Advanced drug delivery reviews最新文献_第6页

Nitric oxide-modulating biomaterials for therapeutic Immunoengineering 用于治疗性免疫工程的一氧化氮调节生物材料

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-13 DOI: 10.1016/j.addr.2025.115718

Yeonju Boo , Sang-Hun Choi , Jihoon Kim , Won Jong Kim

Nitric oxide (NO) plays dual and context-dependent roles in the immune system, functioning as either an immunostimulatory or immunosuppressive mediator depending on its concentration, cellular source, and exposure dynamics. Dysregulated endogenous NO production is implicated in the pathogenesis of a broad spectrum of diseases. Therapeutic modulation of NO levels via engineered delivery systems represents a promising approach for immune regulation. This review provides a comprehensive overview of NO-modulating biomaterials, with a focus on two opposing strategies: NO scavenging to remove pathologically excessive NO and NO delivery to restore physiologically essential NO levels. We first examined the distinct molecular mechanisms and cell type-specific effects of endogenous and exogenous NO, highlighting its pleiotropic immunoregulatory roles in macrophages, dendritic cells, T cells, B cells, neutrophils, and myeloid-derived suppressor cells. We then classify representative NO scavengers and NO donors according to their chemical structures and activation triggers, including pH, redox, enzyme, and stimulus-responsive systems. Next, we discuss the design and application of advanced biomaterial-based platforms that integrate these agents into immunoengineering interventions for various disease models. Finally, we address the key translational challenges and design principles required to achieve precise, spatiotemporally controlled, and disease-selective NO modulation. Collectively, this review summarizes recent advances in NO-regulating biomaterials and highlights their potential to reprogram immune responses for therapeutic benefit.

一氧化氮（NO）在免疫系统中发挥双重和情境依赖的作用，根据其浓度、细胞来源和暴露动力学，作为免疫刺激或免疫抑制介质发挥作用。内源性NO产生失调与多种疾病的发病机制有关。通过工程输送系统对NO水平进行治疗性调节是一种很有前途的免疫调节方法。这篇综述提供了一氧化氮调节生物材料的全面概述，重点介绍了两种相反的策略：清除一氧化氮以去除病理性过量的一氧化氮和输送一氧化氮以恢复生理必需的一氧化氮水平。我们首先研究了内源性和外源性NO的不同分子机制和细胞类型特异性作用，强调了其在巨噬细胞、树突状细胞、T细胞、B细胞、中性粒细胞和髓源性抑制细胞中的多效性免疫调节作用。然后，我们根据它们的化学结构和激活触发因素，包括pH值、氧化还原、酶和刺激反应系统，对有代表性的NO清除剂和NO供体进行分类。接下来，我们将讨论基于先进生物材料的平台的设计和应用，该平台将这些药物整合到各种疾病模型的免疫工程干预中。最后，我们讨论了实现精确、时空控制和疾病选择性NO调节所需的关键转化挑战和设计原则。综上所述，本文综述了no调节生物材料的最新进展，并强调了它们在重编程免疫反应以获得治疗益处方面的潜力。

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引用次数: 0

iPSC-derived T cells and macrophages: Manufacturing and next-generation application approaches ipsc衍生的T细胞和巨噬细胞：制造和下一代应用方法

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-13 DOI: 10.1016/j.addr.2025.115713

Débora Basílio-Queirós , Isabelle Rivière , Sjoukje J.C. van der Stegen , Nico Lachmann

