Nano Today最新文献_第5页

Tracing the graphitization of polymers: A novel approach for direct atomic-scale visualization 追踪聚合物的石墨化：原子尺度直接可视化的新方法

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-23 DOI: 10.1016/j.nantod.2024.102524

Chloé Chemin, Babak Rezaei, Ada-Ioana Bunea, Stephan Sylvest Keller, Alice Bastos da Silva Fanta, Thomas Willum Hansen

Due to its excellent physical, chemical, and electrochemical characteristics, pyrolytic carbon has become a promising material for a wide range of advanced technologies. Pyrolytic carbon can be obtained through the pyrolysis of a polymeric carbon precursor at high temperatures and in inert atmosphere. By tuning the pyrolysis conditions, the hybridization of carbon atoms and thus the physicochemical properties of the derived carbon can be tailored. Advancing its development requires a deeper understanding of the graphitization process. In this context, an in situ microstructural analysis of the pyrolysis process is needed. This work presents the microfabrication of suspended polymer thin film structures on transmission electron microscopy heating chips, by two-photon polymerization 3D printing. We visualized graphitization of these films during in situ transmission electron microscopy heating studies. The favorable identified conditions are a thin film with a thickness of around 700 nm pre-pyrolysis, a pyrolysis profile reaching a maximum temperature of 1300°C and a minimum of 2 h of dwell at this temperature. An increase in the number of stacked graphene layers was observed over dwell time. Overall, the developed method has the potential to enable the visualization of graphitization of different polymer precursors and thus help predict the microstructure and properties of pyrolytic carbon depending on its fabrication conditions.

由于具有出色的物理、化学和电化学特性，热解碳已成为一种前景广阔的材料，可用于多种先进技术。热解碳可在高温和惰性气氛下通过热解聚合物碳前体获得。通过调整热解条件，可以定制碳原子的杂化以及衍生碳的物理化学特性。推进石墨化的发展需要对石墨化过程有更深入的了解。为此，需要对热解过程进行原位微结构分析。本研究通过双光子聚合三维打印技术，在透射电子显微镜加热芯片上实现了悬浮聚合物薄膜结构的微加工。在原位透射电子显微镜加热研究中，我们看到了这些薄膜的石墨化。确定的有利条件是：热解前薄膜厚度约为 700 nm，热解温度最高可达 1300°C，在此温度下至少停留 2 小时。随着停留时间的延长，堆叠石墨烯层的数量也在增加。总之，所开发的方法有望实现不同聚合物前驱体石墨化的可视化，从而有助于根据热解碳的制造条件预测其微观结构和特性。

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引用次数: 0

Therapeutic and responsive release mechanisms of polymer drug conjugates with diverse polymer skeletons 具有不同聚合物骨架的聚合物药物共轭物的治疗和响应释放机制

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-22 DOI: 10.1016/j.nantod.2024.102526

Wenjie Zhao, Kaichuang Sun, Jianqin Yan, Yong Sun, Dengshuai Wei

Polymer-drug conjugates (PDCs) have emerged as an advanced strategy in the drug delivery. The conjugation of therapeutic or diagnostic agents to polymers, such as polyurethane, polyester, RAFT-based polymers, and poly(amino acid)s, presents several advantages, including enhanced drug solubilization, controlled release, reduced immunogenicity, prolonged circulation, improved safety, and increased efficacy. Recent research has focused extensively on engineering efficient tumor microenvironment (TME)-responsive PDCs, leading to significant advancements in cancer diagnosis and therapy. This review discusses the rational design, mechanisms of responsive release, physicochemical properties, and recent developments in various polymer systems for PDCs. We categorize PDCs based on their skeletal designs, including polyurethane, polyester, RAFT polymers, and polyamino acids. Additionally, we emphasize the TME responsiveness of PDCs, highlighting its critical role in various tumor therapies. Finally, we address the current challenges faced by PDCs and offer perspectives for future research, providing insights into the utility and potential of this technology. We hope this review serves as a valuable resource for the selection and optimization of PDCs, facilitating their future applications in cancer therapeutics.

