MOLECULAR PSYCHIATRY
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2025
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IF 10.1
Qin Qian,Li Mengyue,Fan Linlin,Zeng Xin,Zheng Danyang,Wang Han,Jiang Yutong,Ma Xinrui,Xing Lei,Wu Lijie,Liang Shuang
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as “Warburg effect”, is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene MIR137 plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to TLR4 , the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.
研究领域:
神经科学
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分子生物学
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医学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2021
·Vol. 19
·期 1
·1-16
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IF 10.435
Xu Jiangkang,Yang Xiaoye,Ji Jianbo,Gao Yuan,Qiu Na,Xi Yanwei,Liu Anchang,Zhai Guangxi
Background Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. Results Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. Conclusions The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma. Graphic abstract
研究领域:
药学
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纳米技术
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神经科学
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肿瘤学
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DOI
PubMed
高影响因子
ACS Chemical Neuroscience
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2017
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IF 3.883
Jing Sun,Wenjie Xie,Xufeng Zhu,Mengmeng Xu,Jie Liu
Functionalized nanomaterials, which have been applied widely to inhibit amyloid-β protein (Aβ) aggregation, show enormous potential in the field of prevention and treatment of Alzheimer’s disease (AD). A significant body of data has demonstrated that the morphology and size of nanomaterials have remarkable effects on their biological behaviors. In this work, we proposed and designed three kinds of brain-targeting sulfur nanoparticles (RVG@Met@SNPs) with novel morphologies (volute-like, tadpole-like, and sphere-like) and investigated the effect of different RVG@Met@SNPs on Aβ–Cu2+ complex aggregation and their corresponding neurotoxicity. Among them, the sphere-like nanoparticles (RVG@Met@SS) exhibited the most effective inhibitory activity, due to their unique mini size effect, and they reduced 61.6% the Aβ–Cu2+ complex aggregation and increased 92.4% SH-SY5Y cell viability in a dose of 10 μg/mL. In vitro and in vivo, the abilities of different morphologies of RVG@Met@SNPs to cross the blood–brain barrier (BBB) and target brain parenchymal cells were significantly different. Moreover, improvements in learning disability and cognitive loss were shown in the transgenic AD mice model using the Morris water maze test after multiple doses of RVG@Met@SNPs treatment. In general, the purpose of this research is to develop a biological application of sulfur nanoparticles and to provide a novel functionalized nanomaterial to treat AD.
研究领域:
纳米技术
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神经科学
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药学科学
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材料科学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2026
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IF 11
Quan Zhou,Imran Ibrahim Shaikh,Jianfeng Wang,Tongjun Li,Xinrong Wang,Shekhar Singh,Ayesha Younas,Yaru Shi,Kwonseop Kim,Shuanghu Wang,Jian Xiao
Spinal cord injury (SCI) remains a major clinical challenge because the inflammatory and oxidative microenvironment drives secondary tissue damage. Although mollugin (Mol) possesses anti-inflammatory, antioxidant, and neuroprotective activities, its therapeutic application is limited by poor water solubility and rapid clearance. In this study, we developed a RVG-modified liposomal nanoplatform for targeted delivery of mollugin (Mol@Lip-RVG) as a novel therapeutic strategy for SCI. The Mol@Lip-RVG nanoplatform exhibited excellent biocompatibility, favorable physicochemical characteristics, and sustained drug release profile. In vitro studies demonstrated that Mol@Lip-RVG effectively downregulated pro-inflammatory mediators, promoted microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype, and significantly reduced reactive oxygen species production. In SCI mice, the RVG modification enabled efficient crossing of the BSCB and selective accumulation at the injury site through specific binding to nAChRs. This targeted delivery resulted in enhanced neuro-preservation and substantial improvement in motor function recovery, achieved through dual modulation of microglial reprogramming and attenuation of oxidative stress. Mechanistically, we demonstrated that Mol@Lip-RVG exerts its therapeutic effects is associated with inhibition of the NF-κB signaling pathway, thereby suppressing neuroinflammation. Collectively, these findings establish the Mol@Lip-RVG nanoplatform as a promising targeted therapeutic approach that addresses both the delivery challenges and complex pathophysiology of spinal cord injury.
