Journal of Controlled Release最新文献_第8页

Translational m-PBPK Modeling reveals active transcytosis as the pivotal mechanism for nanoparticle tumor delivery: Implications for dose optimization 翻译m-PBPK模型揭示了活跃的胞吞作用是纳米颗粒肿瘤递送的关键机制：对剂量优化的影响

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-03 DOI: 10.1016/j.jconrel.2026.114684

Jinwei Zhu , Hui Lin , Kejie Wang , Sasa Zhang , Hua He , Kun Hao

The long-held assumption that passive diffusion governs nanomedicine entry into the tumors has been increasingly challenged, with accumulating evidence implicating transcytosis as an important route for nanoparticle transport across the tumor endothelium. However, quantitative comparisons of their relative contributions remain scarce. To address this gap, this study developed a minimal physiologically based pharmacokinetic (m-PBPK) model that integrates in vitro cellular kinetic data to quantitatively describe to tumor delivery of nanoparticles and to assess the relative contributions of diffusion- and transcytosis-mediated transport within a model-based context. The framework was evaluated using PEGylated gold nanoparticles (AuNPs) spanning a range of particle sizes and incorporated empirical size-parameter relationships to enable in vitro-in vivo translational analysis. Model simulations suggested that transcytosis-mediated processes account for the majority of tumor AuNP accumulation under the modeled physiological conditions (99.0 %, 95 % CI: 94.7 %–99.8 %), whereas passive diffusion contributed a smaller fraction under most conditions examined. Dose-dependent analysis further indicated a capacity-limited tumor accumulation behavior, with a threshold around 18 mg, beyond which increasing the dose to 100 mg resulted in only a modest (∼15 %) increase in tumor accumulation. Sensitivity analyses indicated that systemic exposure and endothelial intracellular trafficking behavior are key determinants influencing tumor delivery, whereas enhanced intracellular sequestration consistently reduced tumor accumulation across dose levels. Overall, the proposed m-PBPK framework provides mechanistically interpretable, proof-of-concept insights into nanoparticle tumor delivery, supporting quantitative assessment of transcytosis efficiency and dose-dependent accumulation behavior for hypothesis generation in nanomedicine development.

长期以来，纳米药物通过被动扩散进入肿瘤的假设受到越来越多的挑战，越来越多的证据表明，胞吞作用是纳米颗粒通过肿瘤内皮运输的重要途径。然而，对它们的相对贡献的定量比较仍然很少。为了解决这一空白，本研究开发了一个基于生理的最小药代动力学（m-PBPK）模型，该模型整合了体外细胞动力学数据，以定量描述纳米颗粒的肿瘤递送，并评估扩散和胞吞介导的运输在基于模型的背景下的相对贡献。使用聚乙二醇化金纳米颗粒（AuNPs）对该框架进行评估，该框架跨越了一系列粒径，并结合了经验尺寸-参数关系，以实现体内外翻译分析。模型模拟表明，在模拟的生理条件下，胞吞介导的过程占肿瘤AuNP积累的大部分（99.0%,95% CI: 94.7% - 99.8%），而在大多数条件下，被动扩散贡献的比例较小。剂量依赖性分析进一步表明了一种容量有限的肿瘤积累行为，其阈值约为18 mg，超过该阈值，将剂量增加到100 mg仅导致肿瘤积累适度增加（~ 15%）。敏感性分析表明，全身暴露和内皮细胞内运输行为是影响肿瘤递送的关键决定因素，而增强的细胞内隔离在不同剂量水平上一致地减少了肿瘤积累。总的来说，所提出的m-PBPK框架为纳米颗粒肿瘤传递提供了机制上可解释的概念验证，支持对细胞吞噬效率和剂量依赖性积累行为的定量评估，为纳米药物开发中的假设生成提供了支持。

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引用次数: 0

Non-invasive administration of exosomes 非侵入性外泌体给药

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-03 DOI: 10.1016/j.jconrel.2026.114674

