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m6A-modified exosome-derived circHIF1α binding to KH domain of IGF2BP3 mediates DNA damage and arrests G1/S transition phase to resists bacterial infection in bacteremia. m6A修饰的外泌体衍生的circHIF1α与IGF2BP3的KH结构域结合可介导DNA损伤并阻止G1/S转换期,从而在菌血症中抵抗细菌感染。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-24 DOI: 10.1186/s12951-024-02932-4
Jiang Yu, Yidan Gao, Fei Liu, Yuyu Zhang, Jianda Li, Luogang Ding, Sufang Ren, Jie Yang, Jian Jiao, Gong Feng, Zhi Chen, Wenbo Sun, Jiaqiang Wu

Background: Animal and human health are seriously threatened by bacterial infections, which can lead to bacteremia and extremely high rates of morbidity and mortality. Recently, there have been reports indicating the involvement of exosomal circular RNAs (circRNAs) in a range of human disorders and tumor types. However, the role of exosomal circRNAs in bacterial infection remains elusive.

Methods: We extracted and identified exosomes from the culture medium of PIEC cells infected with or without Glaesserella parasuis. RNA sequencing analysis was performed on the exosomes to screen and identify circRNAs (circHIF1α) associated with Glaesserella parasuis infection. PIEC cells were infected with Staphylococcus aureus or Streptococcus suis 2 to further determine whether exosome-derived circHIF1α was the crucial circHIF1α associated with bacterial infections. The transmission process of exosomes and their circHIF1α between cells was clarified via exosome tracing and co-culture assay. Moreover, the mechanism of circHIF1α being packaged into exosomes was explored, and the effects of exosomes and their circHIF1α on cell proliferation, DNA damage and cell cycle were analyzed. In addition, the binding mode and site of interacting proteins with circHIF1α were further determined. In vivo and in vitro, the role of exosomes and their circHIF1α in host resistance to bacterial infection was confirmed.

Results: We first discovered a new circHIF1α that was very stable and detectable, encapsulated into exosomes by hnRNPA2B1, and whose expression in exosomes of bacterially infected PIEC cells significantly decreased. Additionally, exosomal circHIF1α reduced bacterial infection both in vitro and in vivo and suppressed the growth of reception cells. Mechanistically, the circHIF1α interacted with the KH domain of IGF2BP3 in an m6A-modified manner, which mediated DNA damage to arrest the cells at the G1/S phase through the interaction between the regulator of Chromosome Condensation 2 (RCC2) and γ-H2AX protein. Exosomal circHIF1α is a unique therapeutic target for bacterial infection since this work highlights its critical function in fighting bacterial infection.

背景:细菌感染严重威胁着动物和人类的健康,可导致菌血症以及极高的发病率和死亡率。最近有报告表明,外泌体循环 RNA(circRNA)参与了一系列人类疾病和肿瘤类型。然而,外泌体环状核糖核酸在细菌感染中的作用仍然难以捉摸:方法:我们从感染或未感染寄生璃泽氏菌的 PIEC 细胞的培养液中提取并鉴定了外泌体。我们对外泌体进行了RNA测序分析,以筛选和鉴定与寄生璃泽氏菌感染相关的circRNAs(circHIF1α)。用金黄色葡萄球菌或猪链球菌2感染PIEC细胞,进一步确定外泌体衍生的circHIF1α是否是与细菌感染相关的关键circHIF1α。通过外泌体追踪和共培养试验,阐明了外泌体及其circHIF1α在细胞间的传播过程。此外,还探讨了circHIF1α被包装到外泌体中的机制,分析了外泌体及其circHIF1α对细胞增殖、DNA损伤和细胞周期的影响。此外,还进一步确定了与 circHIF1α 相互作用的蛋白质的结合模式和位点。在体内和体外,外泌体及其circHIF1α在宿主抵抗细菌感染中的作用得到了证实:结果:我们首次发现了一种新的circHIF1α,它非常稳定且可检测,被hnRNPA2B1包裹到外泌体中,其在细菌感染的PIEC细胞外泌体中的表达量显著下降。此外,外泌体 circHIF1α 可减少体外和体内的细菌感染,并抑制接收细胞的生长。从机理上讲,circHIF1α以m6A修饰的方式与IGF2BP3的KH结构域相互作用,通过染色体凝集调节因子2(RCC2)和γ-H2AX蛋白之间的相互作用,介导DNA损伤,使细胞停滞在G1/S期。外泌体circHIF1α是细菌感染的一个独特治疗靶点,因为这项研究强调了它在对抗细菌感染中的关键功能。
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引用次数: 0
Maternal exposure to nanopolystyrene induces neurotoxicity in offspring through P53-mediated ferritinophagy and ferroptosis in the rat hippocampus. 母体暴露于纳米多苯乙烯会通过 P53 介导的大鼠海马铁蛋白吞噬和铁变态反应诱导后代神经中毒。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-23 DOI: 10.1186/s12951-024-02911-9
Jiang Chen, Licheng Yan, Yaping Zhang, Xuan Liu, Yizhe Wei, Yiming Zhao, Kang Li, Yue Shi, Huanliang Liu, Wenqing Lai, Lei Tian, Bencheng Lin

