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Bioengineering microspheres regulating mesenchymal stem cell fate accelerate spinal cord injury therapeutics

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-06 DOI: 10.1016/j.nantod.2024.102574

Zhiyi Feng , Yanming Zuo , Jiamen Shen, Qian Zhao, Zhi Qiang Cao, Xiaokun Li, Zhouguang Wang

Stem cell therapies have shown significant promise in addressing spinal cord injury (SCI) due to their ability to protect, regenerate, and replace tissue. However, the efficacy of these therapies encounters post-transplantation challenges, including poor survival, inefficient retention, difficulty in neuron transdifferentiation, and difficulty connecting into the injured area. In this study, we introduce a bioengineering platform to address these problems through regulating of mesenchymal stem cell (MSC) fate. To fabricate this platform, extracellular matrix (ECM) was first obtained and optimized for effective phenotypic neuronal differentiation in vitro. To support stem cell survival and retention, porous microspheres were collected and selected with microfluidic fabrication. When incorporated into the bioengineered microsphere (BEM) platform, the loaded MSCs demonstrated improved survival, considerable retention rates, the ability to differentiate into neuronal cells, and effective tissue integration in contusive SCI models. More importantly, BEM-assisted MSC treatment reduces scar tissue formation, improves the regeneration of nearby tissues and axons, protects the synaptic structure, and enhances signal transduction, thereby accelerating post-SCI recovery. This advancement enhances therapeutic strategies for SCIs and related neuronal disorders.

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引用次数: 0

An orally budesonide-loaded yeast microcapsules-based gel relieves IgA nephropathy via the modulation of gut-kidney axis

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-05 DOI: 10.1016/j.nantod.2024.102572

Ao Sun , Qiuhua Luo , Hongyu Liu , Weiguang Yang , Jiaxin Liu , Xianbao Shi , Yingxin Nie , Jin Sun , Mengchi Sun , Linlin Liu

IgA nephropathy (IgAN) is an autoimmune disease marked by IgA complex deposition in the glomerular mesangium, leading to chronic kidney disease and renal failure. Our clinical studies highlighted the critical role of gut microbiota and mucosal immunity in IgAN pathogenesis, identified through 16S rRNA gut microbiota diversity analysis. Given the established gut-kidney axis in IgAN development, we developed an orally administrated budesonide-encapsulated yeast microcapsules-based pectin gel, termed NYPs@Gel. Yeast microcapsules, compromising β-glucans and polysaccharides, Yeast microcapsules, comprising β-glucans and polysaccharides, protect budesonide from acidic degradation and promote its accumulation in gut-associated lymphoid tissue, thereby triggering mucosal immunity. The coated pectin gels prolong the formulation’s retention time in the intestines and provide sustained drug release. As anticipated, NYPs@Gel effectively enhances intestinal mucosa’s resistance to inflammation, reduces gut-derived IgA production, mitigates the side effects of budesonide, and restores gut microbiota balance. By modulating the gut-kidney axis, NYPs@Gel significantly improves IgAN outcomes, representing substantial advancements in the management and treatment of IgAN and a potential breakthrough in reducing the burden of chronic kidney disease.

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引用次数: 0

Augmenting Tumor Lysis and Immune Response through HIFU-armed Oncolytic Virus Delivery System 通过hifu武装溶瘤病毒传递系统增强肿瘤溶解和免疫反应

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-02 DOI: 10.1016/j.nantod.2024.102571

Xifeng Qin , Mingyang Liu , Hu Wu , Boshu Ouyang , Xu Zhao , Xiaomin Su , Ruizhe Xu , Huiwen Liu , Jiayi Wu , Yue Liu , Ting Wang , Onder Ergonul , Füsun Can , Jia Li , Lin Lin , Funan Liu , Zhiqing Pang