Teertha Ayanji , Na Yan , Litian Jia , Ke Cheng

Exosomes, as naturally derived extracellular vesicles, have emerged as promising therapeutic carriers due to their intrinsic biocompatibility, low immunogenicity, and ability to facilitate intercellular communication. In recent years, the non-invasive administration of exosomes has gained increasing attention as a strategy to enhance patient compliance and improve drug delivery efficiency while circumventing the limitations associated with traditional invasive routes. This review provides a comprehensive overview of the non-invasive delivery of exosome-based therapeutics, spanning oral, intranasal, inhalation, ocular, and transdermal administration. Moreover, we discuss underexplored pathways with unique anatomical and physiological advantages for systemic and local therapy, including sublingual, otic, rectal, and vaginal delivery. Each administration route will outline the key anatomic and biological barriers that exosomes must overcome, along with commonly employed strategies to address them. We further explore the therapeutic potential of non-invasive exosome delivery across various diseases, highlighting the advantages and limitations of each approach. Finally, we discuss the current challenges in translating non-invasive exosome delivery into clinical practice and propose future directions to advance this goal.

外泌体作为天然来源的细胞外囊泡，由于其内在的生物相容性、低免疫原性和促进细胞间通讯的能力，已成为有希望的治疗载体。近年来，外泌体的非侵入性给药越来越受到关注，作为一种提高患者依从性和提高药物递送效率的策略，同时规避了传统侵入性途径的局限性。这篇综述提供了基于外泌体的非侵入性治疗的全面概述，包括口服、鼻内、吸入、眼内和透皮给药。此外，我们还讨论了在全身和局部治疗中具有独特解剖和生理优势的未被探索的途径，包括舌下、耳、直肠和阴道分娩。每种给药途径将概述外泌体必须克服的关键解剖学和生物学障碍，以及解决这些障碍的常用策略。我们进一步探讨了非侵入性外泌体在各种疾病中的治疗潜力，强调了每种方法的优点和局限性。最后，我们讨论了将非侵入性外泌体递送转化为临床实践的当前挑战，并提出了推进这一目标的未来方向。

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引用次数: 0

Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury 线粒体靶向辅酶Q10纳米载体的颗粒大小和脂质组成评估减轻早期对乙酰氨基酚诱导的肝损伤

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-03 DOI: 10.1016/j.jconrel.2026.114682

Mitsue Hibino, Yukari Muramatsu, Hideyoshi Harashima, Yuma Yamada

Acetaminophen (APAP) overdose-induced liver damage is a serious clinical issue primarily caused by mitochondrial dysfunction in hepatocytes. Coenzyme Q₁₀ (CoQ₁₀) exhibits mitochondrial protective effects and is considered a promising therapeutic candidate. However, it has difficulty targeting liver mitochondria because of its high hydrophobicity and low bioavailability. To address the therapeutic limitations of CoQ₁₀ caused by poor mitochondrial bioavailability, this study aimed to establish a rational design to systematically evaluate how particle size and lipid composition influence the therapeutic efficacy of CoQ₁₀-loaded nanocarriers on APAP-induced liver injury (AILI). Three types of CoQ₁₀-loaded mitochondrial-targeted nanocarriers (CoQ₁₀-MITO-Porter) of different particle sizes (50, 100, 200 nm) and CoQ₁₀-LP, which mimics liposomes used in clinical applications, were prepared using a microfluidic device. These nanocarriers were administered to AILI model mice at early stages of disease, and their hepatic and mitochondrial accumulation, therapeutic impact on serum biomarkers, histological damage, and CoQ₁₀ delivery efficiency were evaluated systematically. The 50-nm CoQ₁₀-MITO-Porter showed the highest hepatoprotective efficacy, indicated by marked attenuation of serum alanine aminotransferase levels and reduced hepatic necrosis. The effect decreased with increasing particle size and was minimal for CoQ₁₀-LP. These results highlight the importance of systematic evaluation of nanocarrier physicochemical properties to achieve effective mitochondrial delivery of CoQ₁₀ in early-phase AILI. These findings are expected to serve as a foundation for the development of mitochondria-targeted nanomedicines that alleviate early-phase hepatic damage and may extend to other mitochondrial-related diseases.