There are increasing concerns regarding the rapid expansion of polystyrene nanoplastics (PS-NPs), which could impact human health. Previous studies have shown that nanoplastics can be transferred from mothers to offspring through the placenta and breast milk, resulting in cognitive deficits in offspring. However, the neurotoxic effects of maternal exposure on offspring and its mechanisms remain unclear. In this study, PS-NPs (50 nm) were gavaged to female rats throughout gestation and lactation to establish an offspring exposure model to study the neurotoxicity and behavioral changes caused by PS-NPs on offspring. Neonatal rat hippocampal neuronal cells were used to investigate the pathways through which NPs induce neurodevelopmental toxicity in offspring rats, using iron inhibitors, autophagy inhibitors, reactive oxygen species (ROS) scroungers, P53 inhibitors, and NCOA4 inhibitors. We found that low PS-NPs dosages can cause ferroptosis in the hippocampus of the offspring, resulting in a decline in the cognitive, learning, and memory abilities of the offspring. PS-NPs induced NOCA4-mediated ferritinophagy and promoted ferroptosis by inciting ROS production to activate P53-mediated ferritinophagy. Furthermore, the levels of the antioxidant factors glutathione peroxidase 4 (GPX4) and glutathione (GSH), responsible for ferroptosis, were reduced. In summary, this study revealed that consumption of PS-NPs during gestation and lactation can cause ferroptosis and damage the hippocampus of offspring. Our results can serve as a basis for further research into the neurodevelopmental effects of nanoplastics in offspring.

人们越来越关注聚苯乙烯纳米塑料(PS-NPs)的迅速发展,因为它可能会影响人类健康。先前的研究表明,纳米塑料可通过胎盘和母乳从母体转移给后代,导致后代出现认知障碍。然而,母体接触纳米塑料对后代的神经毒性影响及其机制仍不清楚。本研究通过给雌性大鼠在整个妊娠期和哺乳期灌胃PS-NPs(50 nm),建立子代暴露模型,研究PS-NPs对子代的神经毒性和行为变化。我们利用新生大鼠海马神经元细胞,使用铁抑制剂、自噬抑制剂、活性氧(ROS)拮抗剂、P53抑制剂和NCOA4抑制剂研究了NPs诱导子代大鼠神经发育毒性的途径。我们发现,低剂量的 PS-NPs 可导致子代大鼠海马中的铁变态反应,从而导致子代大鼠的认知、学习和记忆能力下降。PS-NPs 可诱导 NOCA4 介导的噬铁蛋白,并通过产生 ROS 来激活 P53 介导的噬铁蛋白,从而促进铁变态反应。此外,抗氧化因子谷胱甘肽过氧化物酶 4(GPX4)和谷胱甘肽(GSH)的水平也降低了,而谷胱甘肽过氧化物酶 4 和谷胱甘肽(GPX4)对铁细胞凋亡起着重要作用。总之,本研究揭示了在妊娠期和哺乳期摄入 PS-NPs 可导致铁变态反应并损害后代的海马。我们的研究结果可作为进一步研究纳米塑料对后代神经发育影响的基础。
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引用次数: 0
Copper hydrogen phosphate nanosheets functionalized hydrogel with tissue adhesive, antibacterial, and angiogenic capabilities for tracheal mucosal regeneration. 具有组织粘合、抗菌和血管生成功能的磷酸氢化铜纳米片功能化水凝胶用于气管粘膜再生。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-23 DOI: 10.1186/s12951-024-02920-8
Pengli Wang, Erji Gao, Tao Wang, Yanping Feng, Yong Xu, Lefeng Su, Wei Gao, Zheng Ci, Muhammad Rizwan Younis, Jiang Chang, Chen Yang, Liang Duan