聚合物-药物共轭物（PDC）已成为一种先进的给药策略。将治疗或诊断药物与聚氨酯、聚酯、RAFT 基聚合物和聚（氨基酸）等聚合物共轭具有多种优势，包括提高药物溶解度、控制释放、降低免疫原性、延长循环时间、改善安全性和提高疗效。最近的研究广泛集中于设计高效的肿瘤微环境（TME）响应型 PDC，从而在癌症诊断和治疗方面取得了重大进展。本综述讨论了 PDC 的合理设计、响应性释放机制、理化特性以及各种聚合物系统的最新发展。我们根据骨架设计对 PDC 进行了分类，包括聚氨酯、聚酯、RAFT 聚合物和聚氨基酸。此外，我们还强调了 PDC 对 TME 的响应性，突出了它在各种肿瘤疗法中的关键作用。最后，我们探讨了 PDC 目前面临的挑战，并对未来研究提出了展望，为这一技术的实用性和潜力提供了见解。我们希望这篇综述能成为选择和优化 PDCs 的宝贵资源，促进它们未来在癌症治疗中的应用。

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引用次数: 0

High-fidelity CRISPR/Cas13a trans cleavage-driven assembly of single quantum dot nanosensor for ultrasensitive detection of long noncoding RNAs in clinical breast tissues 高保真 CRISPR/Cas13a 反式裂解驱动的单量子点纳米传感器组装，用于超灵敏检测临床乳腺组织中的长非编码 RNA

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-21 DOI: 10.1016/j.nantod.2024.102529

Wen-jing Liu , Hai-juan Li , Jinqiu Tao , Lu-yao Wang , Juan Hu , Chun-yang Zhang

Long noncoding RNAs (lncRNAs) act as critical regulators in various cellular processes, and their dysfunction is implicated in carcinogenesis. Herein, we demonstrate high-fidelity CRISPR/Cas13a trans cleavage-driven assembly of single quantum dot (QD) nanosensor for ultrasensitive detection of long noncoding RNAs in clinical tissues. The presence of lncRNA can activate Cas13a/crRNA to collaterally cleave the substrate probes, producing a T7 promoter fragment that can initiate subsequent transcription amplification to generate efficient fluorescence resonance energy transfer (FRET). Taking advantage of excellent specificity of high-fidelity CRISPR/Cas13a system, high efficiency of transcription amplification, and near-zero background of single QD-based FRET, this nanosensor can achieve a detection limit of 1.65 aM, and it can differentiate target lncRNA from its mismatched members with single-base resolution. Moreover, it can measure lncRNA at the single-cell level, distinguish diﬀerent subtypes of breast cancers, and assess the breast cancer progression. Notably, due to the programmability of crRNAs, this nanosensor can be extended to detect other nucleic acids (e.g., SARS-CoV-2 RNA, circRNA, miRNA, piRNA, and 16S rRNA) by simply altering the spacer region of crRNA, with great potential in lncRNAs-related molecular diagnostics.

长非编码 RNA（lncRNA）是各种细胞过程的关键调控因子，其功能障碍与致癌有关。在这里，我们展示了高保真 CRISPR/Cas13a 反式切割驱动的单量子点（QD）纳米传感器的组装，用于超灵敏检测临床组织中的长非编码 RNA。lncRNA 的存在可激活 Cas13a/crRNA 协同裂解底物探针，产生 T7 启动子片段，从而启动后续转录扩增，产生高效的荧光共振能量转移（FRET）。利用高保真 CRISPR/Cas13a 系统的卓越特异性、高效转录扩增和基于单个 QD 的近零背景 FRET，该纳米传感器的检测限可达到 1.65 aM，并能以单碱基分辨率区分目标 lncRNA 及其不匹配成员。此外，它还能在单细胞水平上测量lncRNA，区分不同亚型的乳腺癌，评估乳腺癌的进展。值得注意的是，由于crRNA的可编程性，这种纳米传感器只需改变crRNA的间隔区，就能扩展到检测其他核酸（如SARS-CoV-2 RNA、circRNA、miRNA、piRNA和16S rRNA），在与lncRNA相关的分子诊断方面具有巨大潜力。

