Universal cell membrane camouflaged nano-prodrugs with right-side-out orientation adapting for positive pathological vascular remodeling in atherosclerosis.

A right-side-out orientated self-assembly of cell membrane-camouflaged nanotherapeutics is crucial for ensuring their biological functionality inherited from the source cells. In this study, a universal and spontaneous right-side-out coupling-driven ROS-responsive nanotherapeutic approach, based on the intrinsic affinity between phosphatidylserine (PS) on the inner leaflet and PS-targeted peptide modified nanoparticles, has been developed to target foam cells in atherosclerotic plaques. Considering the increased osteopontin (OPN) secretion from foam cells in plaques, a bioengineered cell membrane (OEM) with an overexpression of integrin α9ß1 is integrated with ROS-cleavable prodrugs, OEM-coated ETBNPs (OEM-ETBNPs), to enhance targeted drug delivery and on-demand drug release in the local lesion of atherosclerosis. Both in vitro and in vivo experimental results confirm that OEM-ETBNPs are able to inhibit cellular lipid uptake and simultaneously promote intracellular lipid efflux, regulating the positive cellular phenotypic conversion. This finding offers a versatile platform for the biomedical applications of universal cell membrane camouflaging biomimetic nanotechnology.

Reactive oxygen species-responsive nano-platform with dual-targeting and fluorescent lipid-specific imaging capabilities for the management of atherosclerotic plaques.

Atherosclerosis (AS), a pathological cause of cardiovascular disease, results from endothelial injury, local progressive inflammation, and excessive lipid accumulation. AS plaques rich in foam cells are prone to rupture and form thrombus, which can cause life-threatening complications. Therefore, the assessment of atherosclerotic plaque vulnerability and early intervention are crucial in reducing the mortality rates associated with cardiovascular disease. In this work, A fluorescent probe FC-TPA was synthesized, which switches the fluorescence state between protonated and non-protonated, reducing background fluorescence and enhancing imaging signal-to-noise ratio. On this basis, FC-TPA is loaded into cyclodextrin (CD) modified with phosphatidylserine targeting peptide (PTP) and coated with hyaluronic acid (HA) to construct the intelligent responsive diagnostic nanoplatform (HA@PCFT). HA@PCFT effectively targets atherosclerotic plaques, utilizing dual targeting mechanisms. HA binds strongly to CD44, while PTP binds to phosphatidylserine, enabling nanoparticle aggregation at the lesion site. ROS acts as a smart release switch for probes. Both in vitro and in vivo evaluations confirm impressive lipid-specific fluorescence imaging capabilities of HA@PCFT nanoparticles (NPs). The detection of lipid load in atherosclerotic plaque by fluorescence imaging will aid in assessing the vulnerability of atherosclerotic plaque. STATEMENT OF SIGNIFICANCE: Currently, numerous fluorescent probes have been developed for lipid imaging. However, some challenges including inadequate water solubility, nonspecific distribution patterns, and fluorescence background interference, have greatly limited their further applications in vivo. To overcome these limitations, a fluorescent molecule has been designed and synthesized, thoroughly investigating its photophysical properties through both theoretical and experimental approaches. Interestingly, this fluorescent molecule exhibits the reversible fluorescence switching capabilities, mediated by hydrogen bonds, which effectively mitigate background fluorescence interference. Additionally, the fluorescent molecules has been successfully loaded into nanocarriers functionalized with the active targeting abilities, which has significantly improved the solubility of the fluorescent molecules and reduced their nonspecific distribution in vivo for an efficient target imaging in atherosclerosis. This study provides a valuable reference for evaluating the performance of such fluorescent dyes, and offers a promising perspective on the design of the target delivery systems for atherosclerosis.

Discovery of Oral AMP-Activated Protein Kinase Activators for Treating Hyperlipidemia.

Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.

A Macrophage Membrane-Functionalized, Reactive Oxygen Species-Activatable Nanoprodrug to Alleviate Inflammation and Improve the Lipid Metabolism for Atherosclerosis Management.

