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Macrophages overexpressing interleukin‐10 target and prevent atherosclerosis: Regression of plaque formation and reduction in necrotic core 过量表达白细胞介素-10的巨噬细胞能靶向预防动脉粥样硬化:斑块形成的消退和坏死核心的减少
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-17 DOI: 10.1002/btm2.10717
Mingyi Wang, Shanshan Zhou, Yingyun Hu, Wei Tong, Hao Zhou, Mingrui Ma, Xingxuan Cai, Zhengbin Zhang, Luo Zhang, Yundai Chen
Atherosclerosis, a slowly progressing inflammatory disease, is characterized by the presence of monocyte‐derived macrophages. Interventions targeting the inflammatory characteristics of atherosclerosis hold promising potential. Although interleukin (IL)‐10 is widely acknowledged for its anti‐inflammatory effects, systemic administration of IL‐10 has limitations due to its short half‐life and significant systemic side effects. In this study, we aimed to investigate the effectiveness of an approach designed to overexpress IL‐10 in macrophages and subsequently introduce these genetically modified cells into ApoE−/− mice to promote atherosclerosis regression. We engineered RAW264.7 cells to overexpress IL‐10 (referred to as IL‐10M) using lentivirus vectors. The IL‐10M exhibited robust IL‐10 secretion, maintained phagocytic function, improved mitochondrial membrane potentials, reduced superoxide production and showed a tendency toward the M2 phenotype when exposed to inflammatory stimuli. IL‐10M can selectively target plaques in ApoE−/− mice and has the potential to reduce plaque area and necrotic core at both early and late stages of plaque progression. Moreover, there was a significant reduction in MMP9, a biomarker associated with plaque rupture, in IL‐10M‐treated plaques from both the early and late intervention groups. Additionally, the administration of IL‐10M showed no obvious side effects. This study serves as proof that cell therapy based on anti‐inflammatory macrophages might be a promising strategy for the intervention of atherosclerosis.
动脉粥样硬化是一种进展缓慢的炎症性疾病,其特点是存在源自单核细胞的巨噬细胞。针对动脉粥样硬化炎症特征的干预措施具有广阔的前景。虽然白细胞介素(IL)-10的抗炎作用已得到广泛认可,但由于其半衰期短且具有明显的全身副作用,因此全身给药具有局限性。在本研究中,我们的目的是研究在巨噬细胞中过表达 IL-10,并随后将这些转基因细胞导入载脂蛋白E-/-小鼠体内以促进动脉粥样硬化消退的方法的有效性。我们利用慢病毒载体改造了 RAW264.7 细胞,使其过表达 IL-10(简称 IL-10M)。IL-10M表现出强劲的IL-10分泌,维持吞噬功能,改善线粒体膜电位,减少超氧化物的产生,并在受到炎症刺激时表现出M2表型倾向。IL-10M可选择性地靶向载脂蛋白E-/-小鼠的斑块,并有可能在斑块进展的早期和晚期减少斑块面积和坏死核心。此外,在早期和晚期干预组中,经IL-10M处理的斑块中与斑块破裂相关的生物标志物MMP9均有明显减少。此外,服用IL-10M无明显副作用。这项研究证明,基于抗炎巨噬细胞的细胞疗法可能是一种很有前景的动脉粥样硬化干预策略。
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引用次数: 0
Correction to “Self‐assembly of PEG–PPS polymers and LL‐37 peptide nanomicelles improves the oxidative microenvironment and promotes angiogenesis to facilitate chronic wound healing” 更正 "PEG-PPS 聚合物和 LL-37 肽纳米微孔的自组装可改善氧化微环境并促进血管生成,从而促进慢性伤口愈合"
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-09 DOI: 10.1002/btm2.10718
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引用次数: 0
Elucidating the role of carrier proteins in cytokine stabilization within double emulsion‐based polymeric nanoparticles 阐明载体蛋白在双乳液基聚合物纳米粒子中稳定细胞因子的作用
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-06 DOI: 10.1002/btm2.10722
Emily R. Rhodes, Nicole B. Day, Emma C. Aldrich, C. Wyatt Shields, Kayla G. Sprenger
Polymeric micro‐ and nanoparticles are useful vehicles for delivering cytokines to diseased tissues such as solid tumors. Double emulsion solvent evaporation is one of the most common techniques to formulate cytokines into vehicles made from hydrophobic polymers; however, the liquid–liquid interfaces formed during emulsification can greatly affect the stability and therapeutic performance of encapsulated cytokines. To develop more effective cytokine‐delivery systems, a clear molecular understanding of the interactions between relevant proteins and solvents used in the preparation of such particles is needed. We utilized an integrated computational and experimental approach for studying the governing mechanisms by which interleukin‐12 (IL‐12), a clinically relevant cytokine, is protected from denaturation by albumin, a common stabilizing protein, at an organic‐aqueous solvent interface formed during double emulsification. We investigated protein–protein interactions between human (h)IL‐12 and albumin and simulated these components in pure water, dichloromethane (DCM), and along a water/DCM interface to replicate the solvent regimes formed during double emulsification. We observed that (i) hIL‐12 experiences increased structural deviations near the water/DCM interface, and (ii) hIL‐12 structural deviations are reduced in the presence of albumin. Experimentally, we found that hIL‐12 bioactivity is retained when released from particles in which albumin is added to the aqueous phase in molar excess to hIL‐12 and sufficient time is allowed for albumin‐hIL‐12 binding. Findings from this work have implications in establishing design principles to enhance the stability of cytokines and other unstable proteins in particles formed by double emulsification for improved stability and therapeutic efficacy.