对乙酰氨基酚（APAP）过量引起的肝损伤是一个严重的临床问题，主要由肝细胞线粒体功能障碍引起。辅酶Q10 （CoQ10）具有线粒体保护作用，被认为是一种很有前途的治疗候选者。然而，由于其高疏水性和低生物利用度，难以靶向肝脏线粒体。为了解决CoQ10因线粒体生物利用度差而导致的治疗局限性，本研究旨在建立合理设计，系统评估CoQ10纳米载体的粒径和脂质组成对apap诱导的肝损伤（AILI）治疗效果的影响。采用微流控装置制备了3种不同粒径（50、100、200 nm）的coq10 -线粒体靶向纳米载体（CoQ10-MITO-Porter）和临床应用中模拟脂质体的CoQ10-LP。这些纳米载体在疾病早期给予AILI模型小鼠，并系统评估其肝脏和线粒体积累，对血清生物标志物的治疗影响，组织学损伤和辅酶q10递送效率。50 nm的CoQ10-MITO-Porter显示出最高的肝保护效果，表明血清丙氨酸转氨酶水平明显降低，肝坏死减少。随着粒径的增大，效果逐渐减弱，对辅酶q10 - lp影响最小。这些结果强调了系统评估纳米载体的物理化学性质对于实现早期AILI中CoQ10的有效线粒体递送的重要性。这些发现有望为线粒体靶向纳米药物的开发奠定基础，这些药物可以缓解早期肝损伤，并可能扩展到其他线粒体相关疾病。

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引用次数: 0

Large and low-PEG lipid nanoparticles enable efficient dendritic cell targeting for potent mRNA Cancer vaccines 大的和低peg的脂质纳米颗粒使有效的树突状细胞靶向有效的mRNA癌症疫苗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-02 DOI: 10.1016/j.jconrel.2026.114680

Xiaolan Xu , Jiahao An , Dan Bai , Yuanchao Xu , Tingting Wu , Hua Yang , Yueyue Yan , Shaojun Yang , Zifan Wei , Yuchen Yao , Qian Liu , Tao Xu , Lan Zhu

Efficient delivery of messenger RNA (mRNA) to dendritic cells (DCs) remains a major challenge limiting the efficacy of mRNA cancer vaccines. Here, we report a large-sized lipid nanoparticle (LLNP) platform specifically engineered for enhanced DC targeting. By reducing PEG–lipid content to 0.3% and proportionally increasing the concentrations of structural lipids and mRNA sixfold relative to the Moderna classic formulation, we generated LLNPs with enlarged size and optimized surface properties that favor DC uptake. Following intravenous administration, LLNPs achieved markedly enhanced mRNA expression in DCs, with ∼82% of GFP⁺ cells identified as DCs and ∼ 44% of CD11c⁺ DCs expressing GFP. LLNPs also promoted DC maturation and antigen presentation. LLNP-mediated delivery of HPV16 E6E7 mRNA elicited robust effector and memory cytotoxic T lymphocyte responses, enabling effective tumor regression at doses as low as 1 μg. Both conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells contributed to antigen presentation, with cDC1 playing the predominant role. Compared with BioNTech's RNA–lipoplex delivery platform, LLNPs demonstrated superior DC transfection, T cell activation, and antitumor efficacy. Collectively, these findings establish LLNPs as a robust and versatile platform for next-generation mRNA cancer vaccines with enhanced therapeutic potential.

信使RNA （mRNA）向树突状细胞（DCs）的有效递送仍然是限制mRNA癌症疫苗效力的主要挑战。在这里，我们报告了一个专门设计用于增强DC靶向的大尺寸脂质纳米颗粒（LLNP）平台。通过将peg -脂质含量降低至0.3%，并将结构脂质和mRNA的浓度按比例增加六倍（相对于Moderna经典配方），我们生成了尺寸增大、表面性能优化的LLNPs，有利于DC的摄取。静脉给药后，LLNPs显著增强了dc中mRNA的表达，约82%的GFP+细胞被鉴定为dc， ~ 44%的CD11c+ dc表达GFP。LLNPs也促进DC成熟和抗原提呈。llnp介导的HPV16 E6E7 mRNA的递送引起了强大的效应和记忆细胞毒性T淋巴细胞反应，使肿瘤在低至1 μg的剂量下有效消退。传统的1型树突状细胞（cDC1）和传统的2型树突状细胞都参与抗原呈递，其中cDC1起主要作用。与BioNTech的RNA-lipoplex递送平台相比，LLNPs表现出更好的DC转染、T细胞活化和抗肿瘤功效。总的来说，这些发现确立了llnp作为具有增强治疗潜力的下一代mRNA癌症疫苗的强大和通用平台。