Oncolytic viruses (OVs) have hold great promise as a tumor immunotherapy. However, their effectiveness is hindered by the challenge of precise and efficient delivery in vivo and stimulating a robust anti-tumor immune response. In this study, we developed a strategy of high-intensity focused ultrasound (HIFU)-armed oncolytic immunotherapy. It was found that HIFU facilitating efficient delivery of erythrocyte-hijacking OVs to solid tumors and enhancing the penetration of OVs in tumors. Remarkably, HIFU enhanced the oncolytic effect of OVs not only by suppressing the host cell’s ability of virus clearance through downregulating the IFN signaling pathway, but also by enhancing OV replication within tumor cells through upregulating the expression of the oncogene RAS, inducing DNA damage, and promoting OVs-induced autophagy. More importantly, HIFU augmented OVs-mediated anti-tumor immune responses in vivo, leading to remodeling of the tumor microenvironment, resulting in nearly complete tumor regression (97.6 %) within 15 days and 80 % tumor-free status sustained for 120 days. Overall, these findings highlight the potential of HIFU as a novel modality for precise OV delivery, augmented oncolytic effect, and robust immunostimulation in oncolytic immunotherapy of solid tumors.

溶瘤病毒（OVs）作为一种肿瘤免疫疗法具有很大的前景。然而，它们的有效性受到体内精确和有效递送和刺激强大的抗肿瘤免疫反应的挑战的阻碍。在这项研究中，我们开发了一种高强度聚焦超声（HIFU）武装溶瘤免疫治疗策略。研究发现，HIFU可促进劫持红细胞的OVs有效递送至实体肿瘤，并增强OVs在肿瘤中的渗透。值得注意的是，HIFU不仅通过下调IFN信号通路抑制宿主细胞对病毒的清除能力，而且通过上调癌基因RAS的表达，诱导DNA损伤，促进OVs诱导的自噬，增强肿瘤细胞内OV的复制，从而增强OVs的溶瘤作用。更重要的是，HIFU增强了ovs介导的体内抗肿瘤免疫反应，导致肿瘤微环境的重塑，导致15天内几乎完全的肿瘤消退（97.6% %），80 %的无肿瘤状态持续120天。总的来说，这些发现突出了HIFU作为一种精确OV输送、增强溶瘤效应和在实体肿瘤溶瘤免疫治疗中强大的免疫刺激的新模式的潜力。

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引用次数: 0

Outside Back Cover - Graphical abstract TOC/TOC in double column/Cover image legend if applicable, Bar code, Abstracting and Indexing information 封底外-图形摘要TOC/双栏TOC/封面图例（如适用），条形码，摘要和索引信息

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-01 DOI: 10.1016/S1748-0132(24)00426-2

引用次数: 0

Inside Back Cover - Graphical abstract TOC/TOC in double column continued from OBC if required, otherwise blank page 封底内-图解摘要TOC/TOC双栏，如果需要，从OBC继续，否则空白页

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-01 DOI: 10.1016/S1748-0132(24)00425-0

引用次数: 0

Corrigendum to “Engineering catalytic dephosphorylation reaction for endotoxin inactivation” [Nano Today 44 (2022) 101456] “内毒素失活的工程催化去磷酸化反应”的勘误表[纳米今日44 (2022)101456]

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-01 DOI: 10.1016/j.nantod.2024.102525

Meng Gao , Xi Liu , Zhenzhen Wang , Hui Wang , Tristan Asset , Di Wu , Jun Jiang , Qianqian Xie , Shujuan Xu , Xiaoming Cai , Jia Li , Weili Wang , Huizhen Zheng , Xingfa Gao , Nikolai Tarasenko , Benjamin Rotonnelli , Jean-Jacques Gallet , Frédéric Jaouen , Ruibin Li

引用次数: 0

Sequentially amplified integration of catalytic DNA circuits for high-performance intracellular imaging of miRNA and interpretation of mRNA-miRNA signalling pathway 序列扩增整合催化DNA电路，用于miRNA的高性能细胞内成像和mRNA-miRNA信号通路的解释

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-12-01 DOI: 10.1016/j.nantod.2024.102563

