Journal of Controlled Release最新文献_第6页

A hydrogen generator enhances immunogenic transarterial chemoembolization in hepatocellular carcinoma 氢发生器增强肝细胞癌经动脉化疗栓塞的免疫原性

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-06 DOI: 10.1016/j.jconrel.2026.114694

Lei Cao (1) , Li Ren (1) , Longlin Yin (1) , Ping Xie , Guangyin Qiu , Tao Lu , Xueqing Huang , Wenhao Li , Wencheng Wu , Kun Zhang , Shi Zhou

Conventional transarterial chemoembolization (TACE) regimens for hepatocellular carcinoma (HCC) are often compromised in efficacy due to hypoxia and acidosis within the tumor microenvironment (TME), frequently leading to unsatisfactory treatment outcomes and tumor recurrence. To overcome these limitations, this study introduces an innovative approach by incorporating a hydrogen generator (calcium hydride, CaH₂) into an epirubicin (EPI)–iodized oil embolization system. This design enables local hydrogen release to remodel the TME following TACE, thereby enhancing the combined chemo-immunotherapeutic antitumor response. Nano-CaH₂ particles, co-delivered locally via TACE, undergo hydrolysis to continuously release hydrogen gas (H₂) and calcium ions (Ca²⁺). This reaction disrupts mitochondrial function in cancer cells, reduces oxygen consumption, alleviates tumor hypoxia, and consequently counteracts chemoresistance. Simultaneously, EPI induces immunogenic cell death (ICD) in moribund tumor cells, activating the host's antitumor immune response. Additionally, the hydroxide ions generated from CaH₂ hydrolysis neutralize the acidic TME, alleviating immunosuppression and further amplifying the chemo-immunotherapeutic synergy mediated by TACE. This strategy presents a novel method to improve TACE efficacy and facilitate its integration with immunotherapy, demonstrating considerable potential for clinical translation.

传统的经动脉化疗栓塞（TACE）治疗肝细胞癌（HCC）方案往往由于肿瘤微环境（TME）缺氧和酸中毒而降低疗效，经常导致治疗效果不理想和肿瘤复发。为了克服这些限制，本研究引入了一种创新的方法，将氢发生器（氢化钙，CaH₂）纳入表阿霉素（EPI）碘化油栓塞系统。这种设计使局部氢释放能够在TACE后重塑TME，从而增强化疗-免疫治疗联合抗肿瘤反应。纳米cah₂颗粒通过TACE局部共递送，经过水解连续释放氢气（H₂）和钙离子（Ca2+）。这种反应破坏了癌细胞的线粒体功能，减少了氧气消耗，减轻了肿瘤缺氧，从而抵消了化疗耐药性。同时，EPI诱导垂死肿瘤细胞的免疫原性死亡（ICD），激活宿主的抗肿瘤免疫应答。此外，CaH 2水解产生的氢氧根离子中和了酸性TME，减轻了免疫抑制，进一步增强了TACE介导的化学-免疫治疗协同作用。该策略提供了一种提高TACE疗效并促进其与免疫治疗结合的新方法，显示出相当大的临床转化潜力。

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引用次数: 0

Self-amplifying pyroptosis nanoinducers enhance cancer immunotherapy through inflammasome priming and activation 自扩增焦亡纳米诱导剂通过炎性体的启动和激活增强癌症免疫治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-05 DOI: 10.1016/j.jconrel.2026.114689

Wenyu Zhang , Changshun Huang , Chengzhilin Li , Xinyu Wang , Ying Qu , Wenlong Duan , Yingyu Hou , Yingchun Zhao , Qingbin He , Jianwei Jiao , Zhengwei Liu , Runxiao Zheng