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引用次数: 0

Genetically encoded self-assembling affibody-streptavidin nanoparticles for HER2-positive cancer theranostics 用于her2阳性癌症治疗的基因编码自组装修饰物-链亲和素纳米颗粒

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-02 DOI: 10.1016/j.jconrel.2026.114679

Anastasiia S. Obozina , Anna M. Iureva , Alexandr A. Kotov , Sergey M. Deyev , Egor S. Korenkov , Victoria O. Shipunova

Targeted therapy is a revolutionary approach in cancer treatment, enabling the precise elimination of malignant cells with fewer side effects than conventional chemotherapy. Among clinically approved strategies, antibody-drug conjugates (ADCs) and immunotoxins represent a rapidly expanding class of biotherapeutics, often serving as theranostic tools when linked to diagnostic components. However, their production requires complex chemical conjugation, making it a technically and economically demanding process. Similarly, nanoparticle-based systems offer targeted delivery but usually rely on multi-step, poorly reproducible syntheses. Here, we introduce a novel type of genetically encoded self-assembling protein nanoparticles with targeting functionality. These nanometer-sized particles, which we propose to term “avisomes”, self-assemble upon refolding of a fusion protein comprising the HER2-specific affibody Z_HER2:342 and streptavidin (Z_HER2:342-Strp), combining the strengths of bioconjugates and nanoparticles while avoiding the drawbacks of chemical synthesis. Importantly, they are easily and reproducibly synthesized in E. coli. HER2 recognition was confirmed by flow cytometry and fluorescence microscopy. To confer cytotoxic activity, avisomes were loaded with doxorubicin (DOX), yielding Z_HER2:342-Strp-DOX nanoparticles that selectively killed HER2-overexpressing cells in vitro. In vivo, treatment with Z_HER2:342-Strp-DOX significantly suppressed the growth of HER2-positive tumors in BALB/c mice. Notably, therapy was well tolerated, with no abnormal hematological or biochemical changes, and it alleviated DOX-induced neutropenia. These findings establish avisomes as a highly promising theranostic platform for HER2-positive breast cancer. Its genetically encoded, self-assembling nature eliminates the major limitations of ADCs and synthetic nanoparticles, providing a scalable, reproducible, and cost-efficient alternative for next-generation targeted cancer therapy.

靶向治疗是一种革命性的癌症治疗方法，能够精确消除恶性细胞，副作用比传统化疗少。在临床批准的策略中，抗体-药物偶联物（adc）和免疫毒素代表了快速扩展的一类生物治疗药物，通常作为与诊断成分相结合的治疗工具。然而，它们的生产需要复杂的化学偶联，使其成为技术和经济上要求很高的过程。同样，基于纳米颗粒的系统提供靶向递送，但通常依赖于多步骤，可重复性差的合成。在这里，我们介绍了一种具有靶向功能的新型基因编码自组装蛋白质纳米颗粒。这些纳米大小的颗粒，我们将其称为“亲和体”，在包含her2特异性粘附体ZHER2:342和链亲和素（ZHER2:342- strp）的融合蛋白的重新折叠后自组装，结合了生物偶联物和纳米颗粒的优点，同时避免了化学合成的缺点。重要的是，它们很容易在大肠杆菌中合成。流式细胞术和荧光显微镜证实了HER2的识别。为了赋予细胞毒活性，我们将多柔比星（DOX）加载到aviissomes中，生成her2:342-带状DOX纳米颗粒，选择性地杀死体外过表达her2的细胞。在体内，用her2:342- strp - dox治疗可显著抑制BALB/c小鼠her2阳性肿瘤的生长。值得注意的是，治疗耐受性良好，没有异常的血液学或生化变化，并减轻了dox诱导的中性粒细胞减少症。这些发现表明，对于her2阳性乳腺癌，avisomes是一个非常有前景的治疗平台。其基因编码、自组装的特性消除了adc和合成纳米颗粒的主要限制，为下一代靶向癌症治疗提供了可扩展、可重复且经济高效的替代方案。