Mengdi Yu , Yushi Wang , Jinhua Shang , Qingqing Zhang , Yuqian Jiang , Xiaoqing Liu , Fuan Wang

The cascaded catalytic circuits are viable tools for improving the signal gain of biosensors, yet their sensing performance is still limited by the signal leakage from complex biological environment and unsatisfying reaction efficiency from inter-reactants steric hindrance. Herein, we proposed a catalytically localized DNA (CLD) circuit for the accurate and high-efficiency imaging of microRNA (miRNA) in living cells by virtue of the sequentially and successively amplified integration of catalytic DNA circuits. The compact CLD circuit was constructed by integrating two elemental catalytic circuits, cell-responsive EDR module and analyte-sensing CHA module, where CHA module was initially caged in EDR module for eliminating the unwanted off-site and off-target signal leakage. Only by cell-specific messenger RNA (mRNA)-activated EDR operation then the elemental CHA circuit could be successively connected to facilitate the highly efficient intramolecular reaction with low steric hindrance, thus leading to accelerated reaction efficiency for miRNA analyte. The multiple molecular recognition and the spatial self-confinement of the smart CLD circuit enable the accurate and high-efficiency imaging of intracellular miRNA. The interaction network of mRNA and miRNA was then investigated in situ through our CLD circuit, which provides a powerful tool for discovering the underlying signal pathways between these different RNAs in living cells.

级联催化电路是提高生物传感器信号增益的可行工具，但其传感性能仍然受到复杂生物环境信号泄漏和反应物间位阻反应效率不理想的限制。在此，我们提出了一种催化定位DNA （CLD）电路，利用催化DNA电路的顺序和先后扩增整合，用于准确和高效地成像活细胞中的microRNA （miRNA）。紧凑的CLD电路由两个基本催化电路组成，即细胞响应EDR模块和分析物传感CHA模块，其中CHA模块最初被封装在EDR模块中，以消除不必要的场外和场外信号泄漏。只有通过细胞特异性信使RNA （mRNA）激活的EDR操作，才能将元素CHA电路依次连接起来，促进低位阻的高效分子内反应，从而加快miRNA分析物的反应效率。智能CLD电路的多分子识别和空间自约束使细胞内miRNA的准确、高效成像成为可能。然后通过我们的CLD电路原位研究mRNA和miRNA的相互作用网络，这为发现活细胞中这些不同rna之间的潜在信号通路提供了强大的工具。

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引用次数: 0

RVG29-modified oncolytic herpes simplex virus for intracranial tumor treatment rvg29修饰的溶瘤性单纯疱疹病毒治疗颅内肿瘤

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-11-30 DOI: 10.1016/j.nantod.2024.102573

Liting Chen , Chen Xu , Hainan Xu , Hongyu Liu , Zihan Ma , Jiahao Liu , Xiaoyu Gao , Wei Lv , Xinze Du , Xiao Zhao , Jing Shi , Keman Cheng , Funan Liu

Oncolytic virus therapy for brain tumors has achieved breakthrough progress in clinical applications, yet its potential is severely constrained by the mode of administration-direct intratumoral injection into the cranial cavity. Other administration routes face rapid clearance by neutralizing antibodies and obstacles posed by the blood-brain barrier. Herein, we engineered the oncolytic herpes simplex virus type 2 (OH2) with surface modifications of polyethylene glycol (PEG) and rabies virus glycoprotein 29 (RVG29, a BBB-penetrating peptide from the rabies virus), to form OH2-PEG-RVG. OH2-PEG-RVG could efficiently traversed the blood-brain barrier even in BALB/c mice with pre-existing anti-OH2 antibodies, leading to the accumulation of OH2 in the brain. More importantly, OH2-PEG-RVG maintained blood-brain barrier integrity without causing pathological changes or behavioral abnormalities in mice. Furthermore, OH2-PEG-RVG effectively inhibited brain tumor growth, transforming immunologically "cold" tumors into "hot" tumors, inducing a robust anti-tumor immune response, and prolonging the survival of the mice. These findings underscore the potential of OH2-PEG-RVG as a multifaceted therapeutic strategy for effective brain tumor treatment, offering insights into addressing blood-brain barrier limitations.

