Biomaterials最新文献_第5页

Synthetic hydrogel substrate for human induced pluripotent stem cell definitive endoderm differentiation 用于人类诱导多能干细胞最终内胚层分化的合成水凝胶基质

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-25 DOI: 10.1016/j.biomaterials.2024.122920

Adriana Mulero-Russe , Ana Mora-Boza , Elijah N. Marquez , Morgan Ziegelski , Michael Helmrath , Andrés J. García

Human induced pluripotent stem cells (hiPSCs) can give rise to multiple lineages derived from three germ layers, endoderm, mesoderm and ectoderm. Definitive endoderm (DE) cell types and tissues have great potential for regenerative medicine applications. Current hiPSC differentiation protocols focus on the addition of soluble factors; however, extracellular matrix properties are known to also play a role in dictating cell fate. Matrigel™ is the gold standard for DE differentiation, but this xenogeneic, poorly defined basement membrane extract limits the clinical translatability of DE-derived tissues. Here we present a fully defined PEG-based hydrogel substrate to support hiPSC-derived DE differentiation. We screened hydrogel formulations presenting different adhesive peptides and matrix stiffness. Our results demonstrate that presenting a short peptide, cyclic RGD, on the engineered PEG hydrogel supports the transition from undifferentiated hiPSCs to DE using a serum-free, commercially available kit. We show that increasing substrate stiffness (G’ = 1.0–4.0 kPa) results in an increased linear response in DE differentiation efficiency. We also include a temporal analysis of the expression of integrin and syndecan receptors as the hiPSCs undergo specification towards DE lineage. Finally, we show that focal adhesion kinase activity regulates hiPSC growth and DE differentiation efficiency. Overall, we present a fully defined matrix as a synthetic alternative for Matrigel™ supporting DE differentiation.

人类诱导多能干细胞（hiPSCs）可产生源自三个胚层（内胚层、中胚层和外胚层）的多系细胞。明确的内胚层（DE）细胞类型和组织在再生医学应用方面具有巨大潜力。目前的 hiPSC 分化方案侧重于添加可溶性因子；但众所周知，细胞外基质的特性也在决定细胞命运方面发挥作用。Matrigel™ 是 DE 分化的黄金标准，但这种异种、定义不清的基底膜提取物限制了 DE 衍生组织的临床转化能力。在这里，我们提出了一种完全定义的基于 PEG 的水凝胶基底，以支持 hiPSC 衍生的 DE 分化。我们筛选了具有不同粘附肽和基质硬度的水凝胶配方。我们的结果表明，使用无血清的市售试剂盒，在工程化 PEG 水凝胶上呈现短肽（环状 RGD）可支持未分化的 hiPSC 向 DE 过渡。我们的研究表明，增加基质硬度（G' = 1.0-4.0 kPa）可提高 DE 分化效率的线性响应。我们还对 hiPSCs 向 DE 株系分化过程中整合素和辛迪加受体的表达进行了时间分析。最后，我们展示了局灶粘附激酶活性对 hiPSC 生长和 DE 分化效率的调节作用。总之，我们提出了一种完全确定的基质，作为支持 DE 分化的 Matrigel™ 的合成替代物。

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引用次数: 0

Exosome-decorated bio-heterojunctions reduce heat and ROS transfer distance for boosted antibacterial and tumor therapy 外泌体装饰的生物隔膜可减少热量和 ROS 的传递距离，从而促进抗菌和肿瘤治疗。

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-25 DOI: 10.1016/j.biomaterials.2024.122921

Yanni Li , Lin Chen , Yonghao Chen , Hongxing Shi , Sheng Yu , Adeleye Funmilayo , Chao Wu , Chunhui Wang , Yi Deng

Photothermal and photodynamic therapies represent effective modalities for combatting bacteria and tumor cells. However, therapeutic outcomes are constrained by limitations related to the heat and reactive oxygen species (ROS) transfer distance from photosensitizers to targets. To address this issue, we have devised and developed exosome-decorated bio-heterojunctions (E-bioHJ) consisted of MXene (Ti₃C₂), liquid metal (LM) and exosomes sourced from CT26 cells to enhance the phototherapeutic consequences. Engineering E-bioHJ enhances phototherapeutic effect in antibacterial and anti-tumor treatment, which is ascribed to reducing transfer distance of the heat and ROS. When adorned with exosomes, E-bioHJ is targetedly delivered into the cytoplasm of tumor cells to generate amount heat and ROS under 808 nm near-infrared radiation, which further induces mitochondrial dysfunction and apoptosis/necroptosis. As envisaged, this study presents a novel tactic to enhance the antibacterial and anti-tumor efficacy of biomaterials through reducing the heat and ROS delivery travel distance.

