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Engineered bacterium-metal-organic framework biohybrids for boosting radiotherapy with multiple effects 工程细菌-金属-有机框架生物混合体用于增强放射治疗的多重效果。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-19 DOI: 10.1016/j.biomaterials.2024.122901
Jia-Wei Wang , Ping Ji , Jin-Yue Zeng , Jun-Long Liang , Qian Cheng , Miao-Deng Liu , Wei-Hai Chen , Xian-Zheng Zhang
Hypoxia and lactate-overexpressed tumor microenvironment always lead to poor therapeutic effect of radiotherapy. Here, platinum nanoparticles-embellished hafnium metal-organic framework (Hf-MOF-Pt NPs) were elaborately integrated with Shewanella oneidensis MR-1 (SO) to construct an engineered biohybrid platform (SO@Hf-MOF-Pt) for enhancing radiotherapy. Benefiting from the tumor-targeting and metabolic respiration characteristics of SO, SO@Hf-MOF-Pt could enrich in tumor sites and continuously metabolize the overexpressed lactate, which specifically downregulated the expression of hypoxia-inducible factor (HIF-1α), thereby relieving the radiosuppressive tumor microenvironment to some extent. Moreover, SO@Hf-MOF-Pt would react with tumor-overexpressed hydrogen peroxide (H2O2) to generate oxygen (O2) and further inhibit the expression of HIF-1α, resulting in the downregulation of lactate dehydrogenase (LDHA) and subsequently reducing the lactate production. Under these multiple cascaded effects, the radiosuppressive tumor microenvironment was significantly reshaped, thus potentiating the radiosentization of SO@Hf-MOF-Pt and remarkably amplifying the therapeutic outcomes of radiotherapy. The designed biohybrid SO@Hf-MOF-Pt represented promising prospects in sensitizing radiotherapy via bacterium-based metabolic regulation.
缺氧和乳酸盐表达的肿瘤微环境总是导致放疗效果不佳。在这里,铂纳米粒子点缀的铪金属有机框架(Hf-MOF-Pt NPs)与Shewanella oneidensis MR-1(SO)被精心整合,构建了一个工程生物杂交平台(SO@Hf-MOF-Pt),用于提高放疗效果。得益于SO的肿瘤靶向性和代谢呼吸特性,SO@Hf-MOF-Pt可富集于肿瘤部位,并持续代谢过表达的乳酸,从而特异性下调缺氧诱导因子(HIF-1α)的表达,在一定程度上缓解了肿瘤放射抑制微环境。此外,SO@Hf-MOF-Pt 会与肿瘤表达的过氧化氢(H2O2)反应生成氧气(O2),进一步抑制 HIF-1α 的表达,导致乳酸脱氢酶(LDHA)下调,进而减少乳酸的产生。在这些多重级联效应的作用下,具有放射抑制作用的肿瘤微环境被显著重塑,从而增强了SO@Hf-MOF-Pt的放射增效作用,显著提高了放疗的疗效。所设计的生物杂交SO@Hf-MOF-Pt在通过基于细菌的代谢调控实现放疗增敏方面具有广阔的前景。
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引用次数: 0
A Sr@Ag-based spatiotemporal and step-release scaffold against chronic osteomyelitis, fabricated by coaxial 3D-printing 通过同轴三维打印技术制作的基于 Sr@Ag 的时空和阶跃释放支架,可防治慢性骨髓炎。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-18 DOI: 10.1016/j.biomaterials.2024.122899
Jingyun Wang , Qin Zhang , Hetong Wang , Chunlin Liu , Le Jiang , Wanting Liu , Yixian Wu , Yifan Wang , Vivian , Hao Yan , Jun Lin , Xiaodan Sun
Chronic osteomyelitis (OM) represents a severe and persistent infectious bone disease. Effective treatment requires controlled anti-inflammatory releases and bone regeneration across disease phases. A Sr@Ag-based scaffold was successfully printed, featuring micron-scale coaxial fibers containing Ag-doped hydroxyapatite (HA) in the outer layer of PLLA and Sr-doped HA in the inner layer of PLLA, facilitating the spatiotemporal and sequential release of Ag and Sr ions during OM treatment. Most antibacterial agent (Ag) was released during the first 20 days, followed by a slow-release plateau over the next 40 days in phosphate-buffered saline solution (PBS). Meanwhile, the pro-angiogenic agent (Sr) was released in minimal amounts during the initial 20 days, followed by a rapid and considerable release in the following 40 days. The coaxial design effectively inhibited the growth of Staphylococcus aureus and Escherichia coli while preserving the viability of bone cells. The ion-based scaffold exhibited broad-spectrum antibacterial effects and enhanced bone-regenerating gene expression in a complex air-bacteria environment. The Sr@Ag-based coaxial scaffold demonstrated effective antibacterial activity during the early stage and exhibited excellent non-toxic bone regeneration results during the middle and late stages in vivo. This work offered a promising treatment strategy through sequential anti-inflammatory and pro-osteogenic effects for infectious bone-defect diseases.