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DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-16
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IF 10.6
Li Chao,Xiang Zhenyang,Hou Mengfan,Yu Hao,Peng Peng,Lv Yigang,Ma Chao,Ding Han,Jiang Yunpeng,Liu Yang,Zhou Hengxing,Feng Shiqing
Background Spinal cord injury (SCI) often leads to a loss of motor and sensory function. Axon regeneration and outgrowth are key events for functional recovery after spinal cord injury. Endogenous growth of axons is associated with a variety of factors. Inspired by the relationship between developing nerves and blood vessels, we believe spinal cord-derived microvascular endothelial cells (SCMECs) play an important role in axon growth. Results We found SCMECs could promote axon growth when co-cultured with neurons in direct and indirect co-culture systems via downregulating the miR-323-5p expression of neurons. In rats with spinal cord injury, neuron-targeting nanoparticles were employed to regulate miR-323-5p expression in residual neurons and promote function recovery. Conclusions Our study suggests that SCMEC can promote axon outgrowth by downregulating miR-323-5p expression within neurons, and miR-323-5p could be selected as a potential target for spinal cord injury repair. Graphical Abstract
研究领域:
神经科学
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分子生物学
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再生医学
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DOI
PubMed
高影响因子
Acta Biomaterialia
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2019
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IF 6.638
Yushen Jin,Yanyan Li,Xin Yang,Jie Tian
Neuroblastoma accounts for 8–10% of malignancies in infants and children. It is urgent to develop an appropriate theranostic agent for effective diagnosis and therapy of neuroblastoma. Herein, we constructed RVG peptide and IRDye800-conjugated bovine serum albumin-coated triangular gadolinium oxide nanoplates (RVG&IRDye800-Gd 2 O 3 TNs) as a targeting MRI agent for the diagnosis of neuroblastoma preoperation and a fluorescence imaging agent for the guidance of the precise excision of the neuroblastoma in surgery. RVG&IRDye800-Gd 2 O 3 TNs have uniform edge length. The RVG&IRDye800-Gd 2 O 3 TNs show remarkably enhanced affinity to both mouse- and human-derived neuroblastoma cells compared with IRDye800-Gd 2 O 3 TNs (3.07-fold and 3.02-fold, respectively). Because of the increased accumulation in tumor cells, RVG&IRDye800-Gd 2 O 3 TNs exhibit signals threefold to fivefold higher than the surrounding normal tissues, which is propitious to the diagnosis of neuroblastoma preoperation and provides real-time visual guidance of the precise excision of the neuroblastoma. Most importantly, with the guidance of the fluorescence imaging agent, the survival rate increased from 0% to 80% 42 days after surgery compared with that in conventional surgery. These findings indicated that the RVG peptide combined with IRDye800-Gd 2 O 3 TNs has the potential to improve the diagnosis and treatment of patients with neuroblastoma. Statement of significance In this study, we prepared RVG peptide and IRDye800-conjugated bovine serum albumin-coated triangular gadolinium oxide nanoplates (RVG&IRDye800-Gd 2 O 3 TNs) as a targeting MRI agent for the diagnosis of neuroblastoma preoperation and a fluorescence imaging agent for the guidance of the precise excision of the neuroblastoma during surgery. Neuroblastoma was accurately located by MRI imaging, and the tumor margin could be real-time monitored through near-infrared fluorescence imaging. The RVG&IRDye800-Gd 2 O 3 TNs exhibit signals threefold to fivefold higher than those in the surrounding normal tissues, which is propitious to the diagnosis of the neuroblastoma preoperation and provides real-time visual guidance of the precise excision of the neuroblastoma. With the guidance of the fluorescence imaging agent in surgery, the survival rate increased from 0% to 80% 42 days after surgery compared with that in conventional surgery.