光热和光动力疗法是对付细菌和肿瘤细胞的有效方法。然而，从光敏剂到靶点的热量和活性氧（ROS）传递距离限制了治疗效果。为了解决这个问题，我们设计并开发了由 MXene（Ti3C2）、液态金属（LM）和来自 CT26 细胞的外泌体组成的外泌体装饰生物超结（E-bioHJ），以增强光治疗效果。工程E-bioHJ增强了抗菌和抗肿瘤治疗中的光疗效果，这归因于减少了热量和ROS的传递距离。E-bioHJ 与外泌体结合后，在 808 纳米近红外辐射下被靶向递送到肿瘤细胞的细胞质中，产生热量和 ROS，进一步诱导线粒体功能障碍和细胞凋亡/坏死。正如所设想的那样，这项研究提出了一种新方法，通过减少热量和 ROS 的传输距离来提高生物材料的抗菌和抗肿瘤功效。

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引用次数: 0

Bovine serum albumin framed activatable NIR AIE photosensitizer for targeted tumor therapy 用于肿瘤靶向治疗的牛血清白蛋白框架可激活近红外 AIE 光敏剂

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-24 DOI: 10.1016/j.biomaterials.2024.122918

Kun Wu , Jiawei Liu , Xinmin Zhang , Zhicong Chao , Yanyun Fang , Yu Zhu , Yuan Liu , Xiaobo Zhang , Qi Wang , Huangxian Ju , Ying Liu

Organic near-infrared (NIR) photosensitizers (PS) largely facilitate photodynamic therapy (PDT). To overcome aggregation induced quenching and diminishment of reactive oxygen species (ROS) generation capability of NIR-PS, aggregation-induced emission (AIE) effect groups have been introduced to generate NIR AIE photosensitizers. However, currently reported NIR AIE photosensitizers all take “always-on” activity that may cause systemic phototoxic side effects. Tumor microenvironment activatable NIR AIE photosensitizers have not been reported. Here we develop an activatable NIR AIE PS nanoparticle (a-NA-PSNP) for near-infrared-II (NIR-II) fluorescence (FL) imaging-guided PDT under 808 nm excitation. NIR AIE photosensitizer (N-PS) is designed and frames with cysteine (Cys)/glutathione (GSH) responsive charge transfer complex (CTC) in bovine serum albumin (BSA) to obtain a-NA-PSNP. With the aggregated state in BSA, N-PS shows high quantum yield with good photostability. As an energy acceptor, CTC quenchs NIR-II fluorescence and ROS production capability of a-NA-PSNP in normal cells and tissues. CTC is decomposed in response to tumor microenvironment Cys/GSH, therefore recovers NIR-II fluorescence of a-NA-PSNP and efficiently generates ROS under 808 nm light irradiation. The depletion of Cys/GSH also regulates tumor intracellular reductive environment to further facilitate PDT. Both in vitro and in vivo results confirmed the tumor microenvironment selective and efficient activation of a-NA-PSNP, indicating its potential in cancer therapy.