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引用次数: 0

Delivery science: Its increasing importance for the next generation of medicines 给药科学：它对下一代药物越来越重要

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-01-31 DOI: 10.1016/j.jconrel.2026.114663

Marianne Ashford , Annette Bak

The therapeutic landscape has diversified beyond traditional small molecules to encompass a plethora of different modalities including antibodies, peptides and nucleic acids as well as more complex small molecules. Increasingly heterofunctional molecules, targeted drug conjugates, including antibody drug conjugates, oligonucleotide drug conjugates and radionuclide conjugates, are being used to improve efficacy, reduce side effects and enable lower doses. These diverse modalities present distinct delivery needs. This perspective briefly reflects on the main drug modality classes, their delivery challenges and summarises the current delivery solutions and trends including amorphous solid dispersions, long acting injectables, approaches to high concentration subcutaneous delivery of biologics and lipid nanoparticles for delivery of mRNA. There is a continual drive for more patient centric formulations. We argue that this modality evolution heightens the importance of drug delivery as a core design parameter in discovery rather than as a downstream fix. Across modalities, targeted delivery remains pivotal to improve therapeutic index and to lower dose and environmental footprint. Translational success requires early collaboration among preclinical safety, CMC, clinical, and regulatory teams to define critical quality attributes and develop in vitro/in silico tools for predicting in vivo performance. Delivery science is positioned to play a leading role in enabling the next generation of medicines, accelerating translation, and improving patient outcomes.

治疗领域已经超越了传统的小分子，包括抗体、多肽、核酸以及更复杂的小分子等多种不同的形式。越来越多的异功能分子、靶向药物偶联物，包括抗体药物偶联物、寡核苷酸药物偶联物和放射性核素偶联物，正被用于提高疗效、减少副作用和降低剂量。这些不同的模式呈现出不同的交付需求。这一观点简要地反映了主要的药物形态类别，它们的递送挑战，并总结了当前的递送解决方案和趋势，包括无定形固体分散体、长效注射剂、高浓度皮下递送生物制剂的方法和用于递送mRNA的脂质纳米颗粒。人们不断推动以患者为中心的配方。我们认为，这种模式的演变提高了药物递送作为发现的核心设计参数的重要性，而不是作为下游修复。在各种模式中，靶向给药仍然是提高治疗指数和降低剂量和环境足迹的关键。转化的成功需要临床前安全、CMC、临床和监管团队之间的早期合作，以确定关键的质量属性，并开发用于预测体内性能的体外/硅工具。交付科学将在实现下一代药物、加速转化和改善患者预后方面发挥主导作用。

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引用次数: 0

Smart hypoxia-responsive sulfated polysaccharides liposomes for controlled and targeted urokinase delivery in thrombotic therapy 智能低氧反应硫酸多糖脂质体控制和靶向尿激酶输送在血栓治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-01-30 DOI: 10.1016/j.jconrel.2026.114669

Dingfu Wang , Dan Li , Xiaolin Liu , Shixin Wang , Yile Fan , Ling Lu , Chuanbin Shen , Chunxia Li

Thrombosis remains a leading cause of cardiovascular and cerebrovascular mortality worldwide. Plasminogen activators, notably urokinase and alteplase, have been established as standard thrombolytic agents in clinical practice. However, their therapeutic potential is severely compromised by rapid metabolic clearance, non-specific biodistribution, and associated hemorrhagic complications. Here, we designed a dual-functional nano drug delivery platform that leverages P-selectin overexpression on activated platelets and the characteristic hypoxic microenvironment at thrombotic sites for precision thrombolytic intervention. Specifically, we developed a hypoxia-responsive block (PAC) by conjugating polyguluronate sulfate (PGS, P-selectin targeting motif) with azobenzene-modified cholesterol, enabling urokinase encapsulation within PAC@UK liposomes. Under hypoxic conditions that mimic the thrombotic microenvironment, the reductive cleavage of azobenzene moieties initiated sustained urokinase release (96.41% cumulative release), while maintaining exceptional biocompatibility and demonstrating preferential targeting of activated platelets. Comprehensive in vivo validation across zebrafish, murine mesenteric, and carotid artery thrombosis models revealed markedly enhanced thrombolytic efficacy compared to free UK. This biomimetic nanoplatform represents a paradigm shift toward intelligent, site-specific thrombolytic intervention, offering substantial clinical promise for safer and more effective treatment of thrombotic disorders.