慢性骨髓炎(OM)是一种严重而顽固的感染性骨病。有效的治疗需要有控制的抗炎释放和跨疾病阶段的骨再生。我们成功地打印出了一种基于 Sr@Ag 的支架,其特点是在聚乳酸(PLLA)外层含有掺银羟基磷灰石(HA)的微米级同轴纤维,在聚乳酸(PLLA)内层含有掺锶羟基磷灰石(HA),从而促进了在 OM 治疗期间银离子和锶离子的时空顺序释放。在磷酸盐缓冲盐溶液(PBS)中,大部分抗菌剂(Ag)在最初的 20 天内释放,随后的 40 天内缓慢释放。同时,促血管生成剂(Sr)在最初的 20 天内释放量极少,在随后的 40 天内迅速大量释放。同轴设计有效抑制了金黄色葡萄球菌和大肠杆菌的生长,同时保持了骨细胞的活力。基于离子的支架在复杂的空气细菌环境中表现出广谱抗菌效果,并增强了骨再生基因的表达。Sr@Ag 基同轴支架在早期阶段表现出有效的抗菌活性,在中后期阶段表现出优异的无毒骨再生效果。这项研究通过连续的抗炎和促骨生成作用,为治疗感染性骨缺损疾病提供了一种前景广阔的治疗策略。
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引用次数: 0
A MnO2 nanosheets doping double crosslinked hydrogel for cartilage defect repair through alleviating inflammation and guiding chondrogenic differentiation 一种掺杂二氧化锰纳米片的双交联水凝胶,可通过缓解炎症和引导软骨分化修复软骨缺损。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-18 DOI: 10.1016/j.biomaterials.2024.122875
Feilong Zhao , Zhibo Jia , Liyang Zhang , Guodong Liu , Junfei Li , Jianming Zhao , Yajie Xie , Lu Chen , Hongyu Jiang , Wei He , Aiyuan Wang , Jiang Peng , Yudong Zheng
The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO2 nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular H2O2 into O2 and H2O, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects.