有机近红外（NIR）光敏剂（PS）在很大程度上促进了光动力疗法（PDT）。为了克服聚集诱导淬灭和降低近红外光敏剂产生活性氧（ROS）的能力，人们引入了聚集诱导发射（AIE）效应基团来生成近红外 AIE 光敏剂。然而，目前报道的近红外 AIE 光敏剂都具有 "始终开启 "的活性，可能会引起全身光毒性副作用。目前还没有关于可激活肿瘤微环境的近红外 AIE 光敏剂的报道。在此，我们开发了一种可激活的近红外 AIE PS 纳米粒子（a-NA-PSNP），用于 808 纳米激发下的近红外 II（NIR-II）荧光成像（FL）引导的光导放疗。设计了近红外AIE光敏剂（N-PS），并将其与牛血清白蛋白（BSA）中的半胱氨酸（Cys）/谷胱甘肽（GSH）反应性电荷转移复合物（CTC）组装在一起，得到了a-NA-PSNP。通过在 BSA 中的聚集状态，N-PS 显示出较高的量子产率和良好的光稳定性。作为一种能量接受体，四氯化碳可淬灭正常细胞和组织中 a-NA-PSNP 的 NIR-II 荧光和 ROS 生成能力。四氯化碳会随着肿瘤微环境中 Cys/GSH 的分解而分解，从而恢复 a-NA-PSNP 的 NIR-II 荧光，并在 808 纳米光照射下有效地产生 ROS。Cys/GSH 的耗竭还能调节肿瘤细胞内的还原环境，从而进一步促进 PDT。体外和体内研究结果都证实了 a-NA-PSNP 对肿瘤微环境的选择性和高效活化作用，显示了它在癌症治疗中的潜力。

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引用次数: 0

Charge regulated pH/NIR dual responsive nanoplatforms centered on cuproptosis for enhanced cancer theranostics 以杯突症为中心的电荷调节 pH/NIR 双响应纳米平台，用于增强癌症治疗。

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-24 DOI: 10.1016/j.biomaterials.2024.122907

Bin Sun , Wei Gao , Xinyuan Yu , Chunpeng Zhang , Haoyang Du , Yakun Luo , Jiuxin Zhu , Piaoping Yang , Manjie Zhang

Multifunctional nanoplatforms capable of simultaneously executing multimodal therapy and imaging functions are of great potentials for cancer theranostics. We present an elegantly designed, easy-to-fabricate poly(acrylic acid)/mesoporous calcium phosphate/mesoporous copper phosphate nanosphere (PAA/mCaP/mCuP NS) with outstanding pH/NIR-sensitive multimodal-synergic anti-tumor effects. Optimal porous PAA NS scaffolds were prepared at room temperature by balancing the intra-PAA polymer and polymer-solvents Lennard-Jones potentials in a water:isopropyl alcohol (IPA) mix-solvent. Subsequent sponging of Ca²⁺ and Cu²⁺, and adsorption of PO₄³⁻ to the PAA template were achieved through exquisite electrostatic interactions among ions and the ionizable PAA side-chain in an aqueous environment. This forms the basis for the tumor microenvironment pH-triggered release of Cu²⁺ to induce cuproptosis, as well as the photothermal effect originating from CuP, while Ca²⁺ can enhance the nanoplatform's biocompatibility and can damage mitochondria when overloaded. Lastly, PAA/mCaP/mCuP NSs still exhibit high drug loading efficiency for doxorubicin (DOX), enabling chemotherapy. Satisfactory anti-tumor effects of these modalities, along with their synergistic effects, were verified both in vitro and in vivo, with the NSs demonstrating good biodegradation in the latter. The fabricated NS itself holds great promise as an anti-tumor nanomedicine, and the thorough mechanical insights into NS formation may inspire the design of next-generation multifunctional nanoplatforms.

能够同时执行多模式治疗和成像功能的多功能纳米平台在癌症治疗学中具有巨大潜力。我们介绍了一种设计优雅、易于制造的聚丙烯酸/介孔磷酸钙/介孔磷酸铜纳米球（PAA/mCaP/mCuP NS），它具有出色的 pH 值/近红外敏感多模态协同抗肿瘤效应。通过在水：异丙醇（IPA）混合溶剂中平衡 PAA 内聚合物和聚合物溶剂的伦纳德-琼斯电位，在室温下制备了最佳多孔 PAA NS 支架。在水环境中，通过离子与可电离的 PAA 侧链之间微妙的静电相互作用，实现了 Ca2+ 和 Cu2+ 的海绵化以及 PO43- 对 PAA 模板的吸附。这为肿瘤微环境 pH 触发的 Cu2+ 释放诱导杯突效应以及 CuP 产生的光热效应奠定了基础，而 Ca2+ 可增强纳米平台的生物相容性，并在过载时损伤线粒体。最后，PAA/mCaP/mCuP NSs 对多柔比星（DOX）仍具有很高的药物负载效率，从而使化疗成为可能。这些模式的抗肿瘤效果令人满意，其协同效应在体外和体内均得到了验证，其中 NSs 在体内表现出良好的生物降解性。制备的 NS 本身作为一种抗肿瘤纳米药物具有广阔的前景，而对 NS 形成的透彻机械见解可能会对下一代多功能纳米平台的设计有所启发。