Atherosclerosis (AS) management typically relies on therapeutic drug interventions, but these strategies typically have drawbacks, including poor site specificity, high systemic intake, and undesired side effects. The field of cell membrane camouflaged biomimetic nanomedicine offers the potential to address these challenges thanks to its ability to mimic the natural properties of cell membranes that enable enhanced biocompatibility, prolonged blood circulation, targeted drug delivery, and evasion of immune recognition, ultimately leading to improved therapeutic outcomes and reduced side effects. In this study, a novel biomimetic approach is developed to construct the M1 macrophage membrane-coated nanoprodrug (MM@CD-PBA-RVT) for AS management. The advanced MM@CD-PBA-RVT nanotherapeutics are proved to be effective in inhibiting macrophage phagocytosis and facilitating the cargo delivery to the activated endothelial cells of AS lesion both in vitro and in vivo. Over the 30-day period of nanotherapy, MM@CD-PBA-RVT is capable of significantly inhibiting the progression of AS, while also maintaining a favorable safety profile. In conclusion, the biomimetic MM@CD-PBA-RVT shows promise as feasible drug delivery systems for safe and effective anti-AS applications.

m6A methyltransferase METTL14­mediated RP1­228H13.5 promotes the occurrence of liver cancer by targeting hsa­miR­205/ZIK1.

The aim of the present study was to explore the association between N6­methyladenosine (m6A) modification regulatory gene­related long noncoding (lnc)RNA RP1­228H13.5 and cancer prognosis through bioinformatics analysis, as well as the impact of RP1­228H13.5 on cell biology­related behaviors and specific molecular mechanisms. Bioinformatics analysis was used to construct a risk model consisting of nine genes. This model can reflect the survival time and differentiation degree of cancer. Subsequently, a competing endogenous RNA network consisting of 3 m6A­related lncRNAs, six microRNAs (miRs) and 201 mRNAs was constructed. A cell assay confirmed that RP1­228H13.5 is significantly upregulated in liver cancer cells, which can promote liver cancer cell proliferation, migration and invasion, and inhibit liver cancer cell apoptosis. The specific molecular mechanism may be the regulation of the expression of zinc finger protein interacting with K protein 1 (ZIK1) by targeting the downstream hsa­miR­205. Further experiments found that the m6A methyltransferase 14, N6­adenosine­methyltransferase subunit mediates the regulation of miR­205­5p expression by RP1­228H13.5. m6A methylation regulatory factor­related lncRNA has an important role in cancer. The targeting of hsa­miR­205 by RP1­228H13.5 to regulate ZIK1 may serve as a potential mechanism in the occurrence and development of liver cancer.

Hyaluronic acid-decorated curcumin-based coordination nanomedicine for enhancing the infected diabetic wound healing.

Persistent over-oxidation, inflammation and bacterial infection are the primary reasons for impaired wound repairing in diabetic patients. Therefore, crucial strategies to promote diabetic wound repairing involve suppressing the inflammatory response, inhibiting bacterial growth and decreasing reactive oxygen species (ROS) within the wound. In this work, we develop a multifunctional nanomedicine (HA@Cur/Cu) designed to facilitate the repairing process of diabetic wound. The findings demonstrated that the synthesized infinite coordination polymers (ICPs) was effective in enhancing the bioavailability of curcumin and improving the controlled drug release at the site of inflammation. Furthermore, in vitro and in vivo evaluation validate the capacity of HA@Cur/Cu to inhibit bacterial growth and remove excess ROS and inflammatory mediators, thereby significantly promoting the healing of diabetic wound in mice. These compelling findings strongly demonstrate the enormous promise of this multifunctional nanomedicine for the treatment of diabetic wound.

NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis.

Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.

M2 Macrophage Membrane-Camouflaged Fe3 O4 -Cy7 Nanoparticles with Reduced Immunogenicity for Targeted NIR/MR Imaging of Atherosclerosis.