炎症性微环境和软骨生成低下是软骨缺损后的主要症状。尽管与水凝胶相关的各种改良策略都显示出了促进软骨再生的显著能力,但延长炎症时间的不良影响仍然十分严重,阻碍了不同水凝胶植入物在生物医学领域的潜在应用。本文受关节软骨缺损修复微环境的启发,利用酰胺反应将乙烯基和邻苯二酚基团接枝到壳聚糖大分子上,然后进一步载入 MnO2 纳米片(MNS),制备了一种可注射、具有免疫调节和软骨再生能力的 L-MNS-CMDA 水凝胶。光聚合和邻苯二酚氧化聚合的双重交联赋予 L-MNS-CMDA 水凝胶优越的机械性能,为软骨缺损修复提供了合适的机械支持。此外,儿茶酚基团产生的强大组织粘附能力保证了水凝胶在缺损部位的长期保留。同时,L-MNS-CMDA 水凝胶能将外源性和细胞内的 H2O2 分解为 O2 和 H2O,有效缓解长期缺氧造成的细胞氧化应激。在儿茶酚基团和 MNS 的协同作用下,L-MNS-CMDA 水凝胶不仅能抑制巨噬细胞向 M1 表型极化,还能促进其向 M2 表型转化,从而重建免疫友好型微环境,最终促进软骨再生。可以预见的是,水凝胶能明显诱导大鼠骨髓间充质干细胞分化为软骨细胞,并表达大量糖胺聚糖和 II 型胶原蛋白。大鼠膝关节软骨缺损模型表明,L-MNS-CMDA 水凝胶可视化调节植入后的早期炎症反应,促进软骨再生,并在植入后 12 周恢复关节功能。总之,这种多功能 L-MNS-CMDA 水凝胶具有卓越的免疫调节和软骨生成特性,在治疗软骨缺损方面具有巨大的临床潜力。
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引用次数: 0
Optimization of culture conditions to generate vascularized multi-lineage liver organoids with structural complexity and functionality 优化培养条件,生成具有结构复杂性和功能性的血管化多系肝脏器官组织。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-18 DOI: 10.1016/j.biomaterials.2024.122898
Kyun Yoo Chi , Gyeongmin Kim , Hyojin Kim , Hyemin Kim , Seongyea Jo , Jihun Lee , Youngseok Lee , Heeseok Yoon , Seunghyun Cho , Jeongjun Kim , Jin-Seok Lee , Gyu-Bum Yeon , Dae-Sung Kim , Han-Jin Park , Jong-Hoon Kim
Hepatic organoids (HOs), primarily composed of hepatobiliary cells, do not represent the pathogenesis of liver diseases due to the lack of non-parenchymal cells. Multi-lineage liver organoids (mLOs) containing various cell types found in the liver offer a promising in vitro disease model. However, their structural complexity remains challenging to achieve due to the difficulty in optimizing culture conditions that meet the growth need of all component cell types. Here, we demonstrate that cystic HOs generated from hPSCs can be expanded long-term and serve as a continuous source for generating complex mLOs. Assembling cystic HOs with hPSC-derived endothelial and hepatic stellate cell-like cells under conventional HO culture conditions failed to support the development of multiple cell types within mLOs, resulting in biased differentiation towards specific cell types. In contrast, modulating the cAMP/Wnt/Hippo signaling pathways with small molecules during assembly and differentiation phases efficiently generate mLOs containing both hepatic parenchymal and non-parenchymal cells. These mLOs exhibited structural complexity and functional maturity, including vascular network formation between parenchymal lobular structures, cell polarity for bile secretion, and the capacity to respond to fibrotic stimuli. Our study underscores the importance of modulating signaling pathways to enhance mLO structural complexity for applications in modeling liver pathologies.
肝脏器质性组织(HOs)主要由肝胆细胞组成,由于缺乏非实质性细胞,因此不能代表肝脏疾病的发病机制。多线肝脏器官组织(mLO)包含肝脏中的各种细胞类型,是一种很有前景的体外疾病模型。然而,由于难以优化培养条件以满足所有组成细胞类型的生长需要,要实现其结构的复杂性仍然具有挑战性。在这里,我们证明了由 hPSCs 生成的囊性 HOs 可以长期扩增,并可作为生成复杂 mLOs 的持续来源。在传统的 HO 培养条件下,用 hPSC 衍生的内皮细胞和肝星状细胞样细胞组装囊性 HO 无法支持 mLO 内多种细胞类型的发育,导致细胞偏向于特定类型的分化。与此相反,在组装和分化阶段用小分子调节cAMP/Wnt/Hippo信号通路,可有效生成包含肝实质细胞和非肝实质细胞的mLO。这些mLO表现出结构的复杂性和功能的成熟性,包括实质小叶结构之间血管网络的形成、胆汁分泌的细胞极性以及对纤维化刺激做出反应的能力。我们的研究强调了调节信号通路以增强mLO结构复杂性在肝脏病理建模中应用的重要性。
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引用次数: 0
Poly(β-amino ester) polymer library with monomer variation for mRNA delivery 用于递送 mRNA 的单体变化聚(β-氨基酯)聚合物库。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-16 DOI: 10.1016/j.biomaterials.2024.122896
Hong Lyun Kim , Gurusamy Saravanakumar , Seowon Lee , Subin Jang , Seonwoo Kang , Mihyeon Park , Sivasangu Sobha , So-Hee Park , Soo-Min Kim , Jung-Ah Lee , Eunkyung Shin , You-jin Kim , Hye-Sook Jeong , Dokeun Kim , Won Jong Kim
Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications.