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引用次数: 0

Bone mineral density affects tumor growth by shaping microenvironmental heterogeneity 骨矿物质密度通过塑造微环境异质性影响肿瘤生长

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-24 DOI: 10.1016/j.biomaterials.2024.122916

Matthew A. Whitman , Madhav Mantri , Emmanuel Spanos , Lara A. Estroff , Iwijn De Vlaminck , Claudia Fischbach

Breast cancer bone metastasis is a major cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Moreover, mineralized biomaterials are commonly utilized for clinical bone defect repair, but how mineralized biomaterials affect the foreign body response and wound healing is unclear. Here, we investigate how bone mineral affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to bone mineral content depends on the murine tumor model used. While lack of bone mineral induces tumor-promoting microenvironments in both immunocompromised and immunocompetent animals, these changes are mediated by altered fibroblast phenotype in immunocompromised mice and macrophage polarization in immunocompetent mice. Collectively, our findings suggest that bone mineral density affects tumor growth by impacting microenvironmental complexity in an organism-dependent manner.

乳腺癌骨转移是晚期乳腺癌患者死亡的主要原因。虽然矿物质密度降低是已知的骨转移风险因素，但由于研究骨矿密度对肿瘤异质性的单独影响对传统方法而言具有挑战性，因此对其潜在机制的了解仍然很少。此外，矿化生物材料通常用于临床骨缺损修复，但矿化生物材料如何影响异物反应和伤口愈合尚不清楚。在这里，我们通过将单细胞 RNA 序列测定与含矿物质或不含矿物质的脱细胞骨基质相结合，研究骨矿物质如何影响体内肿瘤的生长和微环境的复杂性。我们发现，骨矿物质的缺失会显著影响成纤维细胞和免疫细胞的异质性，促进表型的形成，从而增加肿瘤的生长并改变对损伤或疾病的反应。重要的是，我们观察到基质对骨矿物质含量的反应取决于所使用的小鼠肿瘤模型。虽然在免疫功能低下和免疫功能健全的动物中，骨矿物质的缺乏都会诱发肿瘤促进微环境，但这些变化在免疫功能低下的小鼠中是由成纤维细胞表型的改变介导的，而在免疫功能健全的小鼠中则是由巨噬细胞极化介导的。总之，我们的研究结果表明，骨矿物质密度通过影响微环境的复杂性，以机体依赖的方式影响肿瘤的生长。

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引用次数: 0

Priming of cancer-immunity cycle by alleviating hypoxia-induced ferroptosis resistance and immunosuppression 通过缓解缺氧诱导的铁蛋白沉积抵抗和免疫抑制，启动癌症-免疫循环

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-23 DOI: 10.1016/j.biomaterials.2024.122911

Yun Chen, Mengxuan Zuo, Deblin Jana, Wenbin Zhong, Brynne Shu Ni Tan, Xiaodong Zhang, Xiaokai Chen, Yanli Zhao