Atherosclerosis （AS） is the primary reason behind cardiovascular diseases, leading to approximately one-third of global deaths. Developing a novel multi-model probe to detect AS is urgently required. Macrophages are the primary cells from which AS genesis occurs. Utilizing natural macrophage membranes coated on the surface of nanoparticles is an efficient delivery method to target plaque sites. Herein, Fe3 O4 -Cy7 nanoparticles (Fe3 O4 -Cy7 NPs), functionalized using an M2 macrophage membrane and a liposome extruder for Near-infrared fluorescence and Magnetic resonance imaging, are synthesized. These macrophage membrane-coated nanoparticles (Fe3 O4 @M2 NPs) enhance the recognition and uptake using active macrophages. Moreover, they inhibit uptake using inactive macrophages and human coronary artery endothelial cells. The macrophage membrane-coated nanoparticles (Fe3 O4 @M0 NPs, Fe3 O4 @M1 NPs, Fe3 O4 @M2 NPs) can target specific sites depending on the macrophage membrane type and are related to C-C chemofactor receptor type 2 protein content. Moreover, Fe3 O4 @M2 NPs demonstrate excellent biosafety in vivo after injection, showing a significantly higher Fe concentration in the blood than Fe3 O4 -Cy7 NPs. Therefore, Fe3 O4 @M2 NPs effectively retain the physicochemical properties of nanoparticles and depict reduced immunological response in blood circulation. These NPs mainly reveal enhanced targeting imaging capability for atherosclerotic plaque lesions.

Target Functionalized Carbon Dot Nanozymes with Dual-Model Photoacoustic and Fluorescence Imaging for Visual Therapy in Atherosclerosis.

Multifunctional nanomedicines have been used in atherosclerosis theranostics. Herein, phosphatidylserine-specific peptide CLIKKPF-functionalized carbon-dots nanozymes (pep-CDs) are reported for specific and efficient noninvasive theranostic of atherosclerosis. Surprisingly, pep-CDs are discovered to not only inherit the inherent properties of carbon dots (CDs), including deep-red fluorescence emission, photoacoustic response, and superoxide dismutase-like antioxidant, and anti-inflammatory activities but also possess the ability to target recognition on foam cells and target localization on plaques due to the specific interaction of CLIKKPF with phosphatidylserine on the membrane outer surface of foam cells. Furthermore, the target localization effect of pep-CDs vastly promotes the efficient accumulation of CDs in plaque, thus maximizing AS theranostic of CDs. Interestingly, pep-CDs could be developed to image plaque for monitoring atherosclerosis pathological progression in real-time resulting from the different content of foam cells. This work on the one hand proposes a simple and feasible strategy to construct theranostic nanoplatform employing only a single functional unit (i.e., multifunctional CDs) to simplify the fabrication procedure, on the other hand, highlights the advantages of the active target auxiliary mode for atherosclerosis theranostic applications.

Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis.

Atherosclerosis, cholesterol-driven plaque formation in arteries, is a complex multicellular disease which is a leading cause of vascular diseases. During the progression of atherosclerosis, the autophagic function is impaired, resulting in lipid accumulation-mediated foam cell formation. The stimulation of autophagy is crucial for the recovery of cellular recycling process. One of the potential autophagy inducers is trehalose, a naturally occurring non-reducing disaccharide. However, trehalose has poor bioavailability due to its hydrophilic nature which results in poor penetration through cell membranes. To enhance its bioavailability, we developed trehalose-releasing nanogels (TNG) for the treatment of atherosclerosis. The nanogels were fabricated through copolymerization of 6-O-acryloyl-trehalose with the selected acrylamide-type monomers affording a high trehalose conjugation (~ 58%, w/w). TNG showed a relatively small hydrodynamic diameter (dH, 67 nm) and a uniform spherical shape and were characterized by negative ζ potential (-18 mV). Thanks to the trehalose-rich content, TNG demonstrated excellent colloidal stability in biological media containing serum and were non-hemolytic to red blood cells. In vitro study confirmed that TNG could stimulate autophagy in foam cells and enhance lipid efflux and in vivo study in ApoE-/- mice indicated a significant reduction in atherosclerotic plaques, while increasing autophagic markers. In conclusion, TNG hold great promise as a trehalose delivery system to restore impaired autophagy-mediated lipid efflux in atherosclerosis and subsequently reduce atherosclerotic plaques.

Flexible rotation of linear polarization conversion with a frequency selective surface.

A high-efficiency transmitted polarization converter based on a frequency selective surface (FSS) is proposed in this paper. The FSS-based polarization converter (FSS-PC) is designed based on receiving-via-transmitting (RVT) structure. The receiving and transmitting antenna structures are interconnected by the transmission line, designed in the form of metallized via holes. For any linearly polarized (LP) electromagnetic wave, our proposed FSS-PC has the capability to convert it into another LP electromagnetic wave. This converted wave will have a counterclockwise rotation angle of 2φ relative to the incident wave at 11 GHz. This is achieved by adjusting the relative azimuth φ between the polarization plane of the incident LP wave's electric field and the converter. Meanwhile, the FSS-PC can achieve exceptionally high polarization conversion above -0.30 dB at the central frequency of 11 GHz. Furthermore, as the azimuth of the incident electric field varies, this high-efficiency polarization conversion capability remains stable. The prototype has been fabricated and measured, and the measured results agree well with the simulated ones, thus confirming the effectiveness of the proposed design.