Timely and effective interventions after tracheal mucosal injury are lack in clinical practices, which elevate the risks of airway infection, tracheal cartilage deterioration, and even asphyxiated death. Herein, we proposed a biomaterial-based strategy for the repair of injured tracheal mucosal based on a copper hydrogen phosphate nanosheets (CuHP NSs) functionalized commercial hydrogel (polyethylene glycol disuccinimidyl succinate-human serum albumin, PH). Such CuHP/PH hydrogel achieved favorable injectability, stable gelation, and excellent adhesiveness within the tracheal lumen. Moreover, CuHP NSs within the CuHP/PH hydrogel effectively stimulate the proliferation and migration of endothelial/epithelial cells, enhancing angiogenesis and demonstrating excellent tissue regenerative potential. Additionally, it exhibited significant inhibitory effects on both bacteria and bacterial biofilms. More importantly, when injected injured site of tracheal mucosa under fiberoptic bronchoscopy guidance, our results demonstrated CuHP/PH hydrogel adhered tightly to the tracheal mucosa. The therapeutic effects of the CuHP/PH hydrogel were further confirmed, which significantly improved survival rates, vascular and mucosal regeneration, reduced occurrences of intraluminal infections, tracheal stenosis, and cartilage damage complications. This research presents an initial proposition outlining a strategy employing biomaterials to mitigate tracheal mucosal injury, offering novel perspectives on the treatment of mucosal injuries and other tracheal diseases.

在临床实践中,气管粘膜损伤后缺乏及时有效的干预措施,从而增加了气道感染、气管软骨退化甚至窒息死亡的风险。在此,我们提出了一种基于生物材料的气管粘膜损伤修复策略,其基础是磷酸氢化铜纳米片(CuHP NSs)功能化商用水凝胶(聚乙二醇二琥珀酰亚胺-人血清白蛋白,PH)。这种 CuHP/PH 水凝胶在气管腔内具有良好的注射性、稳定的凝胶化和出色的粘附性。此外,CuHP/PH 水凝胶中的 CuHP NSs 能有效刺激内皮/上皮细胞的增殖和迁移,促进血管生成,显示出卓越的组织再生潜力。此外,它还对细菌和细菌生物膜有明显的抑制作用。更重要的是,在纤维支气管镜引导下,将 CuHP/PH 水凝胶注入气管粘膜损伤部位,结果表明 CuHP/PH 水凝胶与气管粘膜紧密粘合。CuHP/PH 水凝胶的治疗效果得到了进一步证实,其显著提高了存活率、血管和粘膜再生能力,减少了腔内感染、气管狭窄和软骨损伤等并发症的发生。这项研究提出了一个初步主张,概述了采用生物材料减轻气管粘膜损伤的策略,为治疗粘膜损伤和其他气管疾病提供了新的视角。
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引用次数: 0
Photoimmunotherapy using indocyanine green-loaded Codium fragile polysaccharide and chitosan nanoparticles suppresses tumor growth and metastasis. 使用吲哚菁绿负载的脆性钠多糖和壳聚糖纳米粒子的光免疫疗法可抑制肿瘤生长和转移。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-23 DOI: 10.1186/s12951-024-02944-0
Dayoung Ryu, Hae-Bin Park, Eun-Koung An, So-Jung Kim, Da Young Kim, Daeun Lim, Juyoung Hwang, Minseok Kwak, Wonpil Im, Ja-Hyoung Ryu, SangGuan You, Peter C W Lee, Jun-O Jin

Metastasis and recurrence are the main challenges in cancer treatment. Among various therapeutic approaches, immunotherapy holds promise for preventing metastasis and recurrence. In this study, we evaluated the efficacy of treating primary cancer and blocking metastasis and recurrence with photo-immunotherapeutic nanoparticles, which were synthesized using two types of charged polysaccharides. Codium fragile polysaccharide (CFP), which exhibits immune-stimulating properties and carries a negative charge, was combined with positively charged chitosan to synthesize nanoparticles. Additionally, indocyanine green (ICG), a photosensitizer, was loaded inside these particles and was referred to as chitosan-CFP-ICG (CC-ICG). Murine colon cancer cells (CT-26) internalized CC-ICG, and subsequent 808-nanometer laser irradiation promoted apoptotic/necrotic cell death. Moreover, intratumoral injection of CC-ICG, with 808-nanometer laser irradiation eliminated CT-26 tumors in mice. Rechallenged lung metastases of CT-26 cancer were inhibited by dendritic cell activation-mediated cytotoxic T lymphocyte stimulation in mice cured by CC-ICG. These results demonstrated that CC-ICG is a natural tumor therapeutic with the potential to treat primary tumors and suppress metastasis and recurrence.