血栓形成仍然是全世界心脑血管死亡的主要原因。纤溶酶原激活剂，特别是尿激酶和阿替普酶，在临床实践中已被确立为标准的溶栓药物。然而，它们的治疗潜力受到快速代谢清除、非特异性生物分布和相关出血并发症的严重损害。在这里，我们设计了一个双重功能的纳米药物递送平台，利用活化血小板上p选择素的过表达和血栓形成部位特有的缺氧微环境来进行精确的溶栓干预。具体来说，我们通过将聚古脲酸盐（PGS， p -选择素靶向基序）与偶氮苯修饰的胆固醇偶联开发了一种缺氧反应阻滞（PAC），使尿激酶包封在PAC@UK脂质体中。在模拟血栓形成微环境的缺氧条件下，偶氮苯部分的还原裂解启动了持续的尿激酶释放（96.41%的累积释放），同时保持了卓越的生物相容性，并显示出对活化血小板的优先靶向性。在斑马鱼、小鼠肠系膜和颈动脉血栓形成模型中进行的全面体内验证显示，与游离UK相比，溶栓效果显著增强。这种仿生纳米平台代表了向智能、位点特异性溶栓干预的范式转变，为更安全、更有效地治疗血栓性疾病提供了实质性的临床前景。

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引用次数: 0

Intranasal delivery of peptide-modified quercetin liposomes suppresses neuroinflammation 经鼻内递送肽修饰的槲皮素脂质体可抑制神经炎症

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-01-30 DOI: 10.1016/j.jconrel.2026.114678

Changfeng Yin , Guanglin Liu , Xiqian Yuan , Yumeng Zhang , Yushan Tian , Xiao Li , Ling'e Zhang , Xiqun Jiang , Huan Chen , Hongwei Hou , Qingyuan Hu

Neuroinflammation, a central pathological mechanism in central nervous system disorders, remains challenging to treat due to the restrictive nature of the blood-brain barrier and poor drug delivery efficiency. In this study, we developed a novel intranasal brain-targeted delivery system by constructing peptide-modified quercetin liposomes (QuR-lipo). By using intranasal administration to bypass the blood-brain barrier, QuR-lipo demonstrated higher uptake and accumulation in the brain compared to unmodified liposomes. This system disrupts the vicious cycle between neuroinflammation and oxidative stress, thereby improving neurobehavioral outcomes. QuR-lipo displayed a uniform particle size distribution, high encapsulation efficiency, and sustained-release characteristics. In vitro studies showed that QuR-lipo enhanced intracellular drug accumulation by modulating endocytic pathways, effectively inhibited aberrant microglial activation, suppressed pro-inflammatory cytokine cascades, and scavenged reactive oxygen species. In a lipopolysaccharide-induced neuroinflammation animal model, intranasal delivery of QuR-lipo significantly increased brain drug concentration, improved spatial memory deficits and depression-like behaviors, and suppressed microglial activation. Mechanistic studies revealed that QuR-lipo reversed neurological dysfunction by inhibiting the inflammasome signaling axis. Together, these findings provide an innovative strategy for brain-targeted delivery of natural bioactive compounds to treat neurodegenerative diseases.

神经炎症是中枢神经系统疾病的一种中枢病理机制，由于血脑屏障的限制性和较差的药物传递效率，神经炎症的治疗仍然具有挑战性。在这项研究中，我们通过构建肽修饰的槲皮素脂质体（QuR-lipo），开发了一种新的鼻内脑靶向递送系统。通过鼻内给药绕过血脑屏障，与未经修饰的脂质体相比，qur -脂质体在大脑中的吸收和积累更高。这个系统破坏了神经炎症和氧化应激之间的恶性循环，从而改善了神经行为的结果。QuR-lipo具有粒径分布均匀、包封效率高、缓释等特点。体外研究表明，qur -脂质通过调节内吞途径增强细胞内药物积累，有效抑制异常小胶质细胞活化，抑制促炎细胞因子级联反应，清除活性氧。在脂多糖诱导的神经炎症动物模型中，经鼻给药可显著提高脑药物浓度，改善空间记忆缺陷和抑郁样行为，并抑制小胶质细胞激活。机制研究表明，QuR-lipo通过抑制炎性体信号轴逆转神经功能障碍。总之，这些发现为大脑靶向递送天然生物活性化合物以治疗神经退行性疾病提供了一种创新策略。