溶瘤病毒治疗脑肿瘤在临床应用方面取得了突破性进展，但其潜力受到直接在颅腔内注射给药模式的严重制约。其他给药途径面临着通过中和抗体和血脑屏障造成的障碍而迅速清除的问题。在此，我们对溶瘤性单纯疱疹病毒2型（OH2）进行了聚乙二醇（PEG）和狂犬病毒糖蛋白29 （RVG29，一种来自狂犬病毒的bbb穿透肽）的表面修饰，形成OH2-PEG- rvg。OH2- peg - rvg即使在预先存在抗OH2抗体的BALB/c小鼠中也能有效地穿过血脑屏障，导致OH2在大脑中积累。更重要的是，OH2-PEG-RVG在不引起小鼠病理改变或行为异常的情况下保持了血脑屏障的完整性。此外，OH2-PEG-RVG有效抑制脑肿瘤生长，将免疫上的“冷”肿瘤转化为“热”肿瘤，诱导强大的抗肿瘤免疫反应，延长小鼠的生存期。这些发现强调了OH2-PEG-RVG作为一种有效治疗脑肿瘤的多方面治疗策略的潜力，为解决血脑屏障限制提供了见解。

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引用次数: 0

Boosting ubiquitin-proteasome system-mediated androgen receptor degradation and cGAS-STING pathway activation for synergistic prostate cancer therapy by engineered zinc-manganese oxide nanoparticles 工程锌锰氧化物纳米颗粒促进泛素-蛋白酶体系统介导的雄激素受体降解和cGAS-STING通路激活协同前列腺癌治疗

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-11-29 DOI: 10.1016/j.nantod.2024.102560

Linnan Yang , Yi Hu , Hui Peng , Zhengbin Wang , Sixu Chen , Jieying Qian , Yujie Yang , Zhonghua Xu , Jin Wu , Chaozhao Liang , Guilong Zhang , Yunjiao Zhang , Li Zhang

Androgen receptor (AR) is an essential target for prostate cancer (PCa) therapy, while required resistance due to AR overexpression/abnormal splicing often leads to therapeutic failure, and how to realize the synergistic therapeutic efficacy for PCa remains a challenge. Herein, a novel paradigm of zinc-manganese oxide nanoparticles (ZMONPs) is rationally engineered, which can cooperate in promoting ubiquitin-proteasome system (UPS)-mediated AR degradation and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway activation, thereby generating a tumoricidal immune microenvironment to elicit PCa cell death. Upon lysosomal acidolysis, ZMONPs promote zinc ions overload to produce more reactive oxygen species (ROS), which ultimately contribute to UPS-mediated AR degradation and tumoricidal effect. In PCa mouse models, ZMONPs significantly down-regulate the abundance of AR within the tumor microenvironment, further facilitating cGAS-STING signaling pathway activation to secrete C-C motif chemokine ligand 5 (CCL5) and interferon beta (IFN-β), which enhance dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration, thus realizing tumor growth inhibition in a cooperative manner. In addition, co-administration of ZMONPs and docetaxel presents notably synergistic therapeutic efficacy. Collectively, this study highlights the favorable effects of ZMONPs on AR degradation-related hormonal therapy and anti-tumor immunity, which may serve as a promising therapeutic strategy for PCa.