转移和复发是癌症治疗的主要挑战。在各种治疗方法中,免疫疗法有望预防转移和复发。在这项研究中,我们评估了光免疫治疗纳米粒子治疗原发性癌症和阻断转移和复发的疗效,这些纳米粒子是用两种带电多糖合成的。脆性钠多糖(CFP)带负电荷,具有免疫刺激特性,与带正电荷的壳聚糖结合合成纳米粒子。此外,还在这些颗粒中加入了光敏剂吲哚菁绿(ICG),称为壳聚糖-CFP-ICG(CC-ICG)。小鼠结肠癌细胞(CT-26)内化了 CC-ICG,随后 808 纳米激光照射促进了细胞凋亡/坏死。此外,小鼠瘤内注射 CC-ICG 并用 808 纳米激光照射可消除 CT-26 肿瘤。CC-ICG治愈的小鼠在树突状细胞激活介导的细胞毒性T淋巴细胞刺激下,CT-26癌的再侵袭肺转移受到抑制。这些结果表明,CC-ICG 是一种天然的肿瘤治疗药物,具有治疗原发性肿瘤、抑制转移和复发的潜力。
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引用次数: 0
Exosomal miR-1a-3p derived from glucocorticoid-stimulated M1 macrophages promotes the adipogenic differentiation of BMSCs in glucocorticoid-associated osteonecrosis of the femoral head by targeting Cebpz. 糖皮质激素刺激的 M1 巨噬细胞产生的外泌体 miR-1a-3p 通过靶向 Cebpz 促进糖皮质激素相关性股骨头坏死中 BMSCs 的成脂分化。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-22 DOI: 10.1186/s12951-024-02923-5
Ping Duan, Yong-Le Yu, Yan-Nan Cheng, Meng-Han Nie, Qing Yang, Liang-Hui Xia, Yan-Xiao Ji, Zhen-Yu Pan

Background: By interacting with bone marrow mesenchymal stem cells (BMSCs) and regulating their function through exosomes, bone macrophages play crucial roles in various bone-related diseases. Research has highlighted a notable increase in the number of M1 macrophages in glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH). Nevertheless, the intricate crosstalk between M1 macrophages and BMSCs in the glucocorticoid-stimulated environment has not been fully elucidated, and the underlying regulatory mechanisms involved in the occurrence of GA-ONFH remain unclear.

Methods: We employed in vivo mouse models and clinical samples from GA-ONFH patients to investigate the interactions between M1 macrophages and BMSCs. Immunofluorescence staining was used to assess the colocalization of M1 macrophages and BMSCs. Flow cytometry and transcriptomic analysis were performed to evaluate the impact of exosomes derived from normal (n-M1) and glucocorticoid-stimulated M1 macrophages (GC-M1) on BMSC differentiation. Additionally, miR-1a-3p expression was altered in vitro and in vivo to assess its role in regulating adipogenic differentiation.

Results: In vivo, the colocalization of M1 macrophages and BMSCs was observed, and an increase in M1 macrophage numbers and a decrease in bone repair capabilities were further confirmed in both GA-ONFH patients and mouse models. Both n-M1 and GC-M1 were identified as contributors to the inhibition of osteogenic differentiation in BMSCs to a certain extent via exosome secretion. More importantly, exosomes derived from GC-M1 macrophages exhibited a heightened capacity to regulate the adipogenic differentiation of BMSCs, which was mediated by miR-1a-3p. In vivo and in vitro, miR-1a-3p promoted the adipogenic differentiation of BMSCs by targeting Cebpz and played an important role in the onset and progression of GA-ONFH.

Conclusion: We demonstrated that exosomes derived from GC-M1 macrophages disrupt the balance between osteogenic and adipogenic differentiation in BMSCs, contributing to the pathogenesis of GA-ONFH. Inhibiting miR-1a-3p expression, both in vitro and in vivo, significantly mitigates the preferential adipogenic differentiation of BMSCs, thus slowing the progression of GA-ONFH. These findings provide new insights into the regulatory mechanisms underlying GA-ONFH and highlight potential therapeutic targets for intervention.