用于递送 mRNA 的非病毒载体主要包括脂质纳米颗粒(LNPs)和聚合物。虽然 LNPs 以其高效的 mRNA 递送而著称,但它们可能会诱发过度的免疫反应并造成脱靶效应,从而可能导致副作用。在本研究中,我们旨在探索基于聚合物的 mRNA 递送系统,将其作为 LNPs 的可行替代品,重点关注其 mRNA 递送效率和在 mRNA 疫苗中的潜在应用。我们将各种胺单体和丙烯酸酯单体结合在一起,创建了一个聚(β-氨基酯)(PBAE)聚合物库。通过筛选这个聚合物库,我们确定了特定的聚合物纳米颗粒(PNPs),它们具有很高的 mRNA 表达效率,mRNA 表达可持续两周。此外,这些 PNPs 仅在注射部位显示 mRNA 表达,且不显示肝脏毒性。此外,在评估免疫激活时,PNPs 能显著诱导 T 细胞免疫激活,并在斑块减少中和试验中有效。这些结果表明,基于聚合物的 mRNA 递送系统不仅具有用于 mRNA 疫苗的潜力,而且在治疗应用方面也大有可为。
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引用次数: 0
Anti-pyroptosis biomimetic nanoplatform loading puerarin for myocardial infarction repair: From drug discovery to drug delivery 用于心肌梗死修复的装载葛根素的抗血栓形成生物仿生纳米平台:从药物发现到药物输送。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-16 DOI: 10.1016/j.biomaterials.2024.122890
Kun Wang , Yu Sun , Ke Zhu , Yiqiong Liu , Xiao Zheng , Zichen Yang , Fulong Man , Li Huang , Ziyang Zhu , Qi Huang , Yan Li , Haiqing Dong , Jun Zhao , Yongyong Li
Pyroptosis is a critical pathological mechanism implicated in myocardial damage following myocardial infarction (MI), and the crosstalk between macrophages and pyroptotic cardiomyocytes presents a formidable challenge for anti-pyroptosis therapies of MI. However, as single-target pyroptosis inhibitors frequently fail to address this crosstalk, the efficacy of anti-pyroptosis treatment post-MI remains inadequate. Therefore, the exploration of more potent anti-pyroptosis approaches is imperative for improving outcomes in MI treatment, particularly in addressing the crosstalk between macrophages and pyroptotic cardiomyocytes. Here, in response to this crosstalk, we engineered an anti-pyroptosis biomimetic nanoplatform (NM@PDA@PU), employing polydopamine (PDA) nanoparticles enveloped with neutrophil membrane (NM) for targeted delivery of puerarin (PU). Notably, network pharmacology is deployed to discern the most efficacious anti-pyroptosis drug (puerarin) among the 7 primary active monomers of TCM formulations widely applied in clinical practice and reveal the effect of puerarin on the crosstalk. Additionally, targeted delivery of puerarin could disrupt the malignant crosstalk between macrophages and pyroptotic cardiomyocytes, and enhance the effect of anti-pyroptosis by not only directly inhibiting cardiomyocytes pyroptosis through NLRP3-CASP1-IL-1β/IL-18 signal pathway, but reshaping the inflammatory microenvironment by reprogramming macrophages to anti-inflammatory M2 subtype. Overall, NM@PDA@PU could enhance anti-pyroptosis effect by disrupting the crosstalk between M1 macrophages and pyroptotic cardiomyocytes to protect cardiomyocytes, ameliorate cardiac function and improve ventricular remodeling, which providing new insights for the efficient treatment of MI.