聚合物微粒和纳米粒子是向实体瘤等病变组织输送细胞因子的有效载体。双乳液溶剂蒸发是将细胞因子配制成疏水聚合物载体的最常用技术之一;然而,乳化过程中形成的液-液界面会极大地影响封装细胞因子的稳定性和治疗效果。为了开发更有效的细胞因子递送系统,我们需要从分子角度清楚地了解相关蛋白质与用于制备此类微粒的溶剂之间的相互作用。我们采用了一种计算与实验相结合的方法来研究白细胞介素-12(IL-12)(一种临床相关细胞因子)在双乳化过程中形成的有机-水溶剂界面上受到白蛋白(一种常见的稳定蛋白)保护而不变性的调节机制。我们研究了人(h)IL-12 和白蛋白之间的蛋白-蛋白相互作用,并模拟了这些成分在纯水、二氯甲烷(DCM)和水/二氯甲烷界面中的情况,以复制双乳化过程中形成的溶剂体系。我们观察到:(i) hIL-12 在水/DCM 界面附近的结构偏差增大;(ii) hIL-12 的结构偏差在有白蛋白存在时减小。在实验中,我们发现当白蛋白以超过 hIL-12 的摩尔量添加到水相颗粒中,并有足够的时间让白蛋白与 hIL-12 结合时,hIL-12 的生物活性就会被释放出来。这项工作的发现有助于确立设计原则,提高细胞因子和其他不稳定蛋白质在双乳化形成的微粒中的稳定性,从而提高稳定性和疗效。
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引用次数: 0
A stretchable human lung‐on‐chip model of alveolar inflammation for evaluating anti‐inflammatory drug response 用于评估抗炎药物反应的肺泡炎症可拉伸人肺芯片模型
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-05 DOI: 10.1002/btm2.10715
Clémentine Richter, Lorenz Latta, Daria Harig, Patrick Carius, Janick D. Stucki, Nina Hobi, Andreas Hugi, Paul Schumacher, Tobias Krebs, Alexander Gamrekeli, Felix Stöckle, Klaus Urbschat, Galia Montalvo, Franziska Lautenschläger, Brigitta Loretz, Alberto Hidalgo, Nicole Schneider‐Daum, Claus‐Michael Lehr
This study describes a complex human in vitro model for evaluating anti‐inflammatory drug response in the alveoli that may contribute to the reduction of animal testing in the pre‐clinical stage of drug development. The model is based on the human alveolar epithelial cell line Arlo co‐cultured with macrophages differentiated from the THP‐1 cell line, creating a physiological biological microenvironment. To mimic the three‐dimensional architecture and dynamic expansion and relaxation of the air‐blood‐barrier, they are grown on a stretchable microphysiological lung‐on‐chip. For validating the in vitro model, three different protocols have been developed to demonstrate the clinically established anti‐inflammatory effect of glucocorticoids to reduce certain inflammatory markers after different pro‐inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) to simulate an LPS‐induced acute lung injury measured best with cytokine IL‐6 release; (2) an inflammation caused by LPS at ALI (air‐liquid interface) to investigate aerosolized anti‐inflammatory treatment, measured with chemokine IL‐8 release; and (3) an inflammation with a combination of human inflammatory cytokines TNFα and IFNγ to simulate a critical cytokine storm leading to epithelial barrier disruption, where the eventual weakening or protection of the epithelial barrier can be measured. In all cases, the presence of macrophages appeared to be crucial to mediating inflammatory changes in the alveolar epithelium. LPS induction led to inflammatory changes independently of stretch conditions. Dynamic stretch, emulating breathing‐like mechanics, was essential for in vitro modeling of the clinically relevant outcome of epithelial barrier disruption upon TNFα/IFNγ‐induced inflammation.