背景:通过与骨髓间充质干细胞(BMSCs)相互作用并通过外泌体调节其功能,骨巨噬细胞在各种骨相关疾病中发挥着至关重要的作用。研究表明,在糖皮质激素相关性股骨头坏死(GA-ONFH)中,M1巨噬细胞的数量明显增加。然而,在糖皮质激素刺激的环境中,M1 巨噬细胞和 BMSCs 之间错综复杂的相互作用尚未完全阐明,GA-ONFH 发生的潜在调控机制仍不清楚:我们利用体内小鼠模型和 GA-ONFH 患者的临床样本研究了 M1 巨噬细胞和 BMSCs 之间的相互作用。免疫荧光染色用于评估 M1 巨噬细胞和 BMSCs 的共定位。流式细胞术和转录组分析评估了来自正常(n-M1)和糖皮质激素刺激的 M1 巨噬细胞(GC-M1)的外泌体对 BMSC 分化的影响。此外,还改变了miR-1a-3p在体外和体内的表达,以评估其在调节成脂分化中的作用:结果:在 GA-ONFH 患者和小鼠模型中,观察到 M1 巨噬细胞和 BMSCs 的共定位,并进一步证实了 M1 巨噬细胞数量的增加和骨修复能力的下降。研究发现,n-M1 和 GC-M1 在一定程度上通过外泌体分泌抑制了 BMSCs 的成骨分化。更重要的是,从 GC-M1 巨噬细胞中提取的外泌体显示出更强的调节 BMSCs 成脂肪分化的能力,而这是由 miR-1a-3p 介导的。在体内和体外,miR-1a-3p通过靶向Cebpz促进了BMSCs的成脂分化,并在GA-ONFH的发病和进展中发挥了重要作用:结论:我们证明,来自GC-M1巨噬细胞的外泌体破坏了BMSCs成骨和成脂分化之间的平衡,导致了GA-ONFH的发病机制。在体外和体内抑制miR-1a-3p的表达,能显著减轻BMSCs的优先成脂分化,从而减缓GA-ONFH的进展。这些发现为GA-ONFH的调控机制提供了新的见解,并突出了潜在的干预治疗靶点。
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引用次数: 0
GHRH-stimulated pituitary small extracellular vesicles inhibit hepatocyte proliferation and IGF-1 expression by its cargo miR-375-3p. GHRH刺激的垂体细胞外小泡通过其载体miR-375-3p抑制肝细胞增殖和IGF-1的表达。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-22 DOI: 10.1186/s12951-024-02857-y
Jiali Xiong, Yuxuan Wang, Hailong Wang, Junyi Luo, Ting Chen, Jiajie Sun, Qianyun Xi, Yongliang Zhang

Small extracellular vesicles (sEV) have emerged as a novel mode of intercellular material transport and information transmission. It has been suggested hormones may regulate the production and function of sEV. However, the specific impact of growth hormone-releasing hormone (GHRH) on pituitary sEV production and the role of sEV in the regulation of the GHRH-GH-IGF axis has not been previously reported. The results of the present study demonstrated that GHRH increased the production of pituitary sEV by promoting the expression of Rab27a. More importantly, GHRH induced alterations in protein and miRNA levels within GH3-sEV components. Notably, GH3-sEV with GHRH treatment exhibited the enhanced ability to impede BRL 3A cell proliferation and the expression of IGF-1. Conclusively, for the first time, we corroborate the influence of GHRH on pituitary sEV, thereby presenting novel evidence for how sEV participates in the balance of the GHRH-GH-IGF axis. Importantly, this study provides new insight into a novel balance mechanism mediated by sEV within the endocrine system.