Metronidazole-loaded polydopamine nanomedicine with antioxidant and antibacterial bioactivity for periodontitis.

Aim: This study focused on treating periodontitis with bacterial infection and local over accumulation of reactive oxygen species. Materials & methods: Polydopamine nanoparticles (PDA NPs) were exploited as efficient carriers for encapsulated metronidazole (MNZ). The therapeutic efficacy and biocompatibility of PDA@MNZ NPs were investigated through both in vitro and in vivo studies. Results: The nanodrug PDA@MNZ NPs were successfully fabricated, with well-defined physicochemical characteristics. In vitro, the PDA@MNZ NPs effectively eliminated intracellular reactive oxygen species and inhibited the growth of Porphyromonas gingivalis. Moreover, the PDA@MNZ NPs exhibited synergistic therapy for periodontitisin in vivo. Conclusion: PDA@MNZ NPs were confirmed with exceptional antimicrobial and antioxidant functions, offering a promising avenue for synergistic therapy in periodontitis.

MP Allosterically Activates AMPK to Enhance ABCA1 Stability by Retarding the Calpain-Mediated Degradation Pathway.

It is widely recognized that macrophage cholesterol efflux mediated by the ATP-binding cassette transporter A1 (ABCA1) constitutes the initial and rate-limiting step of reverse cholesterol transport (RCT), displaying a negative correlation with the development of atherosclerosis. Although the transcriptional regulation of ABCA1 has been extensively studied in previous research, the impact of post-translational regulation on its expression remains to be elucidated. In this study, we report an AMP-activated protein kinase (AMPK) agonist called ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-((3-hydroxyphenyl) amino)-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl dihydrogen phosphate (MP), which enhances ABCA1 expression through post-translational regulation rather than transcriptional regulation. By integrating the findings of multiple experiments, it is confirmed that MP directly binds to AMPK with a moderate binding affinity, subsequently triggering its allosteric activation. Further investigations conducted on macrophages unveil a novel mechanism through which MP modulates ABCA1 expression. Specifically, MP downregulates the Cav1.2 channel to obstruct the influx of extracellular Ca2+, thereby diminishing intracellular Ca2+ levels, suppressing calcium-activated calpain activity, and reducing the interaction strength between calpain and ABCA1. This cascade of events culminates in the deceleration of calpain-mediated degradation of ABCA1. In conclusion, MP emerges as a potentially promising candidate compound for developing agents aimed at enhancing ABCA1 stability and boosting cellular cholesterol efflux and RCT.

Crystallizing Self-Standing Covalent Organic Framework Membranes for Ultrafast Proton Transport in Flow Batteries.

Covalent organic frameworks (COFs) display great potential to be assembled into proton conductive membranes for their uniform and controllable pore structure, yet constructing self-standing COF membrane with high crystallinity to fully exploit their ordered crystalline channels for efficient ionic conduction remains a great challenge. Here, a macromolecular-mediated crystallization strategy is designed to manipulate the crystallization of self-standing COF membrane, where the -SO3 H groups in introduced sulfonated macromolecule chains function as the sites to interact with the precursors of COF and thus offer long-range ordered template for membrane crystallization. The optimized self-standing COF membrane composed of highly-ordered nanopores exhibits high proton conductivity (75 mS cm-1 at 100 % relative humidity and 20 °C) and excellent flow battery performance, outperforming Nafion 212 and reported membranes. Meanwhile, the long-term run of membrane is achieved with the help of the anchoring effect of flexible macromolecule chains. Our work provides inspiration to design self-standing COF membranes with ordered channels for permselective application.

Exploring a Linear Combination Feature for Predicting the Conductance of Parallel Molecular Circuits.