本研究描述了一种复杂的人体体外模型,用于评估抗炎药物在肺泡中的反应,该模型可能有助于减少药物开发临床前阶段的动物试验。该模型基于人肺泡上皮细胞系 Arlo 与 THP-1 细胞系分化出的巨噬细胞共同培养,创造了一个生理生物微环境。为了模拟气血屏障的三维结构和动态扩张与松弛,它们生长在可拉伸的微生理肺芯片上。为了验证体外模型,我们制定了三种不同的方案,以证明糖皮质激素在不同促炎刺激后减少某些炎症指标的临床公认抗炎效果:(1)细菌LPS(脂多糖)引起的炎症,模拟LPS诱导的急性肺损伤,最好用细胞因子IL-6释放来测量;(2)LPS在ALI(空气-液体界面)引起的炎症,研究气溶胶抗炎治疗,用趋化因子IL-8释放来测量;(3) 结合使用人类炎症细胞因子 TNFα 和 IFNγ 引起的炎症,以模拟导致上皮屏障破坏的临界细胞因子风暴,从而测量上皮屏障的最终削弱或保护情况。在所有情况下,巨噬细胞的存在似乎对肺泡上皮的炎症变化至关重要。LPS 诱导的炎症变化与拉伸条件无关。仿呼吸力学的动态拉伸对于体外模拟 TNFα/IFNγ 诱导炎症时上皮屏障破坏的临床相关结果至关重要。
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引用次数: 0
Correction to “Doxorubicin‐loaded nanoparticle coated with endothelial cells‐derived exosomes for immunogenic chemotherapy of glioblastoma” 对 "涂有内皮细胞衍生外泌体的多柔比星负载纳米粒子用于胶质母细胞瘤的免疫原性化疗 "的更正
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-05 DOI: 10.1002/btm2.10719
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引用次数: 0
Advances in bioengineered CAR T/NK cell therapy for glioblastoma: Overcoming immunosuppression and nanotechnology‐based strategies for enhanced CAR T/NK cell therapy 胶质母细胞瘤生物工程 CAR T/NK 细胞疗法的进展:克服免疫抑制和基于纳米技术的增强 CAR T/NK 细胞疗法策略
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-08-31 DOI: 10.1002/btm2.10716
Nasim Dana, Arezou Dabiri, Majed Bahri Najafi, Azadeh Rahimi, Sayed Mohammad Matin Ishaghi, Laleh Shariati, Minmin Shao, Assunta Borzacchiello, Ilnaz Rahimmanesh, Pooyan Makvandi
Glioblastoma is a strong challenge in the worldwide field of central nervous system malignancies. GBM's inherent heterogeneity, along with the formation of an immunosuppressive tumor microenvironment, supports its resistance to current therapy methods. Immunotherapeutic methods have emerged as potential options in recent years. However, because of the inherent limits of traditional immunotherapeutic techniques innovative approaches are required. Advances in cut‐edge techniques provide a possible route for improving effector cell effectiveness. This review gives insight into the complicated immunosuppressive pathways in GBM, with a particular emphasis on CAR T/NK‐cell treatment as a potential achievement. Recognizing and addressing these concerns might open the way for more effective and focused glioblastoma therapies, providing hope for the future with the aim of improved outcomes for patients. In addition, this review presents valuable insights into the integration of nanotechnology into CAR T/NK cell therapy for enhanced efficiency of these personalized gene therapy products.