雄激素受体（雄激素受体，雄激素受体）是前列腺癌治疗的重要靶点，但由于雄激素受体过表达/剪接异常导致的耐药性往往导致治疗失败，如何实现雄激素受体对前列腺癌的协同治疗效果仍是一个挑战。本文合理设计了一种新型的锌锰氧化物纳米颗粒（ZMONPs），它可以协同促进泛素-蛋白酶体系统（UPS）介导的AR降解和环GMP-AMP合成酶刺激干扰素基因（cGAS-STING）信号通路的激活，从而产生一个杀死肿瘤的免疫微环境，引发PCa细胞死亡。在溶酶体酸解过程中，ZMONPs促进锌离子过载产生更多活性氧（ROS），最终促进ups介导的AR降解和肿瘤杀伤作用。在PCa小鼠模型中，ZMONPs显著下调肿瘤微环境中AR的丰度，进一步促进cGAS-STING信号通路激活，分泌C-C基元趋化因子配体5 （CCL5）和干扰素β (IFN-β)，促进树突状细胞（dc）成熟和细胞毒性T淋巴细胞（ctl）浸润，协同实现肿瘤生长抑制。此外，ZMONPs与多西他赛合用具有显著的协同治疗效果。总之，本研究强调了ZMONPs对AR降解相关激素治疗和抗肿瘤免疫的有利作用，这可能是一种有希望的PCa治疗策略。

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引用次数: 0

SNA·SMNP·CBE system: A novel integrative strategy for β-hemoglobinopathies gene therapy SNA-SMNP-CBE 系统：β-血红蛋白病基因治疗的新型综合策略

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-11-26 DOI: 10.1016/j.nantod.2024.102558

Hongya Cheng , Wenqiao Hui , Hanyue Kang , Zhenni Shi , Jianlei Liu , Xin Wang , Fei Qi , Lin Mao , Huiqian Ding , Rongjian Hu , Nabila Begum , Daoqiang Lu , Dandan Chen , Xinyue Cheng , Miaomiao Wan , Dahai Liu , Hsian-Rong Tseng , Shoudong Ye , Xiaobin Xu , Baowei Zhang , Qian Ban

Here, we developed and demonstrated a novel integrative system—Silica Nanorods (SNA) substrate cell capture combined with Supramolecular Nanoparticle (SMNP) delivery mediated CBE base editing (SNA·SMNP·CBE)—achieving the synchronization of CD34+HSPCs cell capture and gene editing for β-hemoglobinopathies. First, in vitro study shows it enables efficient and precise modification of BCL11A promoter in CD34+HSPCs, yielding the highly editing efficiency of 50.4 %, thus making an alternative strategy to conventional immunomagnetic cell separation and electroporation transfection system mediated CBE editing (IMS·EP·CBE). Then, we transplanted the edited human CD34+HSPCs into severe combined immunodeficiency (SCID) mice by using intraosseous injection strategy. When compared with conventional IMS·EP·CBE methods, our results showed that significantly higher human HBG expression in the bone marrow and peripheral blood of recipient mice, and long-term engraftment, evidenced from similar gene expression profiles to naïve CD34+HSPCs at 14 weeks. Conclusively, our integrative system—SNA·SMNP·CBE·intraosseous injection—offers an appealing novel way for the unique potential of gene therapy in the clinic application for β-hemoglobinopathies patients.

在这里，我们开发并展示了一种新型的整合系统--二氧化硅纳米棒（SNA）基底细胞捕获结合超分子纳米颗粒（SMNP）递送介导的CBE碱基编辑（SNA-SMNP-CBE）--实现了CD34+HSPCs细胞捕获与β-血红蛋白病基因编辑的同步。首先，体外研究表明它能高效、精确地修饰 CD34+HSPCs 的 BCL11A 启动子，编辑效率高达 50.4%，从而成为传统免疫磁性细胞分离和电穿孔转染系统介导的 CBE 编辑（IMS-EP-CBE）的替代策略。然后，我们采用骨内注射策略将编辑后的人 CD34+HSPCs 移植到重症联合免疫缺陷（SCID）小鼠体内。与传统的 IMS-EP-CBE 方法相比，我们的研究结果表明，受体小鼠骨髓和外周血中的人 HBG 表达量显著提高，并且在 14 周时，受体小鼠的基因表达谱与天真 CD34+HSPCs 相似，这证明了我们的研究结果具有长期的移植效果。总之，我们的综合系统--SNA-SMNP-CBE-骨内注射--为β-血红蛋白病患者的临床应用提供了一种具有独特潜力的基因治疗新方法。

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