心肌梗塞(MI)后心肌损伤的一个重要病理机制是嗜热症,巨噬细胞和嗜热心肌细胞之间的串扰给心肌梗塞的抗嗜热症疗法带来了巨大挑战。然而,由于单一靶点的嗜热抑制剂往往无法解决这种串扰,因此心肌梗死后抗嗜热治疗的疗效仍然不足。因此,为了改善心肌梗死治疗的效果,探索更有效的抗嗜热细胞增多方法势在必行,尤其是在解决巨噬细胞和嗜热心肌细胞之间的串扰方面。在这里,针对这种串扰,我们设计了一种抗嗜脓细胞增多的仿生物纳米平台(NM@PDA@PU),利用包裹着中性粒细胞膜(NM)的多巴胺(PDA)纳米颗粒靶向递送葛根素(PU)。值得注意的是,该研究利用网络药理学从广泛应用于临床的中药制剂的 7 种主要活性单体中找出了最有效的抗肺脓肿药物(葛根素),并揭示了葛根素对串联效应的影响。此外,葛根素的靶向给药不仅能通过NLRP3-CASP1-IL-1β/IL-18信号通路直接抑制心肌细胞的脓毒症,还能通过将巨噬细胞重编程为抗炎的M2亚型来重塑炎症微环境,从而破坏巨噬细胞与脓毒症心肌细胞之间的恶性串联,增强抗脓毒症的效果。总之,NM@PDA@PU可通过破坏M1巨噬细胞和脓毒性心肌细胞之间的串联,增强抗脓毒症的效果,从而保护心肌细胞、改善心脏功能和心室重塑,为心肌梗死的高效治疗提供了新的思路。
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引用次数: 0
Endothelium-targeted NF-κB siRNA nanogel for magnetic resonance imaging and visualized-anti-inflammation treatment of atherosclerosis 用于动脉粥样硬化的磁共振成像和可视化抗炎治疗的内皮靶向 NF-κB siRNA 纳米凝胶。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-16 DOI: 10.1016/j.biomaterials.2024.122897
Yuanyuan Guo , Fujun Wang , Sunli Wan , Xinhua Liu , Yu Huang , Miao Xie , Xiaoer Wei , Wangshu Zhu , Tingting Yao , Yuehua Li , Chuan Zhang , Yueqi Zhu
Atherosclerosis-induced lethal cardiovascular disease remains a severe healthcare threat due to the limited drug efficiency and untimely prediction of high-risk events caused by inadequate target specificity of medications, incapable recognition of insensitive patients, and variable morphology of vulnerable plaques. Therefore, it is necessary to develop efficient strategies to improve the diagnosis accuracy and achieve visualized treatment of atherosclerosis. Herein, we establish an inflamed endothelium-targeted three-in-one nucleic acid nanogel system that can reverse the inflammatory state of endothelial cells (ECs) in plaques and simultaneously achieve real-time monitoring of the therapy process for efficient atherosclerosis diagnosis and treatment. For this purpose, contrast agent (Gd-DOTA) and VCAM-1-targeted peptide (VP) are first covalently conjugated onto DNA strands by click reaction respectively, which could self-assemble into Y-shaped structures (Gd-Y1 and VP-Y2 motifs) with magnetic resonance (MR) imaging and endothelium targeting capacities. Thereafter, NF-κB subunit p65-targeting siRNA (siNF-κB) is crosslinked with Gd-Y1 and VP-Y2 motifs to construct the endothelium-targeting nanogel platform. With contrast agents inside, the nanogel enables MR-based diagnosis and visualized therapy of atherosclerosis, providing accurate prognostic analysis and indications for treatment results, which ensures timely disclosure of insensitive individuals and avoids acute lethal events. By delivering siNF-κB to inflammatory endothelium, the nanogel significantly regresses plaques in both the aorta and carotid artery with reduced inflammation cytokines, collagens, macrophages, and apoptotic cells, providing a potential anti-inflammation strategy to treat atherosclerosis and avoid acute cardiovascular disease.