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引用次数: 0

Dual-lock-and-key virus-mimicking nanoprobes for ultra-high accurate and sensitive imaging of viral infections in vivo 用于对体内病毒感染进行超高精度和灵敏度成像的双锁键病毒模拟纳米探针

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-20 DOI: 10.1016/j.nantod.2024.102527

Cong Yu , Hua-Jie Chen , Hao-Yang Liu , Di Ning , Lei Wang , Xue-Hui Shi , Zhi-Gang Wang , Dai-Wen Pang , Shu-Lin Liu

Fluorescence in situ imaging of viral infection lesions in vivo is crucial for precise diagnosis of viral diseases and evaluation of the extent of viral infection. Nevertheless, achieving highly specific and sensitive fluorescence imaging of viral infection sites in vivo has posed a persistent challenge. Here, we developed a dual-lock-and-key virus-mimicking nanoprobe that consisted of polyamide dendrimers (PAMAM) loaded internally with molecular beacons double-triggered by apurinic/apyrimidinic nucleic acid endonuclease 1 (APE1) and viral RNA (vRNA), and surface-modified with the E protein of Japanese encephalitis virus (JEV). This activatable nanoprobe generated dramatically amplified fluorescent signals stimulated by expressed vRNA and APE1 during viral infection, enabling ultrahigh specific and sensitive imaging of the lesions of JEV infection in vivo. This study provides a potential approach for accurate and sensitive detection of viral infection levels and assessment of the efficacy of antiviral drugs in vivo.

体内病毒感染病灶的荧光原位成像对于精确诊断病毒性疾病和评估病毒感染程度至关重要。然而，实现体内病毒感染部位的高特异性和高灵敏度荧光成像一直是个难题。在这里，我们开发了一种双锁键病毒模拟纳米探针，它由聚酰胺树枝状聚合物（PAMAM）组成，内部装有由嘌呤/嘧啶核酸内切酶 1（APE1）和病毒 RNA（vRNA）双重触发的分子信标，表面修饰有日本脑炎病毒（JEV）的 E 蛋白。这种可激活的纳米探针在病毒感染过程中受到表达的 vRNA 和 APE1 的刺激，产生了显著放大的荧光信号，从而实现了对体内 JEV 感染病灶的超高特异性和灵敏度成像。这项研究为准确灵敏地检测病毒感染水平和评估体内抗病毒药物的疗效提供了一种潜在的方法。

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引用次数: 0

Atomic-scale probing of ion migration dynamics in Na3Ni2SbO6 cathode for sodium ion batteries 用于钠离子电池的 Na3Ni2SbO6 阴极中离子迁移动力学的原子尺度探测

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-17 DOI: 10.1016/j.nantod.2024.102523

Ke Qu , Jianwei Zhang , Haonan Wang , Fan Wu , Huahui Lin , Jianchu Chen , Zhengping Ding , Zhenzhong Yang , Peng Gao

Honeycomb-layered phases like Na₃Ni₂SbO₆ have been extensively researched as high-voltage and high-rate capability cathode materials for sodium-ion batteries. However, our understanding of the structural stability and dynamic reaction mechanisms of Na₃Ni₂SbO₆ cathode during cycling, especially at atomic-scale, remains limited. Here, we track the microstructure evolution during extraction of Na⁺ ions in Na₃Ni₂SbO₆ cathode at atomic scale in an aberration-corrected transmission electron microscope. The electron beam irradiation that can provide a driving force for the Na⁺ ion migration, allows us to mimic the battery charge process. By controlling the electron beam dose, we study the structure evolution behavior to obtain insights into understanding the work principle and failure mechanism of Na₃Ni₂SbO₆ cathode under different charge rate conditions. We find that the real-time structural evolution and ion migration pathways of Na₃Ni₂SbO₆ cathode are distinct under different electron beam doses. High-dose irradiation reveals Na ion depletion, surface cracks, and phase transformations, mimicking rapid capacity decay. In contrast, low-dose irradiation shows slower ion migration, ordered Na vacancy formation, and maintaining structural integrity, which more closely resembles the electrochemical process of actual battery. This study provides an atomistic understanding of the structural stability and Na ions deintercalation mechanism in Na₃Ni₂SbO₆ cathodes, offering new insights into optimizing electrode materials.