Chimeric antigen receptor (CAR) technology has transformed the immunotherapy field with significant success in the treatment of hematological diseases. Nonetheless, challenges in scalability, donor variability as well as in the treatment of solid tumors warrants innovative solutions. Induced pluripotent stem cell (iPSC) technology has revolutionized the filed as an emerging renewable source for CAR-based therapies, facilitating the development of off-the-shelf immune cells products. This review focuses on the recent developments of iPSC-derived CAR-T cells and CAR-macrophages, including differentiation protocols, gene engineering strategies and mitigation of Graft-versus-Host Disease (GvHD), as well as alternatives for histocompatibility constraints. Additionally, we will discuss how iPSC-derivation enhances accessibility of low-frequency immune cell populations including MR1-restricted αβT, γδT, Natural Killer T (NKT) and Microglial cells. Despite great progress achieved, the limited but continuously growing clinical experience and manufacturing challenges, warrant further exploration. Advancements in manufacturing scalability and genetic engineering position iPSC-based therapies at the forefront of clinical strategies to address unmet clinical needs in cancer treatment.

嵌合抗原受体（CAR）技术已经改变了免疫治疗领域，在血液疾病的治疗中取得了重大成功。然而，可扩展性、供体可变性以及实体瘤治疗方面的挑战需要创新的解决方案。诱导多能干细胞（iPSC）技术作为基于car的治疗的新兴可再生来源，已经彻底改变了该领域，促进了现成免疫细胞产品的发展。本文综述了ipsc衍生的CAR-T细胞和car -巨噬细胞的最新进展，包括分化方案、基因工程策略和缓解移植物抗宿主病（GvHD），以及组织相容性限制的替代方案。此外，我们将讨论ipsc衍生如何增强低频免疫细胞群的可及性，包括mr1限制性αβT， γδT，自然杀伤T （NKT）和小胶质细胞。尽管取得了很大的进展，但有限但不断增长的临床经验和制造挑战值得进一步探索。制造可扩展性和基因工程的进步使基于ipsc的疗法处于临床策略的前沿，以解决癌症治疗中未满足的临床需求。

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引用次数: 0

Cold atmospheric plasma for gas therapy and gas-activated drug delivery 用于气体治疗和气体活化药物输送的冷大气等离子体

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-13 DOI: 10.1016/j.addr.2025.115719

Qiaoyun Li , Jaehyun Choi , Namjo Shin , Dongun Jin , Enzhen Xu , Byeongjin Ahn , Boyoung Lee , Jaiwoo Lee , Yu-Kyoung Oh

Cold atmospheric plasma (CAP) has emerged as a promising tool for in situ gas delivery due to its ability to generate reactive oxygen and nitrogen species, which play a crucial role in oxidative stress-mediated therapeutic effects. As the fourth state of matter, CAP is characterized by unique physicochemical properties and distinct generation mechanisms, which are discussed in terms of its fundamental principles and production techniques. This review covers current CAP delivery methods, highlighting their critical role in biomedical applications. The diverse therapeutic potential of CAP is explored, including its immunomodulatory effects in cancer therapy and its antimicrobial properties in wound healing through generation of reactive oxygen and nitrogen species. CAP also demonstrates efficacy in oral, inflammatory, gastrointestinal, and neurological conditions by eliminating biofilms, promoting tissue regeneration, and modulating immune and intracellular redox signaling pathways. Additionally, special emphasis is placed on the synergistic integration of CAP with advanced drug delivery systems to enhance therapeutic efficacy. Current challenges, potential limitations, and future directions for CAP-based biomedical applications are addressed. Despite its significant potential, challenges such as precise dose control, biological safety, and clinical translation remain unresolved. Future research should focus on optimizing CAP-based therapies, developing targeted delivery strategies, and conducting comprehensive clinical studies to facilitate its integration into mainstream medical practice.