由于药物的靶向特异性不足、无法识别不敏感患者以及易损斑块的形态多变,导致药物疗效有限且无法及时预测高危事件,动脉粥样硬化引发的致命性心血管疾病仍是严重的医疗威胁。因此,有必要开发有效的策略来提高诊断的准确性,实现动脉粥样硬化的可视化治疗。在此,我们建立了一种以炎症内皮细胞为靶点的三合一核酸纳米凝胶系统,它能逆转斑块中内皮细胞(EC)的炎症状态,同时实现对治疗过程的实时监控,从而达到高效诊断和治疗动脉粥样硬化的目的。为此,首先通过点击反应将造影剂(Gd-DOTA)和 VCAM-1 靶向肽(VP)分别共价键合到 DNA 链上,从而自组装成具有磁共振(MR)成像和内皮靶向能力的 Y 型结构(Gd-Y1 和 VP-Y2 motifs)。随后,NF-κB 亚基 p65 靶向 siRNA(siNF-κB)与 Gd-Y1 和 VP-Y2 基团交联,构建内皮靶向纳米凝胶平台。该纳米凝胶内含造影剂,可对动脉粥样硬化进行基于磁共振的诊断和可视化治疗,提供准确的预后分析和治疗结果指示,确保及时披露不敏感人群,避免急性致死事件的发生。通过向炎症内皮细胞递送 siNF-κB,纳米凝胶能显著消退主动脉和颈动脉的斑块,减少炎症细胞因子、胶原蛋白、巨噬细胞和凋亡细胞,为治疗动脉粥样硬化和避免急性心血管疾病提供了一种潜在的抗炎策略。
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引用次数: 0
Engineering probiotic biohydrogen micro-factories to initiate reductive stress for boosting tumor vulnerability 设计益生菌生物氢微型工厂,启动还原应激,提高肿瘤易感性。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-15 DOI: 10.1016/j.biomaterials.2024.122892
Jie Jiang , Yuhao Lu , Xinyi Zheng , Maomao Xie , Aleksandra Jauković , Meng Gao , Huizhen Zheng
Disruption of redox homeostasis profoundly affects cellular metabolism and activities. While oxidative stress is extensively studied in cancer therapies, research on reductive stress remains in its infancy. Molecular hydrogen (H2), a well-known antioxidant, holds significant potential to induce reductive stress due to its strong antioxidative properties, making it a promising candidate for cancer therapy. However, it remains a major challenge to develop a sustainable H2 delivery system in vivo. Herein, we designed a micro-factory by engineering a gel-based microcapsule that encapsulates Enterobacter aerogenes, a.k.a. probiotic biohydrogen microcapsules (PBMCs), enabling the sustained H2 generation within tumor microenvironment. Notably, PBMCs effectively suppressed the proliferation of eight tumor cell lines as well as drug-resistant cancer cells. The prolonged H2 release from PBMCs induced reductive stress, as evidenced by a significant increase in the GSH/GSSG ratio in 4T1 cells. Moreover, PBMCs displayed significant antitumor effects in breast, melanoma and liver cancer models. The inhibition of PI3K-AKT pathway and the activation of MAPK pathway were identified as key mechanisms responsible for inducing tumor cell cycle arrest and apoptosis. The PBMCs also exhibited synergistic effects in combination with chemotherapeutics, resulting in robust inhibitions of preinvasive carcinoma growth and commonly associated pulmonary metastasis. Overall, our study introduces an innovative strategy to manipulate reductive stress in the tumor microenvironment through in situ H2 generation, thereby enhancing tumor vulnerability.
