel plays a pivotal role in brain edema and neuroinflammation. However, the practical use of the inhibitor glyburide (GLB) is hindered by its low bioavailability. Additionally, the elevated reactive oxygen species (ROS) after AIS exacerbate SUR1-TRPM4 activation, contributing to irreversible brain damage. To overcome these challenges, GLB and superoxide dismutase (SOD) were embedded in a covalent organic framework (COF) with a porous structure and great stability. The resulting S/G@COF demonstrated significant improvements in survival and neurological functions. This was achieved by eliminating ROS, preventing neuronal loss and apoptosis, suppressing neuroinflammation, modulating microglia activation, and ameliorating blood-brain barrier (BBB) disruption. Mechanistic investigations revealed that S/G@COF concurrently activated the Wnt/ß-catenin signaling pathway while suppressing the upregulation of SUR1-TRPM4. This study underscores the potential of employing multi-target therapy and drug modification in cytoprotective strategies for ischemic stroke.

Imine-Linked Covalent Organic Framework Modulates Oxidative Stress in Alzheimer's Disease.

Oxidative stress due to Cu2+-triggered aggregation of ß-amyloid protein (Aß) and reactive oxygen species (ROS) overexpression in the brain is an important hallmark of early stages of Alzheimer's disease (AD) pathogenesis. The ideal modulator for improving the oxidative stress microenvironment in AD brains should take both Cu2+ and ROS into consideration, which has been rarely reported. Here, a combined therapeutic strategy was achieved by co-encapsulating superoxide dismutase (SOD) and catalase (CAT) in imine-linked covalent organic frameworks (COFs), which were modified with peptide KLVFF (T5). The nanocomposite SC@COF-T5 exhibited an oxidative stress eradicating ability through ROS elimination and Cu2+ chelation, combined with the inhibition of Aß42 monomer aggregation and disaggregation of Aß42 fibrils. In vivo experiments indicated that SC@COF-T5 with a high blood-brain barrier (BBB) penetration efficiency was effective to reduce Aß deposition, expression of pro-inflammatory cytokines, ROS levels, and neurologic damage in AD model mice, consequently rescuing memory deficits of AD mice. This work not only confirms the feasibility and merits of the therapeutic strategy regarding multiple targets for treatment of early AD pathogenesis but also opens up a novel direction for imine-linked COFs in biomedical applications.

Brain Glucose Activated MRI Contrast Agent for Early Diagnosis of Alzheimer's Disease.

Brain glucose is an important biomarker of Alzheimer's disease (AD) and has a high specificity especially for early AD. Activatable magnetic resonance imaging (MRI) contrast agents (CAs) serve as a robust technology in the early diagnosis of many diseases; however, there is a lack of glucose-specific MRI CAs. To address this issue, in this work, we synthesized a novel MRI CA (ZIF-8/GOx@MnO2@PEG, ZGMP) that consists of porous zeolitic imidazolate framework-8 (ZIF-8) attached with glucose oxidase (GOx) and modified by MnO2 and PEG. The cascade reaction of brain glucose with ZGMP could result in the production of Mn(II) and an enhanced MRI signal. An early AD mouse model was constructed through injection of the Aß42 oligomer into the parenchyma of mice and utilized to verify the brain glucose activated MRI of ZGMP. The results indicated a higher glucose uptake in early AD mice compared to that in normal mice, with an obviously enhanced T1WI at the region of interest. This work gets rid of the need for a specific scanning sequence for glucose MRI, paving a convenient way for MRI diagnosis of early AD.

Synergistic Reinforcing of Immunogenic Cell Death and Transforming Tumor-Associated Macrophages Via a Multifunctional Cascade Bioreactor for Optimizing Cancer Immunotherapy.

Immunogenic cell death (ICD) has aroused widespread attention because it can reconstruct a tumor microenvironment and activate antitumor immunity. This study proposes a two-way enhancement of ICD based on a CaO2 @CuS-MnO2 @HA (CCMH) nanocomposite to overcome the insufficient damage-associated molecular patterns (DAMPs) of conventional ICD-inducers. The near-infrared (NIR) irradiation (1064 nm) of CuS nanoparticles generates 1 O2 through photodynamic therapy (PDT) to trigger ICD, and it also damages the Ca2+ buffer function of mitochondria. Additionally, CaO2 nanoparticles react with H2 O to produce a large amount of O2 and Ca2+ , which respectively lead to enhanced PDT and Ca2+ overload during mitochondrial damage, thereby triggering a robust ICD activation. Moreover, oxidative-damaged mitochondrial DNA, induced by PDT and released from tumor cells, reprograms the immunosuppressive tumor microenvironment by transforming tumor-associated macrophages to the M1 subphenotype. This study shows that CCMH with NIR-II irradiation can elicit adequate DAMPs and an active tumor-immune microenvironment for both 4T1 and CT26 tumor models. Combining this method with an immune checkpoint blockade can realize an improved immunotherapy efficacy and long-term protection effect for body.

An imine-linked covalent organic framework for renewable and sensitive determination of antibiotic.

Lanthanide-functionalized porous organic materials have been the promising candidates in the chemical and biological sensing. Considering the superior thermal and solvent stability of covalent organic frameworks (COFs), the development of lanthanide ions-functionalized COFs based sensing platform is meaningful, while remains to be a challenge. In this work, a new imine-linked COF which provides suitable coordination sites for Tb3+ was constructed via the Schiff base reaction between P-phenylenediamine (Pda) and 2,6-Diformylpyridine (Dfp). Benefiting from its high signal-to-noise, the COF@Tb shows excellent ability to determinate ciprofloxacin (CIP) with a detection limit of 3.01 nM. The measurement can maintain good stability in the presence of potential interference or in actual sample. Being washed with ethanol after each measurement, COF@Tb can be recycled for five times. This work provides a novel alternative strategy for efficient construction of lanthanide-grafted COFs and may promote the development of porous organic materials based chemical sensing.

"French fries"-like luminescent metal organic frameworks for the fluorescence determination of cytochrome c released by apoptotic cells and screening of anticancer drug activity.

A luminescent metal organic framework was prepared by encapsulating Zn-Ag-In-S quantum dots into "French fries"-like MIL-68(In) metal organic frameworks (ZAISQDs@MIL-68(In)). The ZAISQDs@MIL-68(In) had a maximum excitation wavelength at 370 nm and maximum emission wavelength at 620 nm. It was found that the ZAISQDs@MIL-68(In) was efficiently quenched by cytochrome c (Cyt c), which is an important biomarker of early cell apoptosis. The quenching mechanism was ascribed to be an inner filter effect and dynamic quenching of Cyt c towards the ZAISQDs@MIL-68(In), and the enrichment effect of MIL-68(In). Benefiting from the multiple advantages, ZAISQDs@MIL-68(In) was developed as an assay strategy of Cyt c with logarithmic relation between signal quenching and concentration in the range 0.02 to 3.5 µM. The linear equation was (F0-F)/F0 = 0.5043 + 0.2678 × logcCyt c with a detection limit of 8 nM. Cyt c released by drug induced apoptotic cells was determined by ZAISQDs@MIL-68(In), and this strategy has been utilized for the screening of anticancer drug activity. Graphical abstract Schematic representation of the synthesis of ZAISQDs@MIL-68(In) and its application for Cyt c and screening anticancer drug activity.