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引用次数: 0

Pathology-responsive light-triggered conjunctival adhesive implantable hydrogels for effective anti-scarring after glaucoma filtering surgery 病理反应性光触发结膜黏附植入式水凝胶用于青光眼滤过术后有效抗瘢痕形成

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-01-30 DOI: 10.1016/j.jconrel.2026.114677

Xianmin Shi , Zijun Lin , Danni Xiao, Wanzhen Li, Jue Wang, Yuanfeng He, Conghan Wang, Gengsheng Ye, Yao Liu, Yanjuan Huang, Chunshun Zhao

Glaucoma filtration surgery (GFS) frequently fails due to uncontrolled subconjunctival scarring, driven by a cascade of postoperative inflammation, oxidative stress, and exaggerated myofibroblast activation. To address this, we developed an in-situ light-triggered hydrogel that enables strong conjunctival adhesion, bleb mechanical support, and pathology-responsive smart drug delivery for effective bleb scarring inhibition. The crosslinked hydrogel system prepared from functionalized carboxymethyl chitosan and epigallocatechin gallate (EGCG), prior to ultraviolet light (UV) exposure, was denoted as PNE hydrogel. After injection, PNE can adapt to ocular anatomy, and subsequent transconjunctival light exposure rapidly activates hydrogel crosslinking and covalent tissue adhesion, generating a mechanically robust hydrogel, denoted as PNE-UV hydrogel. Meanwhile, light-induced surface property changes further enhance conjunctival adhesion and reduce interface inflammatory cell infiltration. Concurrently, light-induced hydrophilic-to-hydrophobic hydrogel surface transition promotes water exclusion, further enhancing tissue adhesion to minimize interface inflammatory cell infiltration. With adequate mechanical strength, rapid self-healing, and good biosafety, PNE-UV provides essential mechanical bleb support during wound healing. Crucially, elevated postoperative reactive oxygen species (ROS) triggers intelligent EGCG release for over 17 days, which not only effectively scavenges ROS and promotes macrophage M1-to-M2 polarization to mitigate inflammation, but also suppresses TGF-β1-induced conjunctival fibroblast-to-myofibroblast transdifferentiation and myofibroblast proliferation. In a rabbit model of filtration surgery, PNE-UV hydrogel significantly prolonged bleb survival, reduced intraocular pressure, and decreased collagen deposition via mitigating oxidative stress and inflammation and suppressing fibrotic processes. Collectively, this interfacial adhesion and precise immunomodulation hydrogel presents an effective and clinically translatable strategy for post-GFS scarring prevention.

青光眼滤过手术（GFS）经常因结膜下瘢痕不受控制而失败，这是由术后炎症、氧化应激和肌成纤维细胞激活的级联反应驱动的。为了解决这个问题，我们开发了一种原位光触发水凝胶，它具有很强的结膜粘附性，水泡机械支持和病理反应智能药物递送，可有效抑制水泡瘢痕形成。将羧甲基壳聚糖与表没食子儿茶素没食子酸酯（EGCG）经紫外线照射制备的交联水凝胶体系命名为PNE水凝胶。PNE注射后能够适应眼部解剖结构，随后经结膜光照射迅速激活水凝胶交联和共价组织粘连，生成机械坚固的水凝胶，称为PNE- uv水凝胶。同时，光诱导的表面性质变化进一步增强结膜粘连，减少界面炎症细胞浸润。同时，光诱导的亲水性到疏水性的水凝胶表面转变促进了水的排斥，进一步增强了组织粘连，减少了界面炎症细胞的浸润。PNE-UV具有足够的机械强度，快速自愈和良好的生物安全性，在伤口愈合过程中提供必要的机械气泡支持。至关重要的是，术后活性氧（ROS）升高触发EGCG智能释放超过17天，不仅有效清除ROS，促进巨噬细胞m1 - m2极化减轻炎症，而且抑制TGF-β1诱导的结膜成纤维细胞向肌成纤维细胞转分化和肌成纤维细胞增殖。在兔滤过手术模型中，PNE-UV水凝胶通过减轻氧化应激和炎症以及抑制纤维化过程，显著延长水泡存活时间，降低眼压，减少胶原沉积。总的来说，这种界面粘附和精确的免疫调节水凝胶为gfs后疤痕预防提供了一种有效的临床可翻译策略。