研究领域:
肿瘤学
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纳米医学
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分子影像
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生物医学工程
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DOI
PubMed
高影响因子
Advanced Science
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2025
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IF 14.1
Jiaojiao Li,Maoxiang Xu,Boyu Cai,Xiangyu Li,Zhanping Liang,Xiaohuan Xia,Haitao Zhang,Zhiwen Zhang,Fei Tan,Jialin Charlie Zheng
Traumatic brain injury (TBI) poses serious physical, psychosocial, and economic threats to millions of patients globally each year. While current treatment options, primarily surgery and medication, vary with TBI severity, there is no universal therapeutic agent applicable in both surgical and medical contexts. In the present study, exosomes derived from induced neural stem cells (iNSC-Exo) as a versatile therapeutic agent for TBI are investigated using a preclinical murine model. The iNSC-Exo treatment is found to exert therapeutic effects by mediating anti-neuroinflammation and neuroprotection, thereby promoting functional and cognitive recovery in TBI mice. Besides, two clinically inspired administration modalities are established for iNSC-Exo: local delivery and systemic delivery. Their efficacy is enhanced via a novel injectable hydrogel and RVG targeting for systemic delivery, respectively. Finally, the unprecedented single-cell characterization of mouse brain tissue, both pre- and post-iNSC-Exo treatment, confirms that microglia represent the predominant type of cells affected. Two microglial subpopulations (i.e., Microglia_Nrg3 and Microglia_Rarb) are identified with a reduced state of differentiation, and their connectivity with neurons is predicted through activation of the NRXN signaling pathway. Overall, these findings demonstrated that iNSC-Exo offers a versatile and potent treatment platform with clinical potential for TBI management.
研究领域:
神经科学
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再生医学
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转化医学
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纳米医学
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免疫调节
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药剂学
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分子神经生物学
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产品关联
DOI
PubMed
高影响因子
Nano Today
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2024
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IF 13.2
Yang Xu,Ge Yan,Jingyu Zhao,Yunhao Ren,Qiyao Xiao,Minhong Tan,Lihua Peng
Cell heterogeneous nanomaterials based therapeutic strategies for Parkinson’s disease (PD) have been widely investigated, however, challenged by the potential toxicity, immunogenicity, limited drug loading efficiency, and restricted penetration through biological barriers. Herein, for the first time, a medicinal plant, Pueraria lobata derived exosomes (Pu-Exos) were demonstrated with excellent capability in overcoming cellular membrane and endosomal barriers, ensuring the efficient delivery of incorporated biomacromolecule cargos to SH-SY5Y cells. Upon that, Pu-Exos comprehensively improved the mitochondrial dysfunction of SH-SY5Y cells through removing dysfunctional mitochondria via PINK1-Parkin mediated mitophagy, and restoring ATP supplementation by preserving the activities of mitochondrial respiratory chain complexes I and V. Pu-Exos were then engineered with the ternary ligand, DSPE-PEG-RVG, forming Pu-Exos-PR that were further optimized for the cellular uptake and brain enrichment in vivo , therefore excellently promoting the survival of dopaminergic neurons, with reduced cellular degeneration, denser Nissl substance and increased tyrosine hydroxylase expression, accompanied by obviously alleviated motor and non-motor symptoms. Pu-Exos-PR were shown as a promising exosome with outstanding biocompatibility, efficient incorporation of bioactive agents, and unique feature in penetration through both nasal tissue and blood brain barrier, inaugurating new avenues to brain-targeting delivery for biomacromolecules for PD therapy. This study also casts new insight on the plant-derived exosomes as next generation of cell homogenous nanoplatforms with high efficiency and biosafety for drug delivery and therapy of brain diseases.