细胞外小泡(sEV)已成为细胞间物质运输和信息传递的一种新模式。有研究表明,激素可能会调节细胞外小泡的产生和功能。然而,生长激素释放激素(GHRH)对垂体小囊泡产生的具体影响,以及小囊泡在调节 GHRH-GH-IGF 轴中的作用,此前尚未见报道。本研究结果表明,GHRH 通过促进 Rab27a 的表达来增加垂体 sEV 的产生。更重要的是,GHRH 诱导了 GH3-sEV 成分中蛋白质和 miRNA 水平的改变。值得注意的是,经 GHRH 处理的 GH3-sEV 具有更强的阻碍 BRL 3A 细胞增殖和 IGF-1 表达的能力。最后,我们首次证实了 GHRH 对垂体 sEV 的影响,从而为 sEV 如何参与 GHRH-GH-IGF 轴的平衡提供了新的证据。重要的是,这项研究为了解内分泌系统中由 sEV 介导的新型平衡机制提供了新的视角。
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引用次数: 0
Co-delivery of polyphyllin II and IR780 PLGA nanoparticles induced pyroptosis combined with photothermal to enhance hepatocellular carcinoma immunotherapy. 聚卟啉II和IR780 PLGA纳米颗粒联合给药,诱导热蛋白沉积,结合光热疗法,增强肝细胞癌免疫疗法。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-21 DOI: 10.1186/s12951-024-02887-6
Huating Huang, Jing Fu, Hulinyue Peng, Yuanyuan He, Aqian Chang, Huizhong Zhang, Yang Hao, Xiaohan Xu, Shiman Li, Jingxia Zhao, Jian Ni, Xiaoxv Dong

The clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) is significantly limited by the low immunogenicity of the tumor. Recent studies have revealed that both pyroptosis and photothermal therapy can effectively induce tumor immunogenic cell death (ICD) in liver cancer cells. Polyphyllin II (PPII), the major active component of Rhizoma Paridis, has been demonstrated for the first time to induce pyroptosis in tumor cells, while IR780 is activated by 808 nm laser to transform light energy into heat energy, effectively eliminating tumor cells. However, both PPII and IR780 are afflicted with challenges such as low solubility and poor targeting, significantly limiting their utilization. To address these problems, the pyroptosis inducer PPII and photosensitizer IR780 were co-loaded in PLGA nanoparticles by precipitation method, and the aptamer AS1411 was modified on the surface of nanoparticles to construct the targeting nanoparticles (Apt/PPII/IR780-NPs). The nanoparticles exhibit a pH/NIR dual-response intelligent release feature, which realizes the targeted and controlled release of drugs in tumor site. Furthermore, it can rapidly release PPII to induce cell pyroptosis under laser irradiation, combining with IR780-based photothermal therapy exert a significant synergistic anti-tumor effect in vitro and in vivo. This process not only promotes maturation of DCs and activates effector T cells, thereby initiating adaptive immunity, but also generates enduring and effective immune memory. In addition, Apt/PPII/IR780-NPs significantly improved the Anti-PD-1 efficacy. In summary, chemo-photothermal therapy based on Apt/PPII/IR780-NPs can significantly enhance tumor ICD, which provides a promising new strategy for HCC immunotherapy.

由于肿瘤的免疫原性较低,肝细胞癌(HCC)免疫疗法的临床疗效受到很大限制。最近的研究发现,热释光和光热疗法都能有效诱导肝癌细胞的肿瘤免疫原性细胞死亡(ICD)。研究首次证实,黄连的主要活性成分多叶素Ⅱ(PPⅡ)可诱导肿瘤细胞发生热休克,而IR780在808纳米激光的激活下可将光能转化为热能,有效消灭肿瘤细胞。然而,PPII 和 IR780 都存在溶解度低、靶向性差等问题,极大地限制了它们的应用。为解决这些问题,研究人员采用沉淀法将热变态诱导剂PPII和光敏剂IR780共负载于PLGA纳米颗粒中,并在纳米颗粒表面修饰适配体AS1411,构建了靶向纳米颗粒(Apt/PPII/IR780-NPs)。该纳米颗粒具有 pH/NIR 双响应智能释放特性,实现了药物在肿瘤部位的靶向控释。此外,它还能在激光照射下快速释放 PPII,诱导细胞自燃,与基于 IR780 的光热疗法相结合,在体外和体内发挥显著的协同抗肿瘤作用。这一过程不仅能促进 DCs 成熟,激活效应 T 细胞,从而启动适应性免疫,还能产生持久有效的免疫记忆。此外,Apt/PPII/IR780-NPs 还能显著提高抗 PD-1 的疗效。总之,基于Apt/PPII/IR780-NPs的化疗光热疗法能显著增强肿瘤的ICD,为HCC免疫治疗提供了一种前景广阔的新策略。
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引用次数: 0
Alleviating rheumatoid arthritis with a photo-pharmacotherapeutic glycan-integrated nanogel complex for advanced percutaneous delivery. 用光药物治疗糖集成纳米凝胶复合物缓解类风湿性关节炎,实现先进的经皮给药。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-21 DOI: 10.1186/s12951-024-02877-8
Pei-Wei Weng, Hsien-Tsung Lu, Lekshmi Rethi, Chia-Hung Liu, Chin-Chean Wong, Lekha Rethi, Kevin C-W Wu, Pei-Ru Jheng, Hieu T Nguyen, Andrew E-Y Chuang