冷大气等离子体（CAP）由于其产生活性氧和活性氮的能力而成为原位气体输送的一种有前途的工具，这在氧化应激介导的治疗效果中起着至关重要的作用。CAP作为物质的第四种状态，具有独特的物理化学性质和不同的生成机制，本文就其基本原理和生产工艺进行了探讨。这篇综述涵盖了目前的CAP递送方法，强调了它们在生物医学应用中的关键作用。探讨了CAP的多种治疗潜力，包括其在癌症治疗中的免疫调节作用以及通过产生活性氧和活性氮在伤口愈合中的抗菌特性。CAP通过消除生物膜、促进组织再生、调节免疫和细胞内氧化还原信号通路，在口腔、炎症、胃肠道和神经系统疾病中也显示出疗效。此外，特别强调了CAP与先进药物输送系统的协同整合，以提高治疗效果。讨论了基于cap的生物医学应用的当前挑战、潜在限制和未来方向。尽管其潜力巨大，但诸如精确剂量控制、生物安全性和临床转化等挑战仍未解决。未来的研究应侧重于优化基于cap的治疗方法，制定有针对性的给药策略，并进行全面的临床研究，以促进其融入主流医疗实践。

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引用次数: 0

Advancements in 3D-printing strategies towards developing effective implantable drug delivery systems: Recent applications and opportunities 开发有效植入式药物输送系统的3d打印策略的进展：最近的应用和机会

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-12 DOI: 10.1016/j.addr.2025.115711

Kieran Lau , Hien A. Tran , Renjian Tan , Tushar Kumeria , Asheeta A. Prasad , Richard P. Tan , Khoon S. Lim

The development of implantable drug delivery systems has played a transformative role in modern medicine through enabling more precise, localized and sustained delivery of therapeutics. This has advantages over systemic delivery routes that often provide suboptimal drug concentrations, frequent redosing requirements and off-target effects. However, one ongoing limitation of current implantable systems has been the inability to navigate the complex and dynamic biological processes. The physical architecture of implantable constructs serves as a powerful method to control the therapeutic release from a biomaterial. Additive manufacturing, or commonly 3D-printing, has emerged as one of the most versatile and widely adopted approaches used in the development of novel biomaterials with macro to nanoscale resolution, offering an efficient and cost-effective method to create highly complex geometries, hierarchical architectures to enable region-specific drug loading. Therefore, in this review, we describe and critically evaluate the implementation of 3D-printing techniques towards designing implantable drug delivery systems. Furthermore, we analyze the effectiveness of existing strategies, discussing their utility, with a particular focus on constructs that are capable of control and sustained release of multiple drugs towards therapeutic treatments and tissue engineering. Lastly, this review discusses the current challenges and the keys opportunities that remain underutilized towards the developing the next generation of implantable drug delivery systems.

植入式给药系统的发展通过实现更精确、局部和持续的治疗递送，在现代医学中发挥了变革性作用。这比通常提供次优药物浓度、频繁重新给药和脱靶效应的全身给药途径有优势。然而，当前可植入系统的一个持续限制是无法驾驭复杂和动态的生物过程。植入式结构体的物理结构是控制生物材料治疗释放的有力方法。增材制造，或通常的3d打印，已经成为最通用和广泛采用的方法之一，用于开发具有宏观到纳米级分辨率的新型生物材料，提供了一种高效且具有成本效益的方法来创建高度复杂的几何形状，分层结构，以实现特定区域的药物装载。因此，在这篇综述中，我们描述并批判性地评估了3d打印技术在设计植入式药物输送系统方面的应用。此外，我们分析了现有策略的有效性，讨论了它们的实用性，特别关注能够控制和持续释放多种药物的结构，用于治疗治疗和组织工程。最后，本综述讨论了目前的挑战和关键的机会，仍未充分利用，以开发下一代植入式药物输送系统。

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引用次数: 0

Cell-based treatments of lung diseases: overview and outlook 肺部疾病的细胞治疗：综述与展望

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-11 DOI: 10.1016/j.addr.2025.115712

A.M. van der Does , L. v. Schledorn , R. Olmer

Chronic lung diseases (CLD), including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and pulmonary hypertension, represent a significant health burden worldwide and their incidence is steadily increasing. Specifically, COPD and lung fibrosis lead to progressive tissue loss, particularly in the alveolar region, and can currently mainly be treated symptomatically, with some therapies slowing down progression. Regenerative cell therapy offers promising approaches to repair and restore permanently damaged lung tissue, focusing on different cell types such as epithelial, stromal, endothelial and pluripotent stem cells. Despite positive results in preclinical studies and initial clinical trials, large successes are lagging behind. This shows that there is still a considerable need for further research into e.g. optimal conditions, including cell sources and administration methods in humans. Challenges such as successful translation of beneficial strategies in animal models, safety risks of new strategies and the control of cell localization need to be addressed in more detail. Future research approaches should therefore support the identification of suitable cell types, the improvement of cell protection strategies and the development of predictable human models to enable the successful clinical application of regenerative cell therapy in CLD.

