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Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18 通过向心肌注射编码 T-box 转录因子 18 的 mRNA,对完全性心脏传导阻滞的猪进行瞬时起搏
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-05-02 DOI: 10.1038/s41551-024-01211-9
David W. Wolfson, Nam Kyun Kim, Ki Hong Lee, Jared P. Beyersdorf, Jonathan J. Langberg, Natasha Fernandez, Dahim Choi, Nadine Zureick, Tae Yun Kim, Seongho Bae, Jin-Mo Gu, Jonathan L. Kirschman, Jinqi Fan, Christina Y. Sheng, Danielle Gottlieb Sen, Bret Mettler, Jung Hoon Sung, Young-sup Yoon, Sung-Jin Park, Philip J. Santangelo, Hee Cheol Cho
The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal’s sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers. Intramyocardial injection of synthetic mRNA coding for the embryonic T-box transcription factor 18 gene generates rate-adaptive cardiac pacing and limits innate and inflammatory immune responses, as shown in rodents and pigs.
腺病毒介导的胚胎 T-box 转录因子 18(TBX18)基因体细胞转移可将心室心肌细胞转化为诱导起搏细胞。然而,治疗性 TBX18 诱导心脏起搏的转化面临着安全性挑战。在这里,我们展示了合成 TBX18 mRNA 在动物心肌中的表达可产生新的起搏,并限制先天性和炎症性免疫反应。在大鼠体内,心肌内注射的 mRNA 保持局部表达,而直接在心肌内注射携带报告基因的腺病毒会导致弥散表达,并大量溢出到肝脏、脾脏和肺部。在大鼠体内瞬时表达 TBX18 mRNA 会导致新的自动性和起搏器特性,而且与注射腺病毒相比,炎症基因的表达和活化的巨噬细胞群大幅减少。在啮齿动物和临床相关的完全性心脏传导阻滞猪模型中,心肌内注射 TBX18 mRNA 可提供为期一个月的速率自适应心脏起搏,这与动物的窦性心律和体力活动密切相关。TBX18 mRNA 可能有助于生物心脏起搏器的开发。
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引用次数: 0
Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager 通过将硅糖苷酶与双特异性 T 细胞吸引子融合,对肿瘤细胞进行靶向去硅糖苷化和细胞溶解
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-05-01 DOI: 10.1038/s41551-024-01202-w
Zhuo Yang, Yingqin Hou, Geramie Grande, Jong Hyun Cho, Chao Wang, Yujie Shi, Jaroslav Zak, Yue Wan, Ke Qin, Dongfang Liu, John R. Teijaro, Richard A. Lerner, Peng Wu
Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE–sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation—that is, the removal of terminal sialic acid residues on glycans—at the BiTE-induced T-cell–tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE–sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers. The removal of terminal sialic acid residues on glycans at the T-cell–tumour-cell interface via a sialidase fused to a bispecific T-cell engager enhances the susceptibility of solid cancers to T-cell-mediated cytolysis.
双特异性T细胞吞噬因子(BiTE)通过与特异性细胞表面肿瘤抗原和T细胞受体结合,将肿瘤细胞和细胞毒性T细胞结合在一起,在临床上成功治疗了B细胞恶性肿瘤。在这里,我们展示了 BiTE-硅糖苷酶融合蛋白通过靶向去硅烷基化--即在 BiTE 诱导的 T 细胞-肿瘤细胞界面上去除聚糖上的末端硅酸残基--来提高实体瘤对 BiTE 介导的肿瘤细胞溶解的敏感性。在白血病、黑色素瘤和乳腺癌的异种移植和合成小鼠模型中,与亲代 BiTE 分子相比,通过 BiTE-sialidase 融合蛋白进行的靶向脱ialylation 能在靶抗原存在的情况下增强免疫突触的形成、T 细胞活化和 T 细胞介导的肿瘤细胞细胞溶解。对肿瘤细胞进行有针对性的脱硅烷基化可增强依赖于T细胞吸引剂的疗法的效力。
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引用次数: 0
The myriad ways to engineer cells 改造细胞的无数方法
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-04-23 DOI: 10.1038/s41551-024-01213-7
The widening range of strategies to alter the phenotypes and functions of mammalian cells is a boon for their biomedical applications.
改变哺乳动物细胞表型和功能的策略范围不断扩大,为其生物医学应用带来了福音。
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引用次数: 0
Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells 用于刺激抗原递呈细胞中抗肿瘤先天免疫途径的合成阳离子螺旋多肽
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-04-19 DOI: 10.1038/s41551-024-01194-7
DaeYong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M. Link, Thomas D. Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R. Schrank, Adam J. Grippin, Abin Antony, JongHoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C. Koong, John A. Tainer, Wen Jiang, Betty Y. S. Kim
Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS–STING (for cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses. The hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate antitumour innate immune responses via endoplasmic reticulum stress in antigen-presenting cells.