The prospective of percutaneous drug delivery (PDD) mechanisms to address the limitations of oral and injectable treatment for rheumatoid arthritis (RA) is increasing. These limitations encompass inadequate compliance among patients and acute gastrointestinal side effects. However, the skin's intrinsic layer can frequently hinder the percutaneous dispersion of RA medications, thus mitigating the efficiency of drug delivery. To circumvent this constraint, we developed a strontium ranelate (SrR)-loaded alginate (ALG) phototherapeutic hydrogel to assess its effectiveness in combating RA. Our studies revealed that this SrR-loaded ALG hydrogel incorporating photoelectrically responsive molybdenum disulfide nanoflowers (MoS2 NFs) and photothermally responsive polypyrrole nanoparticles (Ppy NPs) to form ALG@SrR-MoS2 NFs-Ppy NPs demonstrated substantial mechanical strength, potentially enabling delivery of hydrophilic therapeutic agents into the skin and significantly impeding the progression of RA. Comprehensive biochemical, histological, behavioral, and radiographic analyses in an animal model of zymosan-induced RA demonstrated that the application of these phototherapeutic ALG@SrR-MoS2 NFs-Ppy NPs effectively reduced inflammation, increased the presence of heat shock proteins, regulatory cluster of differentiation M2 macrophages, and alleviated joint degeneration associated with RA. As demonstrated by our findings, treating RA and possibly other autoimmune disorders with this phototherapeutic hydrogel system offers a distinctive, highly compliant, and therapeutically efficient method.

针对类风湿性关节炎(RA)口服和注射治疗的局限性,经皮给药机制的前景越来越广阔。这些局限性包括患者依从性不足和急性胃肠道副作用。然而,皮肤的固有层会经常阻碍类风湿性关节炎药物的经皮分散,从而降低给药效率。为了规避这一限制,我们开发了一种负载雷奈酸锶(SrR)的海藻酸盐(ALG)光疗水凝胶,以评估其在抗击 RA 方面的有效性。我们的研究发现,这种负载了SrR的ALG水凝胶结合了光电响应性二硫化钼纳米花(MoS2 NFs)和光热响应性聚吡咯纳米颗粒(Ppy NPs),形成了ALG@SrR-MoS2 NFs-Ppy NPs,显示出很强的机械强度,有可能将亲水性治疗剂输送到皮肤中,并显著阻碍RA的进展。对紫霉素诱导的 RA 动物模型进行的全面生化、组织学、行为学和放射学分析表明,应用这些光疗性 ALG@SrR-MoS2 NFs-Ppy NPs 能有效减轻炎症,增加热休克蛋白、分化调节簇 M2 巨噬细胞的存在,并缓解与 RA 相关的关节退化。我们的研究结果表明,用这种光疗水凝胶系统治疗风湿性关节炎和其他自身免疫性疾病是一种独特、高度顺应性和高效的治疗方法。
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引用次数: 0
A novel anti-CTLA-4 nanobody-IL12 fusion protein in combination with a dendritic cell/tumour fusion cell vaccine enhances the antitumour activity of CD8+ T cells in solid tumours. 新型抗CTLA-4纳米体-IL12融合蛋白与树突状细胞/肿瘤融合细胞疫苗相结合,可增强CD8+T细胞在实体瘤中的抗肿瘤活性。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-19 DOI: 10.1186/s12951-024-02914-6
Meng-Jie Jiang, Hao-Peng Cui, Ting-Ting Li, Xiao-Mei Yang, Xiao-Ling Lu, Ai-Qun Liu

Background: We previously developed a nanobody targeting CTLA-4 and demonstrated that it can boost antitumour T-cell responses in vitro; however, the resulting responses after the injection of T cells into cancer models are usually weak and transient. Here, we explored whether fusing our nanobody to IL-12 would enable it to induce stronger, longer-lasting T-cell immune responses after exposure to immature dendritic cell and tumour cell fusions.