慢性肺病（CLD），包括慢性阻塞性肺病（COPD）、肺纤维化和肺动脉高压，是世界范围内的重大健康负担，其发病率正在稳步上升。具体来说，COPD和肺纤维化导致进行性组织损失，特别是在肺泡区，目前主要是对症治疗，一些治疗可以减缓进展。再生细胞疗法为修复和恢复永久性损伤的肺组织提供了有前途的方法，重点是不同类型的细胞，如上皮细胞、基质细胞、内皮细胞和多能干细胞。尽管在临床前研究和初步临床试验中取得了积极成果，但尚未取得重大成功。这表明，仍有相当大的需要进一步研究，例如，最佳条件，包括细胞来源和人类给药方法。诸如在动物模型中成功翻译有益策略、新策略的安全风险和细胞定位控制等挑战需要更详细地解决。因此，未来的研究方法应该支持识别合适的细胞类型，改进细胞保护策略和开发可预测的人体模型，以使再生细胞治疗在CLD中的成功临床应用。

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引用次数: 0

Repurposing the bacterial surface display technology for drug delivery 重新利用细菌表面展示技术给药

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-03 DOI: 10.1016/j.addr.2025.115701

Shaobo Yang , Mengdi Yang , Maria Jennings , Hania Timek , Amber E. Haley , Rizwan Romee , Jiahe Li

Bacteria have emerged as versatile platforms for therapeutic delivery, owing to their inherent adaptability, genetic tractability, and ability to interface with the human microbiome and immune system. This review explores the evolution of bacterial engineering for medical applications, emphasizing drug delivery strategies enabled by bacterial surface display technologies. We outline the advantages of surface display, such as enhanced localization, prolonged therapeutic activity, and reduced systemic toxicity, over conventional bacterial secretion and lysis-based delivery methods. The review details key biological mechanisms of surface display in both Gram-negative and Gram-positive bacteria, including outer membrane proteins, sortase-mediated anchoring, and spore-based systems. We also highlight emerging applications of surface-displayed cytokines, nanobodies, and immunomodulatory proteins in cancer therapy, vaccine development, microbiome engineering, and animal health. Innovative approaches combining bacterial display with conjugation systems and biosensors expand the potential of these living therapeutics for precise, responsive, and programmable interventions. Furthermore, we propose a future roadmap that leverages computational tools such as AlphaFold and in silico screening to rationally identify optimal outer membrane anchors, accelerating the design of next-generation surface display platforms. While challenges remain, including regulatory hurdles and microbial stability, continued interdisciplinary innovation with synthetic biology promises to transform engineered bacteria into clinically viable therapeutic agents. This review positions bacterial surface display as a powerful and underexplored modality for targeted drug delivery, bridging synthetic biology, immune engineering, and translational medicine.