细胞内 DNA 传感器可调节先天性免疫,并为适应性免疫原性提供桥梁。然而,双链 DNA 或环状核苷酸等天然激动剂对抗原递呈细胞(APC)中传感器的激活作用因细胞内传递、血清稳定性、酶降解和快速全身清除等因素而受到阻碍。在这里,我们展示了螺旋多肽的疏水性、静电荷和次级构象可以优化,从而通过内质网应激刺激 APC 的先天性免疫通路。我们设计的三种多肽中的一种通过促进线粒体 DNA 的释放,优先激活了 APCs 中的两条主要细胞内 DNA 传感途径(cGAS-STING(环磷酸鸟苷-单磷酸腺苷合成酶-干扰素基因刺激器)和 Toll 样受体 9),从而高效地启动了效应 T 细胞。在局部晚期和转移性乳腺癌的合成小鼠模型中,多肽作为单一疗法或与免疫检查点抑制剂一起静脉注射,可产生有效的 DNA 传感器介导的抗肿瘤反应。通过工程阳离子多肽激活多种先天性免疫途径可能会为产生抗肿瘤免疫反应提供治疗优势。
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引用次数: 0
Histopathological biomarkers for predicting the tumour accumulation of nanomedicines 预测纳米药物肿瘤蓄积的组织病理学生物标志物
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-04-08 DOI: 10.1038/s41551-024-01197-4
Jan-Niklas May, Jennifer I. Moss, Florian Mueller, Susanne K. Golombek, Ilaria Biancacci, Larissa Rizzo, Asmaa Said Elshafei, Felix Gremse, Robert Pola, Michal Pechar, Tomáš Etrych, Svea Becker, Christian Trautwein, Roman D. Bülow, Peter Boor, Ruth Knuechel, Saskia von Stillfried, Gert Storm, Sanyogitta Puri, Simon T. Barry, Volkmar Schulz, Fabian Kiessling, Marianne B. Ashford, Twan Lammers

The clinical prospects of cancer nanomedicines depend on effective patient stratification. Here we report the identification of predictive biomarkers of the accumulation of nanomedicines in tumour tissue. By using supervised machine learning on data of the accumulation of nanomedicines in tumour models in mice, we identified the densities of blood vessels and of tumour-associated macrophages as key predictive features. On the basis of these two features, we derived a biomarker score correlating with the concentration of liposomal doxorubicin in tumours and validated it in three syngeneic tumour models in immunocompetent mice and in four cell-line-derived and six patient-derived tumour xenografts in mice. The score effectively discriminated tumours according to the accumulation of nanomedicines (high versus low), with an area under the receiver operating characteristic curve of 0.91. Histopathological assessment of 30 tumour specimens from patients and of 28 corresponding primary tumour biopsies confirmed the score’s effectiveness in predicting the tumour accumulation of liposomal doxorubicin. Biomarkers of the tumour accumulation of nanomedicines may aid the stratification of patients in clinical trials of cancer nanomedicines.

癌症纳米药物的临床前景取决于有效的患者分层。在此,我们报告了纳米药物在肿瘤组织中积累的预测性生物标记物的鉴定结果。通过对纳米药物在小鼠肿瘤模型中的积累数据进行有监督的机器学习,我们发现血管密度和肿瘤相关巨噬细胞密度是关键的预测特征。在这两个特征的基础上,我们得出了与肿瘤中多柔比星脂质体浓度相关的生物标记物评分,并在免疫功能正常小鼠的三个合成肿瘤模型以及小鼠的四个细胞系衍生肿瘤和六个患者衍生肿瘤异种移植物中进行了验证。根据纳米药物的积累情况(高与低),该评分能有效区分肿瘤,接收器操作特征曲线下面积为 0.91。对 30 例患者肿瘤标本和 28 例相应的原发性肿瘤活检组织病理学评估证实,该评分能有效预测肿瘤对脂质体多柔比星的蓄积情况。纳米药物肿瘤蓄积的生物标志物可能有助于在癌症纳米药物临床试验中对患者进行分层。
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引用次数: 0
Author Correction: Optogenetic stimulation of vagal nerves for enhanced glucose-stimulated insulin secretion and β cell proliferation. 作者更正:光遗传刺激迷走神经增强葡萄糖刺激的胰岛素分泌和β细胞增殖。
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-04-02 DOI: 10.1038/s41551-024-01200-y
Yohei Kawana, Junta Imai, Yosuke M Morizawa, Yoko Ikoma, Masato Kohata, H. Komamura, Toshihiro Sato, Tomohito Izumi, Junpei Yamamoto, Akira Endo, Hiroto Sugawara, Haremaru Kubo, Shinichiro Hosaka, Yuichiro Munakata, Yoichiro Asai, Shinjiro Kodama, Kei Takahashi, Keizo Kaneko, Shojiro Sawada, Tetsuya Yamada, Akira Ito, Kuniyasu Niizuma, Teiji Tominaga, Akihiro Yamanaka, Ko Matsui, Hideki Katagiri
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引用次数: 0
Publisher Correction: Bacteria-mediated resistance of neutrophil extracellular traps to enzymatic degradation drives the formation of dental calculi. 出版商更正:细菌介导的中性粒细胞胞外捕获物抗酶降解作用促使牙结石形成。
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-04-02 DOI: 10.1038/s41551-024-01203-9
Mei-Chen Wan, Kai Jiao, Yi-Na Zhu, Qian-Qian Wan, Yi-Peng Zhang, Long-Zhang Niu, Chen Lei, Jing-Han Song, Wei-Cheng Lu, Hua-Jie Liu, Zhao-Yang Ren, Franklin Tay, Li-Na Niu
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引用次数: 0
A serine-conjugated butyrate prodrug with high oral bioavailability suppresses autoimmune arthritis and neuroinflammation in mice 具有高口服生物利用度的丝氨酸结合丁酸盐原药可抑制小鼠的自身免疫性关节炎和神经炎症。
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-04-01 DOI: 10.1038/s41551-024-01190-x
Shijie Cao, Erica Budina, Michal M. Raczy, Ani Solanki, Mindy Nguyen, Taryn N. Beckman, Joseph W. Reda, Kevin Hultgren, Phillip S. Ang, Anna J. Slezak, Lauren A. Hesser, Aaron T. Alpar, Kirsten C. Refvik, Lucas S. Shores, Ishita Pillai, Rachel P. Wallace, Arjun Dhar, Elyse A. Watkins, Jeffrey A. Hubbell
Butyrate—a metabolite produced by commensal bacteria—has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate’s poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-l-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases. The esterification of butyrate to serine makes for an odourless and tasteless oral prodrug that ameliorated disease severity and reduced inflammatory responses in mouse models of rheumatoid arthritis and multiple sclerosis.
