Acta Pharmaceutica Sinica B
·
2026
·
IF 14.6
Tianjiao Hao,Bin Gao,Yuanyuan Zhou,Chang Liu,Chuanjiang Ran,Binghua Chang,Wei You,Qiyue Wang,Jun Ye,Yan Shen
Cardiovascular diseases induced by arterial thrombosis, such as myocardial infarction and ischemic stroke, have gradually emerged as critical threats to human life and health. Sequentially targeted delivery systems are highly desired to be developed to improve the delivery of thrombolytics and anti-inflammatory medications to the site of the thrombus, respectively, to pursue a maximized combinational effect. Herein, we developed a probiotic-platelet hybrid vesicle-targeted drug delivery system (Fer-1@PLevs-C&U) to achieve sequential anti-thrombolytic delivery against thrombus and prevent its recurrence. The hybrid vesicles (PLevs) were prepared by mixing platelet membrane (PM) with Lactobacillus plantarum-derived bacterial extracellular vesicles (Levs) and further decorated with DSPE-PEG 2000 -CREKA, achieving “point-to-point” multi-covalent targeting of thrombus components. After targeted localization to the arterial thrombotic site, Fer-1@PLevs-C&U gradually releases the thrombolytic drug urokinase-type plasminogen activator (UPA) and Ferroptosis inhibitor (Fer-1) to facilitate thrombus dissolution and regulate the inflammatory microenvironment. By enhancing the eNOS expression and reducing the secretion of inflammatory factors TNF- α and IL-6, Fer-1@PLevs-C&U significantly reduced the inflammatory microenvironment and inhibited recurrent thrombus. Therefore, Fer-1@PLevs-C&U constitutes a novel biomimetic drug delivery platform with promising therapeutic potential and practical applicability.
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HUMAN REPRODUCTION
·
2024
·
IF 6
Zhang Xiaoning,Liang Min,Song Dandan,Huang Rongzu,Chen Chen,Liu Xiaojun,Chen Houyang,Wang Qingxin,Sun Xiaoli,Song Jian,Zhang Jiali,Kang Hang,Zeng Xuhui
STUDY QUESTIONWhat is the significance and mechanism of human seminal plasma extracellular vesicles (EVs) in regulating human sperm functions?SUMMARY ANSWEREV increases the intracellular Ca2+ concentrations [Ca2+]i via extracellular Ca2+ influx by activating CatSper channels, and subsequently modulate human sperm motility, especially hyperactivated motility, which is attributed to both protein and non-protein components in EV.WHAT IS KNOWN ALREADYEVs are functional regulators of human sperm function, and EV cargoes from normal and asthenozoospermic seminal plasma are different. Pre-fusion of EV with sperm in the acidic and non-physiological sucrose buffer solution could elevate [Ca2+]i in human sperm. CatSper, a principle Ca2+ channel in human sperm, is responsible for the [Ca2+]i regulation when sperm respond to diverse extracellular stimuli. However, the role of CatSper in EV-evoked calcium signaling and its potential physiological significance remain unclear.STUDY DESIGN, SIZE, DURATIONEV isolated from the seminal plasma of normal and asthenozoospermic semen were utilized to investigate the mechanism by which EV regulates calcium signal in human sperm, including the involvement of CatSper and the responsible cargoes in EV. In addition, the clinical application potential of EV and EV protein-derived peptides were also evaluated. This is a laboratory study that went on for more than 5 years and involved more than 200 separate experiments.PARTICIPANTS/MATERIALS, SETTING, METHODSSemen donors were recruited in accordance with the Institutional Ethics Committee on human subjects of the Affiliated Hospital of Nantong University and Jiangxi Maternal and Child Health Hospital. The Flow NanoAnalyzer, western blotting, and transmission electron microscope were used to systematically characterize seminal plasma EV. Sperm [Ca2+]i responses were examined by fluorimetric measurement. The whole-cell patch-clamp technique was performed to record CatSper currents. Sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm hyperactivation was also evaluated by examining their penetration ability in viscous methylcellulose media. Protein and non-protein components in EV were analyzed by liquid chromatography-mass spectrum. The levels of prostaglandins, reactive oxygen species, malonaldehyde, and DNA integrity were detected by commercial kits.MAIN RESULTS AND THE ROLE OF CHANCEEV increased [Ca2+]i via an extracellular Ca2+ influx, which could be suppressed by a CatSper inhibitor. Also, EV potentiated CatSper currents in human sperm. Furthermore, the EV-in [Ca2+]i increase and CatSper