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引用次数: 0

An elastase-responsive "plug-and-play" quercetin-loaded engineered extracellular vesicle platform anchored with anti-PRDX1 antibody for severe acute pancreatitis therapy 一种弹性酶响应“即插即用”的槲皮素负载工程细胞外囊泡纳米平台，用于治疗严重急性胰腺炎

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-01-30 DOI: 10.1016/j.jconrel.2026.114676

Wenjie Xu , Qiong Liu , Junyong Wu , Beibei Cui , Yucheng Tang , Xinyan Hao , Ruyue Han , Hai Huang , Mengen Guo , Xuyang Hou , Jun He

Severe acute pancreatitis (SAP) is a lethal inflammatory disease driven by a severely disregulated redox state, in which Peroxiredoxin 1 (PRDX1) acts as a key but paradoxical regulator. PRDX1 is a protective intracellular antioxidant, however, it acts as a pro-inflammatory DAMP extracellularly. To address this, we developed a “plug-and-play” therapeutic platform. Considering the microenvironment in SAP, we first engineered HEK-293 T cells to overexpress a CD63-Z domain fusion protein, yielding extracellular vesicles (EVs) capable of high-affinity binding to the Fc region of various antibodies. We then armed these EVs with an anti-PRDX1 antibody via an elastase-responsive linker and co-loaded them with quercetin (Ab-Fc-EL-EV@Que). After active pancreatic targeting, locally concentrated elastase triggered antibody release from the Ab-Fc-EL-EV@Que. to neutralize extracellular PRDX1, which has been confirmed to activate the TLR/NF-κB pathway in macrophages, thereby suppressing the inflammatory cascade. Subsequently, the antibody-detached EVs were internalized by acinar cells, delivering Que. to promote intracellular PRDX1 acetylation, enhance antioxidant capacity, and ultimately protect acinar cells from ferroptosis and apoptosis. This work not only offers a potent, multi-mechanistic modality for SAP by resolving the PRDX1 paradox but also establishes a highly adaptable “plug-and-play” platform for tailored therapies against other complex diseases.

严重急性胰腺炎（SAP）是一种由氧化还原状态严重失调驱动的致死性炎症性疾病，其中过氧化物还氧蛋白1 （PRDX1）是一个关键但矛盾的调节剂。PRDX1是一种保护性的细胞内抗氧化剂，然而，它在细胞外作为一种促炎的DAMP。为了解决这个问题，我们开发了一个“即插即用”的治疗平台。考虑到SAP的微环境，我们首先设计了HEK-293 T细胞，使其过表达CD63-Z结构域融合蛋白，产生能够与各种抗体Fc区高亲和力结合的细胞外囊泡（ev）。然后，我们通过弹性酶应答连接器将抗prdx1抗体武装这些ev，并将槲皮素共同装载在它们身上（Ab-Fc-EL-EV@Que）。活性胰腺靶向后，局部浓缩的弹性酶触发抗体从Ab-Fc-EL-EV@Que释放。中和细胞外PRDX1， PRDX1已被证实在巨噬细胞中激活TLR/NF-κB通路，从而抑制炎症级联。随后，分离抗体的ev被腺泡细胞内化，传递Que。促进细胞内PRDX1乙酰化，增强抗氧化能力，最终保护腺泡细胞免于铁凋亡和凋亡。这项工作不仅通过解决PRDX1悖论为SAP提供了一种有效的多机制模式，而且还建立了一个高度适应性的“即插即用”平台，用于针对其他复杂疾病的定制治疗。

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引用次数: 0