Stimulating a robust cancer-immunity cycle (CIC) holds promising potential for eliciting potent and enduring immune responses for cancer immunotherapy. However, designing a therapeutic nanomaterial capable of both enhancing tumor immunogenicity and mitigating immunosuppression is challenging and often associated with complicated design paradigms and immune-related adverse effects. Herein, a multienzyme-mimetic alloy nanosheet incorporating palladium (Pd) and iron (Fe) is developed, which can prime effective CIC by overcoming ferroptosis resistance for enhancing tumor immunogenicity and reprograming the tumor microenvironment for enhanced second near-infrared (NIR-II) photoimmunotherapy. The nanosheets accumulate in tumors when administered intravenously and counteract hypoxia through catalase-like oxygen production and subsequent reduction of hypoxia-inducible factor-1α, M2-like macrophages, regulatory T-cell, and programmed death-ligand 1 (PD-L1) expression. The surface plasmon resonance of the nanosheets enables NIR-II phototherapy and photoacoustic imaging, coupling with its ferroptosis and tumor microenvironment reprogram properties to synergize with anti-PD-L1 checkpoint blockade therapy to achieve satisfactory antitumor outcome. This study offers a strategy for localized tumor treatment and boosting the CIC through a straightforward and inexpensive nanomaterial design.

激发强大的癌症免疫循环（CIC）有望为癌症免疫疗法带来强效持久的免疫反应。然而，设计一种既能增强肿瘤免疫原性又能减轻免疫抑制的治疗性纳米材料具有挑战性，而且往往涉及复杂的设计范式和与免疫相关的不良反应。在此，我们开发了一种包含钯（Pd）和铁（Fe）的多酶模拟合金纳米片，它可以通过克服铁变态反应抗性来增强肿瘤免疫原性，并重新编程肿瘤微环境以增强第二次近红外（NIR-II）光免疫疗法，从而为有效的CIC提供能量。静脉注射纳米片时，纳米片会在肿瘤内积聚，并通过催化酶样产氧作用抵消缺氧，进而减少缺氧诱导因子-1α、M2 样巨噬细胞、调节性 T 细胞和程序性死亡配体 1 (PD-L1) 的表达。纳米片的表面等离子体共振可实现近红外-II光疗和光声成像，再加上其铁蛋白沉降和肿瘤微环境重编程特性，可与抗PD-L1检查点阻断疗法协同作用，达到令人满意的抗肿瘤效果。这项研究提供了一种通过简单、廉价的纳米材料设计进行肿瘤局部治疗和增强 CIC 的策略。

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引用次数: 0

Targeting senescence with radioactive 223Ra/Ba SAzymes enables senolytics-unlocked One‐Two punch strategy to boost anti-tumor immunotherapy 利用放射性223Ra/Ba SAzymes靶向衰老，实现衰老分解-解锁-一举两得战略，促进抗肿瘤免疫疗法。

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-23 DOI: 10.1016/j.biomaterials.2024.122915

Jiajia Zhang , Shenghong Zhang , Chao Cheng , Chunyan Zhu , Taixia Wang , Linglin Tang , Jingjing Lou , Xian Li , Hai Wang , Fan Hu , Ming Sun , Kun Zhang , Fei Yu

Senescent cells are characterized by a persistent cessation of their cell cycle, rendering them valuable targets for anti-tumor strategies in cancer treatment. Numerous studies have explored induced senescence as a promising approach in tumor therapy. Nevertheless, these treatments often come with drawbacks, including adverse side effects and weaker senescence-inducing effects. To address these challenges, we synthesized ²²³Ra/Ba single-atom nanozyme (SAzyme), wherein Ba SAzyme acts concurrently as a carrier for ²²³RaCl₂, facilitating targeted delivery and minimizing side effects. The ²²³Ra/Ba SAzyme complex enhances various enzyme-mimicking functions, including catalase (CAT) and peroxidase (POD) activities. Importantly, ²²³Ra/Ba SAzyme induces cellular senescence and boost anti-tumor immunity. The persistent presence of a senescence-associated secretory phenotype (SASP) in the tumor microenvironment presents risks of immune suppression and tumor recurrence, which can be effectively mitigated by senolytics. As a result, ²²³Ra/Ba SAzyme were combined with anti-PD-L1 checkpoint blockade to achieve a one-two punch therapy, wherein ²²³Ra/Ba SAzyme exploits senescence followed by anti-PD-L1 therapy to eradicate senescent cells. This one‐two punch strategy approach presents a straightforward and potent intervention for both primary tumors and distant tumor.