currents were absent in a CatSper-deficient sperm, confirming the crucial role of CatSper in EV induced Ca2+ signaling in human sperm. Both proteins and non-protein components of EV contributed to the increase of [Ca2+]i, which were important for the effects of EV on human sperm. Consequently, EV and its cargos promoted sperm hyperactivated motility. In addition, seminal plasma EV protein-derived peptides, such as NAT1-derived peptide (N-P) and THBS-1-derived peptide (T-P), could activate the sperm calcium signal and enhance sperm function. Interestingly, EV derived from asthenozoospermic semen caused a lower increase of [Ca2+]i than that isolated from normal seminal plasma (N-EV), and N-EV significantly improved sperm motility and function in both asthenozoospermic samples and frozen-thawed sperm.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis was an in vitro study and caution must be taken when extrapolating the physiological relevance to in vivo regulation of sperm.WIDER IMPLICATIONS OF THE FINDINGSOur findings demonstrate that the CatSper-mediated-Ca2+ signaling is involved in EV-modulated sperm function under near physiological conditions, and EV and their derivates are a novel CatSper and sperm function regulators with potential for clinical application. They may be developed to improve sperm motility resulting from low [Ca2+]i response and/or freezing and thawing.STUDY FUNDING/COMPETING INTEREST(S)This research was supported by the National Natural Science Foundation of China (32271167), the Social Development Project of Jiangsu Province (BE2022765), the Nantong Social and People's Livelihood Science and Technology Plan (MS22022087), the Basic Science Research Program of Nantong (JC22022086), and the Jiangsu Innovation and Entrepreneurship Talent Plan (JSSCRC2021543). The authors declare no conflict of interest.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yue Li,Yayue Zhang,Xuran Ding,Taotao Zou,Hu Li,Ke Xu,Cheng Su,Yuting Wang,Ziming Zhao,Yuan He
Effective delivery of drugs to the inflamed colon is an attractive strategy for treating inflammatory bowel disease (IBD). Here we designed a drug delivery platform for IBD treatment by hybridizing platelet membrane (PM) with phosphatidylserine (PS)-containing liposomes (PM-Lipo). Introducing PM into hybrid nanovesicles enhanced their adhesion to the inflammatory endothelium in vitro , and increased their recruitment to the inflamed colon in a mouse IBD model. Meanwhile, adding PS into PM-Lipo improved macrophage targeting and uptake in vitro and in vivo . Rosiglitazone (ROSI) loading PM-Lipo (PM-Lipo-ROSI) effectively reprogrammed the pro-inflammatory macrophages towards an anti-inflammatory status in the inflamed colon, reducing pro-inflammatory cytokine secretion and immune cell infiltration. Moreover, PM-Lipo-ROSI also promoted the epithelial barrier regeneration of the damaged colon. The present study not only provides a novel paradigm for the precision treatment of IBD, but also lays a theoretical foundation for developing nanomedicines for other inflammatory diseases.
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PLoS One
·
2019
·Vol. 14
·期 10
·e0223096
·
IF 2.776
Lili Wang,Yunqian Li,Ran Guo,Shanshan Li,Anqi Chang,Zhixiang Zhu,Pengfei Tu
Activated platelets release adenosine trisphosphate (ATP) and bioluminescence analysis of ATP release is usually used to monitor activation of platelets induced by various stimulants. However, bioluminescence analysis of ATP possesses poor linearity, the signal is quickly attenuated, and the accuracy of ATP release from platelets is hard to determine accurately enough to be used in a high throughput screening of platelet inhibitors. The present study was designed to optimize bioluminescence analysis of ATP released by platelets and expand its application in high throughput screening of platelet inhibitors. The results showed that accuracy of ATP analysis was significantly improved by adding coenzyme A (CoA) and signal attenuation of ATP analysis was greatly postponed by adding bovine serum albumin (BSA) both in Hank’s balanced salt solution (HBSS) and Tyrode’s buffer. Furthermore, ATP release of activated platelets and inhibitory effects of Ly294002 and Staurosporine on platelet activation were accurately determined by our optimized bioluminescence analysis of ATP. Thus, we have successfully constructed an optimized bioluminescence analysis of ATP which can be used in high throughput screening of platelet inhibitors.