An accurate rule for predicting conductance is the cornerstone of developing molecular circuits and provides a promising solution for miniaturizing electric circuits. The successful prediction of series molecular circuits has proven the possibility of establishing a rule for molecular circuits under quantum mechanics. However, the quantitatively accurate prediction has not been validated by experiments for parallel molecular circuits. Here we used 1,3-dihydrobenzothiophene (DBT) to build the parallel molecular circuits. The theoretical simulation and single-molecule conductance measurements demonstrated that the conductance of the molecule containing one DBT is the unprecedented linear combination of the conductance of the two individual channels with respective contribution weights of 0.37 and 0.63. With these weights, the conductance of the molecule containing two DBTs is predicted as 1.81 nS, matching perfectly with the measured conductance (1.82 nS). This feature offers a potential rule for quantitatively predicting the conductance of parallel molecular circuits.

Reactive Oxygen Species-Responsive Sequentially Targeted AIE Fluorescent Probe for Precisely Identifying the Atherosclerotic Plaques.

The formation of atherosclerosis is the root cause of various cardiovascular diseases (CVDs). Therefore, effective CVD interventions call for precise identification of the plaques to aid in clinical treatment of such diseases. Herein, a reactive oxygen species (ROS)-responsive sequentially targeted fluorescent probe is developed for atherosclerotic plaque recognition. An aggregation-induced emission active fluorophore is linked to maleimide (polyethylene glycol) hydroxyl with a ROS-responsive cleavable bond, which is further functionalized with CLIKKPF peptide (TPAMCF) for specifically binding to phosphatidylserine of the foam cells. After being assembled in aqueous medium, TPAMCF nanoparticles can efficiently accumulate in the plaques through the high affinity of CLIKKPF to the externalized phosphatidylserine of the foam cells. Activated by the locally accumulated ROS in foam cells, the nanoparticles are interrupted, and then TPA can be released and subsequently identify the lipid droplets inside the foam cells to achieve fluorescence imaging of the plaques. Such nanoprobes have the favorable ROS response performance and exhibit a special target binding to the foam cells in vitro. In addition, nanoprobe-based fluorescence imaging permitted the high-contrast and precise detection of atherosclerosis specimens ex vivo. Therefore, as a promising fluorescent probe, TPAMCF is capable of being a potential candidate for the detection of atherosclerotic plaque.

Bayesian models for spatial count data with informative finite populations with application to the American community survey.

The American Community Survey (ACS) is an ongoing program conducted by the US Census Bureau that publishes estimates of important demographic statistics over pre-specified administrative areas. ACS provides spatially referenced count-valued outcomes that are paired with finite populations. For example, the number of people below the poverty line and the total population for each county are estimated by ACS. One common assumption is that the spatially referenced count-valued outcome given the finite population is binomial distributed. This conditionally specified (CS) model does not define the joint relationship between the count-valued outcome and the finite population. Thus, we consider a joint model for the count-valued outcome and the finite population. When cross-dependence in our joint model can be leveraged to 'improve spatial prediction' we say that the finite population is 'informative.' We model the count given the finite population as binomial and the finite population as negative binomial and use multivariate logit-beta prior distributions. This leads to closed-form expressions of the full-conditional distributions for an efficient Gibbs sampler. We illustrate our model through simulations and our motivating application of ACS poverty estimates. These empirical analyses show the benefits of using our proposed model over the more traditional CS binomial model.

Two-Dimensional MFI-Type Zeolite Flow Battery Membranes.

Vanadium flow battery (VFB) is one of the most reliable stationary electrochemical energy-storage technologies, and a membrane with high vanadium resistance and proton conductivity is essential for manufacturing high-performance VFBs. In this study, a two-dimensional (2D) MFI-type zeolite membrane was fabricated from zeolite nanosheet modules, which displayed excellent vanadium resistance (0.07 mmol L-1 h-1 ) and proton conductivity (0.16 S cm-1 ), yielding a coulombic efficiency of 93.9 %, a voltage efficiency of 87.6 %, and an energy efficiency of 82.3 % at 40 mA cm-2 . The self-discharge period of a VFB equipped with 2D MFI-type zeolite membrane increased up to 116.2 h, which was significantly longer than that of the commercial perfluorinated sulfonate membrane (45.9 h). Furthermore, the corresponding battery performance remained stable over 1000 cycles (>1500 h) at 80 mA cm-2 . These findings demonstrate that 2D MFI-type membranes are promising ion-conductive membranes applicable for stationary electrochemical energy-storage devices.