Pyroptosis, a unique type of inflammatory programmed cell death, has recently been identified as a promising therapeutic target for activating the immune system. Nevertheless, the effectiveness of pyroptosis in tumor immunotherapy is impeded by critical factors such as the failure to address nuclear factor-κB (NF-κB) priming, insufficient inflammasome activation, and limited light and oxygen penetration. To confront these challenges, we constructed crystalline dendritic mesoporous gadolinium oxide (DM-Gd₂O₃ nanoparticles) loaded with a peroxyoxalate-based chemiluminescence system and encapsulated by calcium carbonate (CaCO₃) nanoparticles to form self-amplifying pyroptosis nanoinducers. Within the tumor microenvironment (TME), the release of pH-responsive calcium (Ca²⁺) and gadolinium ions (Gd³⁺) promotes the priming of NF-κB and disrupts lysosomal membrane phosphate groups, thereby inducing lysosomal rupture. Additionally, bis(3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl) oxalate (CPPO) reacts with hydrogen peroxide (H₂O₂) to form a high-energy intermediate that emits light, exciting chlorin e6 (Ce6) to produce singlet oxygen. This process overcomes the limitations of light penetration and tumor hypoxia, synergizes with pyroptosis, and triggers a strong antitumor immune response in vitro and in vivo. This study introduces a novel approach to the design of self-amplifying pyroptosis nanoinducers for tumor immunotherapy.

焦亡是一种独特类型的炎性程序性细胞死亡，最近被确定为激活免疫系统的有希望的治疗靶点。然而，在肿瘤免疫治疗中，焦细胞凋亡的有效性受到一些关键因素的阻碍，如未能解决核因子-κB （NF-κB）的启动，炎症小体激活不足，以及光和氧穿透有限。为了应对这些挑战，我们构建了晶体树突状介孔氧化钆（DM-Gd2O3纳米颗粒），负载过氧草酸盐基化学发光系统，并被碳酸钙（CaCO3）纳米颗粒包裹，形成自扩增的焦亡纳米诱导剂。在肿瘤微环境（TME）内，ph响应性钙（Ca2+）和钆离子（Gd3+）的释放促进NF-κB的启动，破坏溶酶体膜磷酸基团，从而诱导溶酶体破裂。此外，二（3,4,6-三氯-2-（戊氧羰基）苯基）草酸盐（CPPO）与过氧化氢（H2O2）反应形成发光的高能中间体，激发氯e6 （Ce6）产生单线态氧。这一过程克服了光穿透和肿瘤缺氧的限制，与焦亡协同作用，在体外和体内引发了强烈的抗肿瘤免疫反应。本研究介绍了一种设计用于肿瘤免疫治疗的自扩增焦亡纳米诱导剂的新方法。

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引用次数: 0

Selective tumor lysis by charge-alternating spherical membrane-lytic peptide bottlebrushes via redox backbone degradation and pH-gated unmasking 电荷交替球形膜解肽瓶刷通过氧化还原主干降解和ph门控解掩膜的选择性肿瘤裂解

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-05 DOI: 10.1016/j.jconrel.2026.114692

Lubin Ning , Rui Xu , Chaoke Qin , Lei Sun , Liming Shao , Hongrui Zhang , Li Yan , Gengzhi Ren , Xiuying Sun , Hao Chang , Xiangdong Cheng , Fie Jia

The clinical utility of membrane-lytic peptides (MLPs) as cancer therapeutics is severely compromised by their inherent instability, rapid clearance, and non-specific toxicity, including hemolysis. We report a unimolecular nanoparticle platform, the Charge-Alternating Spherical MLP (CAS-MLP), engineered to overcome these barriers through a synergistic structural and chemical design. Structurally, MLPs are grafted as side chains onto a redox-responsive poly(disulfide) backbone, forming a bottlebrush architecture that enhances proteolytic stability and prolongs circulation. Chemically, the MLPs' lytic activity is temporarily neutralized using detachable charge-alternating (CA) reagents via maleamic anhydride-amine chemistry. This “smart” shielding minimizes hemolysis and off-target toxicity while also serving as a conjugation point for cancer-specific ligands, enabling precisely tuned targeting. This platform is designed for sequential intracellular activation: after ligand-mediated uptake, the acidic endosomal environment triggers CA reagent detachment, while the reductive cytosol degrades the poly(disulfide) backbone. This dual-stimuli-triggered disassembly selectively restores the MLP's lytic function inside the cancer cell. In vivo, the CAS-MLP platform demonstrates potent tumor growth suppression with negligible side effects. By leveraging the abundant lysine residues of MLPs, this approach provides a versatile and effective solution to key challenges in MLP-based therapy.