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Pharmaceutics
·
2025
·Vol. 17
·期 11
·1478
·
IF 5.5
Hao Li,Xiaowei Xie,Yu Zhang,Xiaopeng Han,Ting Shi,Jiayin Li,Wanyu Chen,Qin Wei,Hong Pan,Shuxian Xu,Qiuyu Chen,Lifang Yin,Chao Qin
Background/Objectives:Cerebral ischemia–reperfusion injury (CIRI) remains a major challenge in the treatment of ischemic stroke, characterized by intertwined oxidative stress and neuroinflammation. Existing monotherapies often fail to address this dual pathology effectively. We developed PLSCZ, a biomimetic nanoplatform integrating a catalytic core of imidazolate framework-8 (ZIF-8)-encapsulated superoxide dismutase (SOD) and catalase (CAT) enzymes with a hybrid platelet membrane shell. This design strategically employs metal–organic frameworks (MOFs) to effectively overcome the critical limitations of enzyme instability and provide a cascade catalytic environment, while the biomimetic surface modification enhances targeting capability, thereby enabling dual-pathway intervention against CIRI.Methods:PLSCZ was engineered by co-encapsulating SOD and CAT within a ZIF-8 core to form a cascade antioxidant system (SCZ). The core was further coated with a hybrid membrane composed of rapamycin-loaded phospholipids and natural platelet membranes. The nanoparticle was characterized by size, structure, enzyme activity, and targeting capability. In vitro and in vivo efficacy was evaluated using oxygen–glucose deprivation/reoxygenation (OGD/R) models and a transient middle cerebral artery occlusion/reperfusion (tMCAO/r) rat model.Results:In vitro, PLSCZ exhibited enhanced enzymatic stability and cascade catalytic efficiency, significantly scavenging reactive oxygen species (ROS) and restoring mitochondrial function. The platelet membrane conferred active targeting to ischemic brain regions and promoted immune evasion. PLSCZ effectively polarized microglia toward the anti-inflammatory M2 phenotype, reduced pro-inflammatory cytokine levels, restored autophagic flux, and preserved blood–brain barrier integrity. In vivo, in tMCAO/r rats, PLSCZ markedly targeted the ischemic hemisphere, reduced infarct volume, improved neurological function, and attenuated neuroinflammation.Conclusions:By synergistic ROS scavenging and anti-inflammatory action, the PLSCZ nanozyme overcomes the limitations of conventional monotherapies for CIRI. This biomimetic, multi-functional platform effectively reduces oxidative stress, modulates the phenotype of microglia, decreases infarct volume, and promotes neurological recovery, offering a promising multi-mechanistic nanotherapeutic for CIRI and a rational design model for MOF-based platforms.
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PHARMACOLOGICAL RESEARCH
·
2025
·
IF 10.5
Ning Yu,Shule Zhang,Rui Fang,Yingxin Zhang,Xi Xu,Lijuan Cao,Jianfa Zhang
Clinically approved thrombolytic agents carry significant bleeding risks due to systemic plasminogen activation. Heparin analogs prevent thrombus formation but lack direct thrombolytic activity. Here, we report a previously unrecognized thrombolytic mechanism of octaparin, a synthetic heparin analog. Studies demonstrated that octaparin exhibits potent anticoagulant and thrombolytic activity both in vitro and in vivo , with a lower bleeding risk compared to conventional heparin-based agents. Octaparin directly binds fibrin monomers, altering their secondary conformation to inhibit polymerization and destabilize preformed thrombi, while preserving tissue factor-driven coagulation. In murine models of pulmonary embolism and inferior vena cava thrombosis, octaparin both prevented and dose-dependently dissolved established clots without compromising hemostatic integrity, sharply contrasting with conventional thrombolytics that induce hemorrhage. Further analyses using molecular docking, microscale thermophoresis, and spectroscopy confirmed that octaparin induces changes in fibrin monomer folding that compromise fibrin network stability. In human systems, octaparin selectively prolonged intrinsic coagulation time, reduced clot retraction, did not induce platelet activation, and its effects were reversible with protamine sulfate. This study establishes targeted fibrin destabilization as a viable therapeutic strategy, revealing a previously unrecognized thrombolytic mechanism achievable through heparin-based molecular design.
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TALANTA
·
2025
·
IF 6.1
Xiaoying Wang,Xiaoxing Fang,Xuewei Li,Hejiang Cheng,Hua Jiang,Ji Zheng
Tumor cell-platelet interaction is a critical pathway for promoting hematogenous metastasis by enhancing the survival rate of tumor cells. To establish a quantitative platform for evaluating cell interaction dynamics and drug interventions, we developed a novel porphyrin-based colorimetric system for real-time monitoring of tumor cell-platelet binding events. This detection system demonstrates excellent analytical performance, with a linear response range of 5.0 × 10 3 - 1.0 × 10 6 platelets and a limit of detection of 5.0 × 10 3 platelets. A comprehensive evaluation of lung adenocarcinoma cell lines revealed distinct platelet-binding capacities, with PC9R exhibiting the strongest platelet-binding ability, followed by A549, and PC9 showing the weakest ability. Moreover, we investigated the intervention of drugs and found that aspirin pretreatment could significantly reduce platelet binding in three cell lines. Among them, the inhibition of PC9R was most pronounced, followed by A549, and the weakest effect in PC9. The results indicate that drug pretreatment can significantly inhibit platelet binding in cell lines, and the inhibitory effect is positively correlated with platelet binding capacity-cells with stronger binding affinity show greater sensitivity to drug interventions. This study holds promise for analyzing the interaction between platelets and other cells, and may provide a basis for personalized selection of aspirin interventions.
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