氧化还原平衡的破坏会严重影响细胞的新陈代谢和活动。虽然氧化应激在癌症治疗中被广泛研究,但还原应激的研究仍处于起步阶段。分子氢(H2)是一种众所周知的抗氧化剂,由于其强大的抗氧化特性,它在诱导还原应激方面具有很大的潜力,因此是一种很有希望的癌症治疗候选物质。然而,开发一种可持续的体内氢气输送系统仍是一项重大挑战。在这里,我们设计了一种基于凝胶的微胶囊,它能封装产气肠杆菌(又称益生菌生物氢微胶囊(PBMCs)),从而在肿瘤微环境中持续产生H2。值得注意的是,PBMCs 能有效抑制八种肿瘤细胞系以及耐药癌细胞的增殖。4T1 细胞中的 GSH/GSSG 比值显著增加,证明了 PBMCs 长期释放 H2 引发了还原应激。此外,PBMCs 还在乳腺癌、黑色素瘤和肝癌模型中显示出显著的抗肿瘤作用。抑制 PI3K-AKT 通路和激活 MAPK 通路是诱导肿瘤细胞周期停止和凋亡的关键机制。PBMCs 与化疗药物联合使用还能产生协同效应,从而有力地抑制浸润前癌细胞的生长和常见的肺转移。总之,我们的研究提出了一种创新策略,通过原位生成 H2 来操纵肿瘤微环境中的还原应激,从而增强肿瘤的脆弱性。
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引用次数: 0
Exosomes from hypoxic urine-derived stem cells facilitate healing of diabetic wound by targeting SERPINE1 through miR-486-5p 缺氧尿源干细胞的外泌体通过 miR-486-5p 靶向 SERPINE1 促进糖尿病伤口愈合
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-15 DOI: 10.1016/j.biomaterials.2024.122893
Ming-Hui Fan , Xiu-Zhen Zhang , Yan-Lin Jiang , Jin-Kui Pi , Ji-Ye Zhang , Yue-Qi Zhang , Fei Xing , Hui-Qi Xie
Vascular pathologies and injuries are important factors for the delayed wound healing in diabetes. Previous studies have demonstrated that hypoxic environments could induce formation of new blood vessels by regulating intercellular communication and cellular behaviors. In this study, we have enhanced the angiogenic potential of exosomes by subjecting urine-derived stem cells (USCs) to hypoxic preconditioning. To prolong the retention of exosomes at the wound site, we have also engineered a novel dECM hydrogel termed SISMA, which was modified from porcine small intestinal submucosa (SIS). For its rapid and controllable gelation kinetics, excellent biocompatibility, and exosome release capability, the SISMA hydrogel has proven to be a reliable delivery vehicle for exosomes. The hypoxia-induced exosomes-loaded hydrogel has promoted endothelial cell proliferation, migration, and tube formation. More importantly, as evidenced by significant in vivo vascular regeneration in the early stages post-injury, it has facilitated tissue repair. This may because miR-486–5p in H-exo inhibit SERPINE1 activity in endothelial cell. Additionally, miRNA sequencing analysis suggested that the underlying mechanism for enhanced angiogenesis may be associated with the activation of classical HIF-1α signaling pathway. In summary, our study has presented a novel non-invasive, cell-free therapeutic approach for accelerating diabetes wound healing and development of a practical and efficient exosomes delivery platform.