Na3Ni2SbO6 等蜂窝层相作为钠离子电池的高电压和高倍率阴极材料已被广泛研究。然而，我们对 Na3Ni2SbO6 阴极在循环过程中的结构稳定性和动态反应机制的了解仍然有限，尤其是在原子尺度上。在此，我们使用畸变校正透射电子显微镜在原子尺度上跟踪 Na3Ni2SbO6 阴极中 Na+ 离子萃取过程中的微观结构演变。电子束辐照可为 Na+ 离子迁移提供驱动力，使我们能够模拟电池充电过程。通过控制电子束剂量，我们研究了Na3Ni2SbO6阴极在不同充电速率条件下的结构演化行为，从而深入了解了Na3Ni2SbO6阴极的工作原理和失效机理。我们发现，在不同电子束剂量下，Na3Ni2SbO6阴极的实时结构演化和离子迁移途径各不相同。高剂量辐照显示了 Na 离子耗竭、表面裂纹和相变，模拟了容量的快速衰减。相比之下，低剂量辐照显示出离子迁移速度较慢、有序的 Na 空位形成以及结构完整性的保持，这与实际电池的电化学过程更为接近。这项研究提供了对 Na3Ni2SbO6 阴极结构稳定性和 Na 离子脱闰机制的原子论理解，为优化电极材料提供了新的见解。

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引用次数: 0

Three-dimensional magnetophoretic bioassay based on artificial intelligence-mediated load assignment for the femtomolar and washing-free detection of analytes 基于人工智能负载分配的三维磁泳生物分析法，用于飞摩尔和免清洗分析物检测

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-16 DOI: 10.1016/j.nantod.2024.102522

Ting Xiao , Weiqi Zhao , Minjie Han , Xiaolin Huang , Ben Zhong Tang , Yiping Chen

The quantification of low-abundance biomarkers or trace harmful substances in complex samples at femtomolar-level sensitivity requires labor-intensive incubation and multiwashing steps. Herein, we explore a trajectory/accumulation/color three-dimensional microfluidic magnetophoresis immunoassay (TAC-MMI) based on an artificial intelligence (AI)-assisted load assignment strategy, enabling washing-free and femtomolar detection of interleukin-6 in serum samples and chloramphenicol in food samples within 30 min. The biorecognition between targets and biometric molecules (antigens and antibodies) immobilized on magnetic nanoparticles (MNPs) and polystyrene microsphere-horseradish peroxidase (PM-HRP) conjugate induces MNP-target-PM-HRP immunocomplexes with different magnetic contents, where the concentration of targets is transformed into spatial visualization information through magnetophoretic force using a linear microtube array within a microfluidic chip. The visualization information can be enhanced by the HRP-catalyzed color reaction. Trajectory-accumulation-color of PM in each microtube is precisely assigned significance and identified via AI for bioanalysis. TAC-MMI demonstrates high sensitivity (fM level), rapidity (30 min), and ease of use without washing steps. The three-dimensional sensing strategy based on load-assignment improved sensitivity by more than 96-fold compared with the traditional one-dimensional sensing strategy. Compared to chemiluminescence immunoassay (CLIA), TAC-MMI achieved 15-fold improvement in sensitivity in only one-third of the time required for CLIA, suggesting a promising magnetophoretic bioassay for diagnostic technology.