细菌由于其固有的适应性、遗传易感性以及与人类微生物组和免疫系统交互的能力，已经成为治疗递送的多功能平台。这篇综述探讨了细菌工程在医学应用中的发展，强调了细菌表面显示技术使药物传递策略成为可能。我们概述了与传统的细菌分泌和基于裂解的递送方法相比，表面显示的优点-例如增强定位，延长治疗活性和降低全身毒性。本文详细介绍了革兰氏阴性菌和革兰氏阳性菌表面展示的关键生物学机制，包括外膜蛋白、排序酶介导的锚定和基于孢子的系统。我们还重点介绍了表面显示的细胞因子、纳米体和免疫调节蛋白在癌症治疗、疫苗开发、微生物组工程和动物健康方面的新应用。将细菌展示与偶联系统和生物传感器相结合的创新方法扩大了这些生物治疗的潜力，以实现精确、灵敏和可编程的干预。此外，我们提出了一个未来的路线图，利用AlphaFold和硅筛选等计算工具来合理识别最佳的外膜锚点，加速下一代表面显示平台的设计。尽管挑战依然存在，包括监管障碍和微生物稳定性，但合成生物学的持续跨学科创新有望将工程细菌转化为临床可行的治疗药物。这篇综述将细菌表面展示定位为靶向药物递送、桥接合成生物学、免疫工程和转化医学的一种强大而尚未开发的模式。

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引用次数: 0

Recent advances in gene delivery for melanocyte-associated disorders 黑色素细胞相关疾病基因传递的最新进展

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-03 DOI: 10.1016/j.addr.2025.115703

Tanya Chhibber , Dekker C. Deacon , Hamidreza Ghandehari , Robert L. Judson-Torres

Melanocytes are cells that produce the pigment melanin, which provides color to the skin, eyes, and hair. Dysregulation in melanocyte function, viability, or differentiation can result in melanocyte-associated disorders that can be broadly classified based on etiology as melanocyte hyperproliferation and hyperactivation, defects in melanin synthesis, inflammatory alterations in melanin production/trafficking, melanocyte destruction, and defects in melanocyte migration. While most of these disorders are of benign origin, the cosmetic implications of these conditions are associated with significant psychosocial burden and cultural stigma, having a significant impact on affected individuals. These conditions are primarily driven by changes in underlying gene expression (both at the genetic and epigenetic levels). Targeting the underlying genetic and transcriptomic changes in melanocyte-associated disorders using gene replacement (plasmid DNA, mRNA), gene knockdown (siRNA), or miRNA replacement (miRNA) presents a promising strategy for developing treatments for these conditions. The delivery of naked nucleic acid molecules is challenging, and lipid- and polymer-based particles have been widely evaluated for the successful delivery of biologically active nucleic acids to the melanocytes. This review provides an overview of melanocyte-associated pigmentary disorders and their underlying genetic factors and examines current preclinical and clinical efforts using non-viral polymeric and lipid-based delivery systems for plasmid DNA and RNA-based therapeutics.

黑色素细胞是存在于皮肤表皮和真皮交界处的细胞，产生黑色素，黑色素为皮肤、眼睛和头发提供颜色。黑素细胞功能、活力或分化的失调可导致黑素细胞相关疾病，这些疾病可根据病因大致分类为黑素细胞过度增殖和过度活化、黑色素合成缺陷、黑色素生产/运输的炎症改变、黑素细胞破坏和黑素细胞迁移缺陷。虽然这些疾病大多是良性的，但这些疾病对美容的影响与严重的社会心理负担和文化耻辱有关，对受影响的个人产生重大影响。这些情况主要是由潜在基因表达的变化驱动的（在遗传和表观遗传水平上）。利用基因替代（质粒DNA， mRNA）、基因敲低（siRNA）或miRNA替代（miRNA）靶向黑素细胞相关疾病的潜在遗传和转录组学变化，为这些疾病的治疗提供了一种有希望的策略。裸核酸分子的递送具有挑战性，脂质和聚合物基颗粒已被广泛评估为成功将生物活性核酸递送到黑素细胞。本文综述了黑素细胞相关的色素紊乱及其潜在的遗传因素，并检查了目前使用非病毒聚合物和脂质递送系统进行质粒DNA和rna治疗的临床前和临床研究。

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引用次数: 0

20 years of Flash NanoPrecipitation – from controlled precipitation to global medicine 20年的闪蒸纳米沉淀——从可控沉淀到全球医学

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-02 DOI: 10.1016/j.addr.2025.115700