衰老细胞的特点是细胞周期持续停止，这使它们成为癌症治疗中抗肿瘤策略的重要目标。许多研究都将诱导衰老作为一种有前景的肿瘤治疗方法。然而，这些治疗方法往往存在缺点，包括不良副作用和较弱的衰老诱导效应。为了应对这些挑战，我们合成了223Ra/Ba单原子纳米酶（SAzyme），其中Ba SAzyme同时作为223RaCl2的载体，促进靶向递送并最大限度地减少副作用。223Ra/Ba SAzyme 复合物可增强各种酶模拟功能，包括过氧化氢酶（CAT）和过氧化物酶（POD）活性。重要的是，223Ra/Ba SAzyme 能诱导细胞衰老，增强抗肿瘤免疫力。衰老相关分泌表型（SASP）在肿瘤微环境中的持续存在会带来免疫抑制和肿瘤复发的风险，而衰老解毒剂可以有效缓解这种风险。因此，223Ra/Ba SAzyme与抗PD-L1检查点阻断相结合，实现了一举两得的疗法，即223Ra/Ba SAzyme利用衰老，然后通过抗PD-L1疗法消灭衰老细胞。这种一举两得的策略方法为原发性肿瘤和远处肿瘤提供了一种直接而有效的干预手段。

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引用次数: 0

m7G-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes m7G修饰的mt-tRF3b-LeuTAA通过SIRT3的SUMO化调控软骨细胞的有丝分裂和代谢重编程。

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-23 DOI: 10.1016/j.biomaterials.2024.122903

Dianbo Long , Zengfa Deng , Xiaoyi Zhao , Yiyang Xu , Wei Li , Xiaolin Mo , Yanlin Zhong , Ming Li , Aishan He , Ziji Zhang , Yan Kang , Guping Mao

N7-methylguanosine (m⁷G) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the m⁷G methyltransferase complex. METTL1-catalyzed m⁷G as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that m⁷G modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of m⁷G modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and m⁷G levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated m⁷G modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/m⁷G/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.

N7-甲基鸟苷（m7G）修饰是最普遍的 RNA 修饰之一，而类甲基转移酶蛋白-1（METTL1）是 m7G 甲基转移酶复合物的关键组成部分。METTL1 催化的 m7G 是一种新的 RNA 修饰途径，可调节 RNA 结构、生物发生和细胞迁移。越来越多的证据表明，m7G修饰与骨关节炎（OA）的病理生理过程有关。然而，m7G修饰在OA进展过程中的潜在分子机制仍未完全阐明。我们在这里发现，OA软骨细胞中的METTL1和m7G水平明显升高。此外，METTL1 介导的 m7G 修饰上调了 mt-tRF3b-LeuTAA 的表达，从而加剧了软骨细胞的退化。从机制上讲，mt-tRF3b-LeuTAA降低了SUMO特异性蛋白酶1（SENP1）蛋白的表达，并上调了sirtuin 3（SIRT3）的SUMO化水平，从而抑制了PTEN诱导激酶1（PINK1）/Parkin介导的线粒体有丝分裂。关节内注射PMC-tRF3b-LeuTAA抑制剂（聚酰胺胺-聚乙二醇表面修饰的最小自身肽和软骨细胞亲和肽，PMC）可减轻体内内侧半月板（DMM）小鼠软骨退化的不稳定性。我们的研究表明，METTL1/m7G/mt-tRF3b-LeuTAA轴通过SIRT3 SUMOylation抑制有丝分裂并促进线粒体功能障碍，从而加速软骨降解。

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引用次数: 0

Biomimetic non-collagenous proteins-calcium phosphate complex with superior osteogenesis via regulating macrophage IL-27 secretion 生物仿生非胶原蛋白-磷酸钙复合物通过调节巨噬细胞 IL-27 的分泌实现卓越的成骨能力

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-23 DOI: 10.1016/j.biomaterials.2024.122917

Shenglong Tan , Xinghong Luo , Yifan Wang , Shangsi Chen , Tao Jiang , Xiaoshan Yang , Xinyi Peng , Xinyao Zhang , Sheng Zhang , Chengfei Zhang , Zhenzhen Liu , Dandan Ma

Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration.