要以飞摩尔级的灵敏度定量复杂样品中的低丰度生物标记物或痕量有害物质，需要耗费大量人力的孵育和多次洗涤步骤。在此，我们探索了一种基于人工智能（AI）辅助负载分配策略的轨迹/累积/颜色三维微流控磁泳免疫分析法（TAC-MMI），可在 30 分钟内免洗、飞摩尔级地检测血清样品中的白细胞介素-6 和食品样品中的氯霉素。固定在磁性纳米颗粒（MNPs）和聚苯乙烯微球-辣根过氧化物酶（PM-HRP）共轭物上的目标物和生物识别分子（抗原和抗体）之间的生物识别诱导了不同磁性含量的 MNP-目标物-PM-HRP 免疫复合物，目标物的浓度通过微流控芯片内的线性微管阵列的磁导力转化为空间可视化信息。可视化信息可通过 HRP 催化的颜色反应得到增强。每个微管中可吸入颗粒物的轨迹-累积-颜色都被精确地赋予了意义，并通过人工智能进行生物分析识别。TAC-MMI 具有高灵敏度（fM 级）、快速（30 分钟）和使用方便等特点，无需清洗步骤。与传统的一维传感策略相比，基于负载分配的三维传感策略将灵敏度提高了 96 倍以上。与化学发光免疫测定（CLIA）相比，TAC-MMI 的灵敏度提高了 15 倍，所需的时间仅为 CLIA 的三分之一，这表明磁浮生物测定诊断技术前景广阔。

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引用次数: 0

In vivo engineering chimeric antigen receptor immune cells with emerging nanotechnologies 利用新兴纳米技术在体内制造嵌合抗原受体免疫细胞

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-10 DOI: 10.1016/j.nantod.2024.102517

Hui Ren , Yuzhi Jin , Huanhuan Huang , Wei Wu , Xiaomeng Dai , Weijia Fang , Jing Qin , Hongjun Li , Peng Zhao

Adoptive cell therapy with chimeric antigen receptor (CAR) has revolutionized cancer treatment in the past decade. Now several adoptive cell therapies are approved, and researchers are extending the application of adoptive cell therapy beyond oncology, such as autoimmune diseases, inherited blood disorders, infectious diseases and fibrosis. Evidence from clinical studies underscores the potential of cell therapy in cancer and noncancerous conditions. However, conventional manufacture of adoptive CAR-cell ex vivo is time-consuming and expensive in which immune cells are extracted from the patients, engineered to target cancer cells and reinjected to the body. The ways to produce CAR-cell in the body, as a promising alternative, may make the awfully expensive and personalized cell therapy more accessible. Here, we thoroughly summarize the current state of clinical trials on adoptive cell therapy, representing by CAR-T, CAR-nature killer cell (CAR-NK) and CAR-Macrophage (CAR-M), and highlight the latest advances in off-the-shelf nanocarrier- and virus-based in vivo CAR cargo delivery strategies, and corresponding precision targeting strategies, to provide a future perspective regarding in vivo engineering CAR-cell.

过去十年间，采用嵌合抗原受体（CAR）的收养细胞疗法彻底改变了癌症治疗。现在，多种采用性细胞疗法已获得批准，研究人员正在将采用性细胞疗法的应用范围扩展到肿瘤以外的领域，如自身免疫性疾病、遗传性血液病、传染性疾病和纤维化。临床研究的证据强调了细胞疗法在癌症和非癌症疾病中的潜力。然而，传统的体外 CAR 细胞制造既耗时又昂贵，需要从患者体内提取免疫细胞，设计成针对癌细胞的细胞，然后再注射到体内。在体内制造 CAR 细胞的方法是一种很有前景的替代方法，它可以使昂贵的个性化细胞疗法变得更容易获得。在此，我们全面总结了以CAR-T、CAR-自然杀伤细胞（CAR-NK）和CAR-巨噬细胞（CAR-M）为代表的采用性细胞疗法的临床试验现状，并重点介绍了基于现成纳米载体和病毒的体内CAR货物递送策略以及相应的精准靶向策略的最新进展，以提供有关体内工程CAR-细胞的未来展望。