Kurt D. Ristroph , Nathalie M. Pinkerton , Chester E. Markwalter , Suzanne M. D'Addio , Marian E. Gindy , Robert F. Pagels

In the twenty years since the development of Flash NanoPrecipitation (FNP) technology, an antisolvent precipitation technique that uses rapid turbulent mixing to drive self-assembly of polymeric or lipid nanoparticles, the platform has been used for a wide variety of drug delivery applications in research and industry – most notably as the enabling technology for the global manufacture of the Pfizer-BioNTech COMIRNATY® mRNA lipid nanoparticle vaccine against SARS-CoV-2. Importantly, this makes FNP the only publicly-known manufacturing technology for global commercial-scale lipid nanoparticle formulation. This situation makes the technique remarkable and noteworthy and worth discussing broadly, which this article aims to do. It also sets FNP mixing as the benchmark technology against which other LNP manufacturing processes should be compared. Here we review the principles underpinning this continuous antisolvent precipitation technique, its scalability and use with downstream unit operations, and its utility in nanomedicine research. We discuss the current intellectual property landscape surrounding FNP technology and give examples of its industrial implementation for SARS-CoV-2 and low-cost antimalarial formulations. We end with a survey on recent improvements and extensions to the platform that enable the encapsulation of new classes of molecules and greater flexibility in manufacturing as FNP moves into its third decade.

Flash nanop沉淀法（FNP）技术是一种使用快速湍流混合来驱动聚合物或脂质纳米颗粒自组装的抗溶剂沉淀技术，自开发以来的二十年中，该平台已被用于研究和工业中的各种药物输送应用-最值得注意的是作为全球生产的辉瑞- biontech COMIRNATY®mRNA脂质纳米颗粒疫苗的使能技术。重要的是，这使得FNP成为全球商业规模的脂质纳米颗粒配方中唯一公开的制造技术。这种情况使得该技术引人注目，值得广泛讨论，这也是本文所要做的。它还将FNP混合作为基准技术，与其他LNP制造工艺进行比较。本文综述了这种连续抗溶剂沉淀技术的原理、其可扩展性和在下游单元操作中的应用，以及它在纳米医学研究中的应用。我们讨论了围绕FNP技术的当前知识产权格局，并举例说明了其在SARS-CoV-2和低成本抗疟制剂中的工业实施。最后，我们对平台的最新改进和扩展进行了调查，这些改进和扩展使FNP进入第三个十年时能够封装新类别的分子，并在制造中具有更大的灵活性。

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引用次数: 0

Towards airway microbiome engineering for improving respiratory health. 改善呼吸道健康的气道微生物组工程研究。

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-01 Epub Date: 2025-08-06 DOI: 10.1016/j.addr.2025.115662

Kelsey E Hern, Arthur Prindle

The known roles of human-associated microbes in health and disease have expanded in recent years. While the gut microbiome is the most well studied, the airway microbiome is gaining attention as an important gatekeeper of respiratory health. Compared to the gut, the airway microbiome has lower species complexity, greater niche stability, and represents an immediate point of contact with the outside world. These features make it an attractive target for improving respiratory health. As respiratory disease continues to increase among humans, it will be critical to develop novel approaches to combat new and emergent bacterial infections, viruses, and cancers for which we do not currently have treatments. This review seeks to define strategies for airway microbiome engineering-the intentional manipulation of airway associated microbes to restore species balance, enhance protective functions, or treat disease. We summarize the growing body of literature linking the airway microbiome to respiratory health and discuss both broad-spectrum and high precision technologies that hold particular promise for further development. We argue that inhaled probiotics and bacteriophage are among the most attractive technologies for clinical translation of airway microbiome engineering to improve respiratory health.