血管病变和损伤是糖尿病患者伤口愈合延迟的重要因素。以往的研究表明,缺氧环境可通过调节细胞间的交流和细胞行为诱导新血管的形成。在这项研究中,我们通过对尿源性干细胞(USCs)进行缺氧预处理,增强了外泌体的血管生成潜能。为了延长外泌体在伤口部位的滞留时间,我们还设计了一种新型 dECM 水凝胶,称为 SISMA,它是由猪小肠粘膜下层(SIS)改性而成的。SISMA 水凝胶具有快速可控的凝胶化动力学、良好的生物相容性和外泌体释放能力,已被证明是一种可靠的外泌体输送载体。缺氧诱导的外泌体负载水凝胶促进了内皮细胞的增殖、迁移和管道形成。更重要的是,在损伤后的早期阶段,体内血管再生显著,证明它促进了组织修复。这可能是因为 H-exo 中的 miR-486-5p 抑制了内皮细胞中 SERPINE1 的活性。此外,miRNA 测序分析表明,血管生成增强的潜在机制可能与经典 HIF-1α 信号通路的激活有关。总之,我们的研究提出了一种新的非侵入性、无细胞治疗方法,可用于加速糖尿病伤口愈合,并开发了一种实用、高效的外泌体递送平台。
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引用次数: 0
Neutrophils exhibit flexible migration strategies and trail formation mechanisms on varying adhesive substrates 中性粒细胞在不同的粘附基质上表现出灵活的迁移策略和痕迹形成机制。
IF 12.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-13 DOI: 10.1016/j.biomaterials.2024.122881
Wenbo Gao , Xiaoning Zhang , Wenhui Hu , Jie Han , Xiaoheng Liu , Yan Zhang , Mian Long
Substrate anchorage is essential for cell migration, and actin polymerization at cell front and myosin contractility at cell rear are known to govern cell forward movement. Yet their differential driving strategies for neutrophil migration on distinct adhesiveness substrates and their contributions to the migration-induced trail formation remain unclear. Here we explore the morphological changes, migration dynamics, and trail formation of neutrophils on ICAM-1 and PLL substrates, with a focus on the relationships among adhesive forces, traction forces, and out-of-plane forces. Results indicate that, on ICAM-1, neutrophil migration and trail formation rely on the coordinated interactions of Arp2/3 and myosin, along with biochemical regulation (via Syk and calpain) of adhesion and de-adhesion. This pattern leads to traction forces being concentrated at relatively fewer adhesive sites, facilitating cell forward migration. On PLL, however, neutrophils primarily depend on Arp2/3-mediated actin polymerization, resulting in a broader distribution of traction forces and weaker adhesions, which allows for higher leading-edge migrating velocities. Elevated membrane tension and out-of-plane forces generated by bleb protrusions on PLL reduce the reliance on myosin-driven contraction at the trailing edge, enabling easier tail detachment through elastic recoil. This work highlights the differential impact of substrate adhesiveness on neutrophil migration and trail formation and dynamics, providing new insights into cell migration mechanisms and potential therapeutic targets for inflammatory and immune-related disorders.
基底锚定对细胞迁移至关重要,而细胞前部的肌动蛋白聚合和细胞后部的肌球蛋白收缩是细胞向前运动的主导因素。然而,它们对中性粒细胞在不同粘附性基底上迁移的不同驱动策略以及它们对迁移诱导的痕迹形成的贡献仍不清楚。在此,我们探讨了中性粒细胞在 ICAM-1 和 PLL 基质上的形态变化、迁移动力学和痕迹形成,重点研究了粘附力、牵引力和平面外力之间的关系。结果表明,在 ICAM-1 上,中性粒细胞的迁移和痕迹形成依赖于 Arp2/3 和肌球蛋白的协调相互作用,以及粘附和去粘附的生化调控(通过 Syk 和 calpain)。这种模式导致牵引力集中在相对较少的粘附点,有利于细胞向前迁移。然而,在 PLL 上,中性粒细胞主要依赖 Arp2/3 介导的肌动蛋白聚合,导致牵引力分布更广,粘附力更弱,从而使前缘迁移速度更高。膜张力的升高和蚕泡突起对 PLL 产生的平面外力减少了后缘对肌球蛋白驱动的收缩的依赖,使尾部更容易通过弹性反冲脱离。这项研究强调了基质粘附性对中性粒细胞迁移和尾迹形成及动力学的不同影响,为细胞迁移机制以及炎症和免疫相关疾病的潜在治疗靶点提供了新的见解。
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引用次数: 0
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