丁酸盐是一种由共生细菌产生的代谢产物,因其对免疫细胞(包括调节性 T 细胞、巨噬细胞和树突状细胞)的免疫调节作用而被广泛研究。然而,由于丁酸盐在肠道中的代谢速度快、效力低(因此必须加大剂量)以及气味和味道难闻,丁酸盐的口服生物利用度较低,这阻碍了丁酸盐作为药物的开发。我们在此报告,通过将丁酸酯酯化为丝氨酸,可以提高丁酸酯的口服生物利用度。丝氨酸是一种氨基酸转运体,可以帮助产生的无味无臭原药(O-丁酰-L-丝氨酸,我们将其命名为 SerBut)从肠道中排出,从而提高其全身吸收率。在胶原抗体诱导的关节炎(类风湿性关节炎的一种模型)和实验性自身免疫性脑脊髓炎(多发性硬化症的一种模型)小鼠中,我们发现 SerBut 能显著改善疾病的严重程度,调节全身和疾病相关组织中的关键免疫细胞群,并在不影响疫苗接种的整体免疫反应的情况下减少炎症反应。SerBut可能成为治疗自身免疫性疾病和炎症性疾病的一种有前途的疗法。
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引用次数: 0
Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression 具有奇异抗原受体的间充质基质细胞可增强免疫抑制。
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-04-01 DOI: 10.1038/s41551-024-01195-6
Olivia Sirpilla, R. Leo Sakemura, Mehrdad Hefazi, Truc N. Huynh, Ismail Can, James H. Girsch, Erin E. Tapper, Michelle J. Cox, Kendall J. Schick, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Ekene J. Ogbodo, Brooke L. Kimball, Long K. Mai, Omar L. Gutierrez-Ruiz, Makena L. Rodriguez, Martina Gluscevic, Daniel P. Larson, Alex M. Abel, Wesley A. Wierson, Gloria Olivier, Elizabeth L. Siegler, Saad S. Kenderian
Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression. Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.
异体间充质干细胞(MSCs)是治疗许多免疫系统疾病的安全疗法。然而,使用间充质干细胞进行的临床试验显示疗效并不一致,主要原因是间充质干细胞对靶组织的免疫抑制不足。在这里,我们展示了通过基因改造间充质干细胞,使其具有奇异抗原受体(CAR),可以增强抗原特异性免疫抑制。CAR-间充质干细胞能有效抑制T细胞,并定位到E-cadherin+结肠细胞,从而改善动物的症状,提高存活率。在抗原特异性刺激下,CAR-间充质干细胞上调了免疫抑制基因和T细胞抑制受体的表达,以及免疫抑制细胞因子的产生,同时在动物模型中保持了干细胞表型和安全性。CAR-间充质干细胞可能是一种广泛适用的增强免疫抑制的治疗技术。
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引用次数: 0
Mineralized bacteria as an immunotherapy agent against various cancer types 将矿化细菌作为针对各种癌症的免疫疗法药物
IF 28.1 1区 医学 Q1 Computer Science Pub Date : 2024-03-27 DOI: 10.1038/s41551-024-01192-9
By coating manganese dioxide on the surface of fixed bacteria, we obtained mineralized bacteria with the ability to potently activate multiple immune signalling pathways. Immunotherapy with mineralized bacteria suppressed various types of cancer in multiple animal models, eliciting both immune memory and abscopal antitumour effects.
通过在固定细菌表面涂覆二氧化锰,我们获得了能够有效激活多种免疫信号通路的矿化细菌。在多种动物模型中,矿化细菌的免疫疗法抑制了各种类型的癌症,激发了免疫记忆和腹腔抗肿瘤效应。
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引用次数: 0
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Nature Biomedical Engineering
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