近年来，与人类有关的微生物在健康和疾病中的已知作用有所扩大。虽然肠道微生物组是研究得最充分的，但气道微生物组作为呼吸健康的重要看门人正在受到关注。与肠道相比，气道微生物群具有更低的物种复杂性，更大的生态位稳定性，并且代表了与外部世界的直接接触点。这些特点使它成为改善呼吸系统健康的一个有吸引力的目标。随着人类呼吸系统疾病的持续增加，开发新的方法来对抗新的和紧急的细菌感染、病毒和癌症将是至关重要的，我们目前还没有治疗方法。本综述旨在定义气道微生物组工程的策略-有意操纵气道相关微生物以恢复物种平衡，增强保护功能或治疗疾病。我们总结了越来越多的文献将气道微生物组与呼吸健康联系起来，并讨论了具有进一步发展前景的广谱和高精度技术。我们认为，吸入益生菌和噬菌体是气道微生物组工程临床翻译中最具吸引力的技术之一，可以改善呼吸道健康。

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引用次数: 0

In vitro models of the interplay between glioblastoma and blood–brain barrier for stratifying drug efficacy 胶质母细胞瘤和血脑屏障细胞相互作用的体外模型对药物疗效的分层

IF 17.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Advanced drug delivery reviews

Pub Date : 2025-10-01 DOI: 10.1016/j.addr.2025.115702

Cecília Ferreira , Bruno Sarmento , Cláudia Martins

Glioblastoma (GBM) is the most lethal brain cancer in adults, with a dismal prognosis and no curative therapies available. The treatment landscape remains largely stagnant, relying on tumor resection, temozolomide (TMZ) chemotherapy, and radiotherapy, which are hampered by the blood-brain barrier (BBB) that limits drug blood-to-brain permeability and, consequently, therapeutic efficacy. Over 98 % of potential therapeutic candidates fail to penetrate the BBB, significantly contributing to the high recurrence rates of GBM. The urgent need for improved drug delivery strategies is compounded by the limitations of current preclinical models, which often inadequately mimic the complex BBB-GBM interaction. This review discusses recent advancements in the development of in vitro models that accurately replicate the BBB and GBM interplay, ranging from simplified two-dimensional (2D) systems to sophisticated three-dimensional (3D) constructs. Innovations such as microfluidic devices and multicellular spheroid cultures are highlighted as promising methods to enhance physiological relevance and predictive value in drug testing. By emphasizing the interplay between GBM and its microenvironment with the BBB, these models aim to accelerate the discovery and efficacy testing of novel anti-GBM agents. Ultimately, this review underscores the critical need for more representative in vitro platforms that not only reduce reliance on animal models but also adhere to the principles of the 3Rs (replacement, reduction, refinement) in biomedical research, paving the way for more effective therapeutic interventions against GBM.

胶质母细胞瘤（GBM）是成人中最致命的脑癌，预后不佳，没有治愈的治疗方法。目前的治疗方案仍然停滞不前，主要依靠肿瘤切除、替莫唑胺（TMZ）化疗和放射治疗，但这些方法受到血脑屏障（BBB）的阻碍，血脑屏障限制了药物的血脑通透性，从而影响了治疗效果。超过98% %的潜在治疗候选物不能穿透血脑屏障，这是导致GBM高复发率的重要原因。由于目前临床前模型的局限性，迫切需要改进给药策略，这些模型往往不能充分模拟复杂的BBB-GBM相互作用。本文讨论了精确复制血脑屏障和GBM相互作用的体外模型的最新进展，范围从简化的二维（2D）系统到复杂的三维（3D）结构。微流体装置和多细胞球体培养等创新被强调为有希望的方法，以增强药物测试中的生理相关性和预测价值。通过强调GBM及其微环境与血脑屏障之间的相互作用，这些模型旨在加速新型抗GBM药物的发现和疗效测试。最后，这篇综述强调了对更具代表性的体外平台的迫切需要，不仅要减少对动物模型的依赖，而且要坚持生物医学研究中的3r（替代、减少、改进）原则，为更有效地治疗GBM铺平道路。

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引用次数: 0