创伤性缺损或骨折不愈合给组织工程和再生医学领域带来了巨大挑战。虽然合成磷酸钙基生物材料（CaPs）（如二水合磷酸钙（DCPA））通常用于骨修复，但其不充分的细胞免疫反应严重阻碍了持续降解和最佳成骨过程。在本研究中，我们从天然骨形成所必需的酸性非胶原蛋白-磷酸钙复合物（ANCPs-CaP）的关键结构中汲取灵感，制备了仿生矿化二水磷酸钙（MDCPA）。这种制备方法以植物提取的非胶原蛋白 Zein 为有机模板，以酸性人工唾液为矿化介质。理化性质分析表明，MDCPA 是 Zein 和 DCPA 的复合物，与天然 ANCP-CaP 相似。此外，MDCPA 还表现出更强的生物降解性和成骨潜力。机理研究发现，MDCPA 可被巨噬细胞通过 FCγRIII 受体吞噬和降解，从而导致白细胞介素 27（IL-27）的释放，IL-27 可通过骨免疫调节促进成骨分化。利用 IL-27 基因敲除小鼠进一步证实了 IL-27 在成骨过程中的关键作用。此外，MDCPA 仅在 4 w 内就能有效愈合大鼠颅骨的临界大小缺损，为临界大小骨缺损的再生提供了良好的基础和有价值的见解。

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引用次数: 0

Amplifying glioblastoma immunotherapy: T cell shielding through Nitric oxide/reactive oxygen species scavenging nanoparticles Potentiates anti-PD-1 增强胶质母细胞瘤免疫疗法：通过一氧化氮/活性氧清除纳米粒子保护 T 细胞增强抗 PD-1 能力

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials

Pub Date : 2024-10-22 DOI: 10.1016/j.biomaterials.2024.122904

Jihye Lee , Yeoul Kang , Hyori Lee , Gurusamy Saravanakumar , Soon A Park , Stephen Ahn , Won Jong Kim

Despite the success of immune checkpoint blockade (ICB) therapy in various cancers, its efficacy faces challenges in glioblastoma (GBM) due to the immunosuppressive cold-tumor microenvironment. The scarcity of tumor-infiltrating T cells and the suppression of T cell activity significantly limit therapeutic outcomes in GBM. Nitric oxide (NO) and reactive oxygen species (ROS) from tumor-associated myeloid cells (TAMCs) are key contributors to T cell suppression, reducing ICB therapy effectiveness. In this study, we developed NO-ROS scavenging micelles that effectively scavenge both NO and ROS, protecting T cells from their exhausting effects. This leads to a significant increase in T cell infiltration and activation. Moreover, when combined with αPD-1, the survival rate increases to 40 % up to 120 days, enhancing therapeutic efficacy compared to αPD-1 alone. This approach not only protects T cells from the inhibitory effects of NO and ROS but also has the potential to reshape the tumor microenvironment, overcoming T cell suppression in cold tumors.

尽管免疫检查点阻断疗法（ICB）在多种癌症中取得了成功，但由于免疫抑制性冷肿瘤微环境，它在胶质母细胞瘤（GBM）中的疗效面临挑战。肿瘤浸润 T 细胞的稀缺和 T 细胞活性的抑制极大地限制了 GBM 的治疗效果。一氧化氮（NO）和肿瘤相关髓系细胞（TAMCs）产生的活性氧（ROS）是抑制T细胞的关键因素，从而降低了ICB疗法的疗效。在这项研究中，我们开发了能有效清除 NO 和 ROS 的 NO-ROS 清除胶束，保护 T 细胞免受它们的衰竭效应。这导致 T 细胞浸润和活化明显增加。此外，与 αPD-1 结合使用时，存活率可提高到 40%，最长可达 120 天，与单独使用 αPD-1 相比，疗效更佳。这种方法不仅能保护 T 细胞免受 NO 和 ROS 的抑制作用，还有可能重塑肿瘤微环境，克服冷肿瘤对 T 细胞的抑制。

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引用次数: 0