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引用次数: 0

Biomimetic nanoreactor of catalase and nitric oxide enhance peroxynitrite generation for radiosensitization 过氧化氢酶和一氧化氮的仿生纳米反应器可增强过氧化亚硝酸盐的生成，从而提高辐射敏感性

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-07 DOI: 10.1016/j.nantod.2024.102519

Yao Wu , Yongping Li , Honglei Xie , Yichen Zhang , Xinyue Bao , Xianyi Sha , Jingyuan Wen , Yaping Li , Zhiwen Zhang

The redundant DNA-repairing capacity and robust hypoxia in tumors pose significant challenges of cancer radiotherapy. Herein, an amphiphilic nitric oxide (NO)-supplying conjugate (PEG−SMA−NO) was synthesized and integrated with oxygen-producing catalase (CAT) to fabricate a biomimetic nanoreactor (termed as CAT@PNN), aiming to enhance peroxynitrite generation upon X-ray radiation for radiosensitization. CAT@PNN effectively reduced the hypoxic levels and produced abundant NO molecules in tumors. Upon X-ray radiation, excessive peroxynitrite radicals were generated with profound spatiotemporal distribution profiles, which effectively downregulated the expression of DNA-repairing RAD51, reduced the proportion of cancer-stem like cells, and enhanced the levels of DNA damages, cell apoptosis and lipid peroxidation to aid radiosensitization. Specifically, the combination of single treatment of CAT@PNN with X-ray radiation resulted in a 95.41 % inhibition of tumor growth and significantly extended survival in 4T1 tumor model. Therefore, the biomimetic nanoreactor of CAT@PNN offers a promising peroxynitrite-generating nanoplatform to enhance radiosensitization in cancer radiotherapy.

肿瘤中冗余的DNA修复能力和强大的缺氧能力给癌症放疗带来了巨大挑战。本文合成了一种两亲性一氧化氮（NO）供应共轭物（PEG-SMA-NO），并将其与产氧过氧化氢酶（CAT）结合，制成了一种仿生纳米反应器（CAT@PNN），旨在增强X射线辐射时过氧亚硝酸盐的生成，从而实现放射增敏。CAT@PNN能有效降低肿瘤的缺氧水平，并产生丰富的NO分子。在X射线照射下，过氧化亚硝酸自由基的生成具有深刻的时空分布特征，可有效下调DNA修复RAD51的表达，降低癌干细胞的比例，并提高DNA损伤、细胞凋亡和脂质过氧化的水平，从而帮助放射增敏。具体而言，在 4T1 肿瘤模型中，将 CAT@PNN 与 X 射线辐射结合使用，可使肿瘤生长抑制率达到 95.41%，并显著延长存活时间。因此，CAT@PNN 的仿生纳米反应器为提高癌症放疗的放射增敏提供了一个前景广阔的过亚硝酸盐生成纳米平台。

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引用次数: 0

Liquid-liquid phase separation in human diseases: Functions, mechanisms and treatments 人类疾病中的液-液相分离：功能、机制和治疗

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-07 DOI: 10.1016/j.nantod.2024.102521

Tongqing Yue , Fei Zhang , Yanan Wei, Zejun Wang

Cells are separated into functional regions by non-membrane organelles and membrane-enclosed organelles, ensuring that various cellular activities occur in a controlled manner in space and time. There is increasing evidence that large numbers of non-membrane compartments, collectively referred to as biomacromolecular condensates or droplets, are formed in cells through liquid-liquid phase separation (LLPS). Phase-separated condensates play a role in numerous biological activities and intracellular spatiotemporal regulation, such as cellular transcription, chromatin maintenance, signal transduction, and immune response. However, abnormal phase separation and transformation are closely linked to many major human diseases. This review comprehensively summarizes the detailed mechanisms of biomacromolecular condensates formation and physiological functions, and discusses the latest progress in elucidating the pathological mechanisms of various human diseases caused by abnormal LLPS and their treatment options.