Results: The fusion protein enhanced the response of CD8+ T cells to tumour antigens in vitro and led to stronger, more persistent immune responses after the T cells were injected into mice bearing different types of xenografts.

Conclusion: Our in vitro and in vivo results suggest the anticancer potential of our nanobody-interleukin fusion system and support the clinical application of this fusion approach for various nanobodies.

背景:我们之前开发了一种靶向 CTLA-4 的纳米抗体,并证明它能在体外增强抗肿瘤 T 细胞反应;然而,将 T 细胞注射到癌症模型后产生的反应通常较弱且短暂。在此,我们探讨了将纳米抗体与IL-12融合是否能使其在暴露于未成熟树突状细胞和肿瘤细胞融合后诱导更强、更持久的T细胞免疫反应:结果:融合蛋白在体外增强了CD8+ T细胞对肿瘤抗原的反应,并在T细胞被注射到携带不同类型异种移植物的小鼠体内后产生了更强、更持久的免疫反应:我们的体外和体内研究结果表明,我们的纳米抗体-白细胞介素融合系统具有抗癌潜力,并支持将这种融合方法用于各种纳米抗体的临床应用。
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引用次数: 0
Lactobacillus rhamnosus GG-derived extracellular vesicles promote wound healing via miR-21-5p-mediated re-epithelization and angiogenesis. 鼠李糖乳杆菌 GG 衍生的细胞外囊泡通过 miR-21-5p 介导的再上皮化和血管生成促进伤口愈合。
IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-10-19 DOI: 10.1186/s12951-024-02893-8
Juan Wang, Xiaojie Li, Xinyue Zhao, Siqi Yuan, Hanyu Dou, Ting Cheng, Taomin Huang, Zhi Lv, Yidong Tu, Yejiao Shi, Xiaolei Ding

Extracellular vesicles (EVs), especially those derived from stem cells, have emerged as a novel treatment for promoting wound healing in regenerative medicine. However, the clinical application of mammalian cells-derived EVs is hindered by their high cost and low yields. Inspired by the ability of EVs to mediate interkingdom communication, we explored the therapeutic potential of EVs released by the probiotic strain Lactobacillus rhamnosus GG (LGG) in skin wound healing and elucidated the underlying mechanism involved. Using full-thickness skin wound-healing mouse models, we found that LGG-EVs accelerated wound healing procedures, including increased re-epithelialization and promoted angiogenesis. Using in vitro experiments, we further demonstrated that LGG-EVs boosted the proliferation and migration capacities of both epithelial and endothelial cells, as well as promoted endothelial tube formation. miRNA profiling analysis revealed that miR-21-5p was highly enriched in LGG-EVs and LGG-EV treatment significantly increased miR-21-5p level in recipient cells. Mechanically, LGG-EVs induced regulatory effects via miR-21-5p mediated metabolic signaling rewiring. Our results suggest that EVs derived from LGG could serve as a promising candidate for accelerating wound healing and possibly for treating chronic and impaired healing conditions.

细胞外囊泡(EVs),尤其是源自干细胞的EVs,已成为再生医学中促进伤口愈合的一种新疗法。然而,源自哺乳动物细胞的EVs成本高、产量低,阻碍了其临床应用。受EVs介导王国间交流能力的启发,我们探索了益生菌株鼠李糖乳杆菌(LGG)释放的EVs在皮肤伤口愈合中的治疗潜力,并阐明了其中的潜在机制。通过使用全厚皮肤伤口愈合小鼠模型,我们发现 LGG-EVs 加速了伤口愈合过程,包括增加再上皮化和促进血管生成。通过体外实验,我们进一步证实了 LGG-EVs 可提高上皮细胞和内皮细胞的增殖和迁移能力,并促进内皮管的形成。miRNA 图谱分析表明,miR-21-5p 在 LGG-EVs 中高度富集,LGG-EV 处理可显著提高受体细胞中的 miR-21-5p 水平。从机理上讲,LGG-EV 通过 miR-21-5p 介导的代谢信号重构诱导了调控效应。我们的研究结果表明,从 LGG 提取的 EVs 有可能成为加速伤口愈合的候选物质,也有可能用于治疗慢性和受损的愈合状况。
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引用次数: 0
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Journal of Nanobiotechnology
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