胶质母细胞瘤是世界范围内中枢神经系统恶性肿瘤领域的一个严峻挑战。胶质母细胞瘤固有的异质性以及免疫抑制性肿瘤微环境的形成,使其对目前的治疗方法产生了抗药性。近年来,免疫治疗方法已成为潜在的选择。然而,由于传统的免疫治疗技术存在固有的局限性,因此需要创新的方法。尖端技术的进步为提高效应细胞的有效性提供了可能的途径。本综述深入探讨了 GBM 复杂的免疫抑制途径,并特别强调了 CAR T/NK 细胞治疗这一潜在成果。认识并解决这些问题可能会为更有效、更有针对性的胶质母细胞瘤疗法开辟道路,为未来带来希望,从而改善患者的预后。此外,本综述还就如何将纳米技术融入 CAR T/NK 细胞疗法以提高这些个性化基因治疗产品的效率提出了宝贵的见解。
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引用次数: 0
Targeting the epigenome with advanced delivery strategies for epigenetic modulators 以表观基因组为目标,采用先进的表观遗传调节剂递送策略
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-08-17 DOI: 10.1002/btm2.10710
Sonia Guha, Yogeswaran Jagadeesan, Murali Monohar Pandey, Anupama Mittal, Deepak Chitkara
Epigenetics mechanisms play a significant role in human diseases by altering DNA methylation status, chromatin structure, and/or modifying histone proteins. By modulating the epigenetic status, the expression of genes can be regulated without any change in the DNA sequence itself. Epigenetic drugs exhibit promising therapeutic efficacy against several epigenetically originated diseases including several cancers, neurodegenerative diseases, metabolic disorders, cardiovascular disorders, and so forth. Currently, a considerable amount of research is focused on discovering new drug molecules to combat the existing research gap in epigenetic drug therapy. A novel and efficient delivery system can be established as a promising approach to overcome the drawbacks associated with the current epigenetic modulators. Therefore, formulating the existing epigenetic drugs with distinct encapsulation strategies in nanocarriers, including solid lipid nanoparticles, nanogels, bio‐engineered nanocarriers, liposomes, surface modified nanoparticles, and polymer–drug conjugates have been examined for therapeutic efficacy. Nonetheless, several epigenetic modulators are untouched for their therapeutic potential through different delivery strategies. This review provides a comprehensive up to date discussion on the research findings of various epigenetics mechanism, epigenetic modulators, and delivery strategies utilized to improve their therapeutic outcome. Furthermore, this review also highlights the recently emerged CRISPR tool for epigenome editing.
表观遗传学机制通过改变 DNA 甲基化状态、染色质结构和/或修饰组蛋白,在人类疾病中发挥着重要作用。通过调节表观遗传状态,可以在不改变 DNA 序列本身的情况下调节基因的表达。表观遗传药物对几种由表观遗传引起的疾病,包括几种癌症、神经退行性疾病、代谢紊乱、心血管疾病等具有良好的疗效。目前,大量研究都集中在发现新的药物分子上,以填补表观遗传药物治疗领域现有的研究空白。建立新颖高效的给药系统是克服现有表观遗传调节剂弊端的有效方法。因此,研究人员采用不同的封装策略将现有的表观遗传药物配制成纳米载体,包括固体脂质纳米颗粒、纳米凝胶、生物工程纳米载体、脂质体、表面修饰纳米颗粒和聚合物-药物共轭物,以研究其疗效。然而,还有一些表观遗传调节剂尚未通过不同的递送策略发挥其治疗潜力。本综述对各种表观遗传学机制、表观遗传学调节剂以及用于改善治疗效果的给药策略的研究成果进行了全面的最新讨论。此外,本综述还重点介绍了最近出现的用于表观基因组编辑的 CRISPR 工具。
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引用次数: 0
A temperature responsive hydrogel encapsulated with adipose‐derived stem cells and melanin promotes repair and regeneration of endometrial injury 包裹了脂肪干细胞和黑色素的温度响应水凝胶可促进子宫内膜损伤的修复和再生
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-08-16 DOI: 10.1002/btm2.10714
Ruigao Song, Chicheng Ma, Hongxia Li, Yu Cheng, Xianmei Cui, Zanhong Wang, Lijuan Huang, Chunying Song, Yukai Jing, Bing Cao, Lili Wang, Qing Tian, Xi Wang, Ruiping Zhang, Hanwang Zhang
The endometrium, the inner lining of the uterus, assumes a crucial role in the female reproductive system. Disorders and injuries impacting the endometrium can lead to profound consequences, including infertility and compromised women's overall health. Recent advancements in stem cell research have opened new possibilities for the treatment and repair of endometrial issues. In the present study, we constructed a degradable hydrogel by loading adipose‐derived stem cells (ADSCs) and melanin nanoparticles (MNP). In vitro cell experiments validated the biocompatibility of the prepared hydrogels and their adeptness in encapsulating ADSCs. Subsequently, we explored the impact of hydrogel@ADSC@MNP constructs in the healing process of uterine injury in mice. The results indicated that hydrogel@ADSC@MNP could augment endometrial thickness and ameliorate endometrial interstitial fibrosis. The injured tissue adjacent to hydrogel@ADSC@MNP constructs exhibited higher levels of bFGF, IGF‐1, and VEGFA compared with the corresponding tissue in mice receiving hydrogel constructs alone or in the model group. Furthermore, the hydrogel@ADSC@MNP system enhanced the proliferative capabilities of uterine endometrial cells, facilitated microvasculature regeneration, and reinstated the endometrium's capacity to receive the embryos. Our findings strongly suggest that the hydrogel@ADSC@MNP system holds significant promise for repairing and regenerating damaged endometrium.