研究领域:
神经科学
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药学
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分子生物学
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生物技术
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产品关联
DOI
高影响因子
International Journal of Medical Sciences
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2024
·Vol. 21
·期 15
·3018
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IF 3.2
Qi Zhang,Chao Hu,Baoqing Qu,Cuiping Zhang,Longtao He
This work aimed to demonstrate the therapeutic effects of tumor microenvironment-responsive nanotherapeutic drugs targeting PSD95/Discs-large/ZO-1 domain (PDZ)-binding-kinase (PBK) in medulloblastoma Daoy and ONS-76 cells. The objective was to provide critical theoretical and practical foundations for the clinical adoption of tumor microenvironment-responsive nanotherapeutic drugs targeting PBK. The rabies virus glycoprotein (RVG) was utilized as a specific targeting molecule to form a tumor microenvironment-responsive nanocomplex, HPAA/RVG/PBK-siRNA, which incorporated glutathione (GSH) as a microenvironment stimulus factor within a hyperbranched polymer polyamide amine (HPAA). This nanocomplex also carried PBK-small interfering RNA (siRNA) for targeted PBK therapy. Characterization of HPAA, maleimide-polyethylene glycol-N-succinyl ester (MAL-PEG-NHS), HPAA-PEG, RVG, HPAA-RVG, and HPAA/RVG/PBK-siRNA was conducted using nuclear magnetic resonance spectroscopy, high-performance liquid chromatography (HPLC), dynamic light scattering, and transmission electron microscopy (TEM). Flow cytometry was employed to assess endocytosis and cell transfection of HPAA-RVG and HPAA/RVG/PBK-siRNA in Daoy and ONS-76 cells. The two cell lines were treated with HPAA/RVG/PBK-siRNA (HPAA/siRNA group), methoxy-PEG polyethylenimine (PEI-25k)/PBK-siRNA (PEI group), HPAA/RVG nanocarriers without PBK-siRNA (HPAA/RVG group), Dharmacon™ non-targeting siRNA (shNTC group), PBK-siRNA (Control group 1), AChR inhibitor (Control group 2), and GSH inhibitor (Control group 3), and compared with the control group (medium without any substances). Western blot analysis validated PBK expression levels (ELs) in various cell groups. Additionally, cell viability and proliferation were evaluated using methyl tetrazolium (MTT) assays and 5-Bromo-2'-deoxyuridine (BrdU) incorporation assays. The results revealed proton absorption peaks for HPAA at 2.78 ppm, 3.21 ppm, and 3.49 ppm, while RVG and HPAA-RVG exhibited characteristic absorption peaks at 23.653 min and 23.584 min, respectively, with peak areas of 4,856.6 and 6,927.3 for RVG. The nanoparticle sizes were 50-100 nm for HPAA-RVG and 100 nm for HPAA/RVG/PBK-siRNA, displaying spherical morphology and uniform size distribution. The average potential of HPAA-PEG was lower than that of HPAA ( P <0.05), and HPAA-RVG showed dramatically lower potential than HPAA ( P <0.001). At 8 hours, Daoy cells displayed higher endocytosis rates versus ONS-76 cells ( P <0.05). The transfection rates of HPAA-RVG in both ONS-76 and Daoy cells were higher than those of HPAA, with Daoy cells showing higher transfection rates than HPAA ( P <0.05). Under HPAA-RVG treatment, AChR levels in ONS-76 cells were significantly lower than those in Daoy cells ( P < 0.05). Compared to the control group, the PBK protein expression levels, cell survival rates, and the number of cells in the proliferative phase were significantly reduced in Control group 1, the PEI group, and the HPAA/siRNA group in both ONS-76 and Daoy cells, with the ONS-76 cells in the HPAA/siRNA group showing the lowest values among these groups ( P < 0.05). In summary, the findings indicated that the tumor microenvironment-responsive nanocomposite HPAA/RVG/PBK-siRNA selectively inhibited PBK expression in Daoy medulloblastoma cells, showcasing potential applicability in medulloblastoma therapy.
研究领域:
肿瘤学
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药学
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）