细胞被非膜细胞器和膜封闭细胞器分隔成功能区，确保各种细胞活动在空间和时间上以受控方式进行。越来越多的证据表明，细胞内通过液-液相分离（LLPS）形成了大量非膜区室，统称为生物分子凝聚体或液滴。相分离的凝聚体在许多生物活动和细胞内时空调节中发挥作用，如细胞转录、染色质维持、信号转导和免疫反应。然而，异常的相分离和转化与许多重大人类疾病密切相关。这篇综述全面总结了生物大分子凝聚物形成的详细机制和生理功能，并探讨了阐明由异常 LLPS 引起的各种人类疾病的病理机制及其治疗方案的最新进展。

引用次数: 0

MCL1 inhibitor S63845 delivered by follicle-stimulating hormone modified liposome potentiates carboplatin efficacy in ovarian cancer 通过卵泡刺激素修饰脂质体递送的 MCL1 抑制剂 S63845 可增强卡铂对卵巢癌的疗效

IF 13.2 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Today

Pub Date : 2024-10-05 DOI: 10.1016/j.nantod.2024.102513

Yanan Zhang , Qingzhen Wang , Wenxin Li , Xin Li , Yuqing Li , Zhihua Liu , Huige Zhou , Aiping Luo , Chunying Chen , Bin Li

Platinum resistance cause therapeutic failure and poor prognosis in ovarian cancer, and evasion of apoptosis is a critical factor in chemoresistance. A limited number of FDA-approved anticancer drugs directly target apoptotic pathways. Here, we discovered that MCL1, a critical anti-apoptotic protein, is amplified and associated with platinum resistance and survival in ovarian cancer, assisting in personalized treatment. We further identified S63845 through drug-based screening, the most potent MCL1 inhibitor, which efficiently enhanced carboplatin (CBP) sensitivity in various ovarian cancer models, including primary ovarian cancer cells, orthotopic ovarian cancer, peritoneal metastasis, and human patient-derived xenograft (PDX) models. Mechanistically, S63845 competitively binds to MCL1, disrupts the binding of apoptosis effector (BAK and BAX) or pro-apoptotic BH3 protein (BIM) to MCL1 respectively, and eventually enhances CBP-induced apoptosis.To promote the clinical transformation of S63845, we developed follicle-stimulating hormone-modified liposome nanoparticles (S63845@Lipo-FSH) to enhance stability, membrane penetration, and tumor-targeting capabilities. S63845@Lipo-FSH exhibits a superior therapeutic efficacy and tumor targeting compared to free S63845, even when the dose of S63845 is reduced to one-fifth. Overall, targeting MCL1 by S63845@Lipo-FSH enhances CBP efficiency in ovarian cancer, with safety and efficacy, suggesting that this strategy is effective and promising for clinical application.

铂类药物的耐药性会导致卵巢癌治疗失败和预后不良，而细胞凋亡的逃避是导致化疗耐药性的关键因素。美国 FDA 批准的抗癌药物中，直接针对细胞凋亡通路的药物数量有限。在这里，我们发现卵巢癌中关键的抗凋亡蛋白MCL1被扩增，并与铂类药物耐药性和生存率相关，这有助于个性化治疗。我们通过药物筛选进一步确定了 S63845，它是最有效的 MCL1 抑制剂，能有效提高卡铂（CBP）在各种卵巢癌模型中的敏感性，包括原发性卵巢癌细胞、正位卵巢癌、腹膜转移瘤和人类患者来源异种移植（PDX）模型。为促进S63845的临床转化，我们开发了卵泡刺激素修饰的脂质体纳米颗粒（S63845@Lipo-FSH），以增强其稳定性、膜穿透性和肿瘤靶向能力。与游离 S63845 相比，即使 S63845 的剂量减少到五分之一，S63845@脂质-FSH 也能显示出更优越的疗效和肿瘤靶向性。总之，S63845@Lipo-FSH靶向MCL1能提高CBP对卵巢癌的治疗效率，而且安全有效，表明这种策略是有效的，具有临床应用前景。

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引用次数: 0