子宫内膜是子宫的内壁,在女性生殖系统中起着至关重要的作用。影响子宫内膜的疾病和损伤可导致严重后果,包括不孕不育和损害妇女的整体健康。干细胞研究的最新进展为治疗和修复子宫内膜问题提供了新的可能性。在本研究中,我们通过负载脂肪来源干细胞(ADSCs)和黑色素纳米颗粒(MNP)构建了一种可降解水凝胶。体外细胞实验验证了所制备水凝胶的生物相容性及其包裹 ADSCs 的能力。随后,我们探讨了水凝胶@ADSC@MNP构建物对小鼠子宫损伤愈合过程的影响。结果表明,水凝胶@ADSC@MNP能增加子宫内膜厚度,改善子宫内膜间质纤维化。与单独接受水凝胶构建物的小鼠或模型组的相应组织相比,水凝胶@ADSC@MNP构建物附近的损伤组织显示出更高水平的bFGF、IGF-1和VEGFA。此外,水凝胶@ADSC@MNP 系统增强了子宫内膜细胞的增殖能力,促进了微血管再生,并恢复了子宫内膜接收胚胎的能力。我们的研究结果有力地表明,水凝胶@ADSC@MNP系统在修复和再生受损子宫内膜方面大有可为。
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引用次数: 0
Unleashing the potential of mRNA: Overcoming delivery challenges with nanoparticles 释放 mRNA 的潜力:利用纳米颗粒克服递送难题
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-08-15 DOI: 10.1002/btm2.10713
Qiang Chen, Ku‐Geng Huo, Sheng‐Min Ji, Shu‐De Pang, Tian‐Ying Sun, Yi Niu, Zi‐Hao Jiang, Peng Zhang, Shu‐Xin Han, Jin‐Yao Li
Messenger RNA (mRNA) has emerged as a promising therapeutic strategy for various diseases, including cancer, infectious diseases, and genetic disorders. The mRNA‐based therapeutics have gained significant attention due to their ability to regulate targeted cells, activate immune cells, and avoid potential risks associated with DNA‐based technology. However, the clinical application of mRNA in cancer therapy is hindered by the instability of RNA, physiological barriers, and the risk of immunogenic hurdles. To overcome these challenges and ensure the safe delivery of mRNA therapeutics to target sites, nanoparticle‐based delivery systems have been explored as potential tools in vitro and in vivo applications. This review provides a comprehensive overview of the current status of mRNA therapy, discussing its advantages and limitations, delivery strategies and materials, as well as applications in different fields. By exploring these aspects, the researcher can gain a more complete understanding of the current state, prospects, and challenges of mRNA technologies.
信使核糖核酸(mRNA)已成为治疗各种疾病(包括癌症、传染病和遗传性疾病)的一种前景广阔的治疗策略。基于 mRNA 的疗法能够调控靶细胞、激活免疫细胞并避免与 DNA 技术相关的潜在风险,因而备受关注。然而,mRNA 在癌症治疗中的临床应用受到 RNA 不稳定性、生理障碍和免疫原性障碍风险的阻碍。为了克服这些挑战并确保将 mRNA 疗法安全地输送到靶点,人们探索了基于纳米颗粒的输送系统,将其作为体外和体内应用的潜在工具。本综述全面概述了 mRNA 疗法的现状,讨论了其优势和局限性、递送策略和材料以及在不同领域的应用。通过对这些方面的探讨,研究人员可以更全面地了解 mRNA 技术的现状、前景和挑战。
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引用次数: 0
Correction to “Activation of NR1H3 attenuates the severity of septic myocardial injury by inhibiting NLRP3 inflammasome” 对 "通过抑制 NLRP3 炎症小体激活 NR1H3 减轻脓毒症心肌损伤的严重程度 "的更正
IF 7.4 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-08-15 DOI: 10.1002/btm2.10707
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引用次数: 0
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