由于其固有的不稳定性、快速清除和非特异性毒性（包括溶血），膜溶肽（MLPs）作为癌症治疗药物的临床应用受到严重损害。我们报道了一种单分子纳米粒子平台，即电荷交替球形MLP (CAS-MLP)，通过协同结构和化学设计克服了这些障碍。在结构上，mlp作为侧链接枝到氧化还原反应的聚二硫骨架上，形成一个瓶刷结构，增强蛋白水解稳定性并延长循环时间。化学上，通过马来酸酐-胺化学，使用可分离的电荷交替（CA）试剂暂时中和MLPs的裂解活性。这种“智能”屏蔽可以最大限度地减少溶血和脱靶毒性，同时也可以作为癌症特异性配体的缀合点，从而实现精确调谐靶向。该平台设计用于连续的细胞内激活：在配体介导的摄取后，酸性内体环境触发CA试剂脱离，而还原性细胞质降解聚二硫烷骨架。这种双重刺激触发的分解选择性地恢复了MLP在癌细胞内的裂解功能。在体内，CAS-MLP平台显示出有效的肿瘤生长抑制作用，副作用可以忽略不计。通过利用mlp丰富的赖氨酸残基，该方法为mlp治疗中的关键挑战提供了一种通用且有效的解决方案。

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引用次数: 0

Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming 用于利拉鲁肽时空递送的可注射希夫碱工程水凝胶通过多模态微环境重编程协调糖尿病牙周炎的回归

IF 10.8 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-05 DOI: 10.1016/j.jconrel.2026.114688

Jiamin Li, Rongrong Li, Yan Zhou, Shengping Zheng, Jingjing Xu, Jingli Zhu, Yunqing Pang, Jing Wang

The treatment of diabetic periodontitis is significantly challenged by a pathological microenvironment characterized by hyperglycemia, proinflammatory cytokine storm, and excessive reactive oxygen species (ROS), with current therapeutic strategies offering limited efficacy and susceptibility to antibiotic resistance. Although liraglutide (LIRA) possesses multifaceted therapeutic potential, including glycemic control, anti-inflammation, antioxidation, and osteoprotection, its systemic administration fails to achieve effective local concentrations within periodontal tissues. To address this, we engineered an injectable carboxymethyl chitosan-oxidized dextran hydrogel (LIRA@CMCS-OD) via dynamic Schiff base bonds for localized LIRA delivery. This hydrogel exhibited excellent injectability, tissue adhesion, biocompatibility, and pH-responsive drug release kinetics. In vitro studies demonstrated that LIRA@CMCS-OD inhibited Porphyromonas gingivalis growth, effectively scavenged intracellular ROS in human periodontal ligament cells (hPDLCs), and robustly promoted hPDLCs osteogenic differentiation. In a diabetic periodontitis rat model, local application of LIRA@CMCS-OD significantly ameliorated gingival inflammation and tooth mobility, enhanced alveolar bone regeneration, and demonstrated favorable biosafety. By enabling sustained local drug release and orchestrating a synergistic “antibacterial action-antioxidation- osteogenic protection” mechanism, this LIRA-loaded injectable hydrogel presents a potent and safe therapeutic strategy for diabetic periodontitis.

糖尿病牙周炎的治疗受到以高血糖、促炎细胞因子风暴和过多活性氧（ROS）为特征的病理微环境的显著挑战，目前的治疗策略疗效有限，易受抗生素耐药性的影响。尽管利拉鲁肽（liraglutide， LIRA）具有多方面的治疗潜力，包括血糖控制、抗炎症、抗氧化和骨保护，但其全身给药不能在牙周组织内达到有效的局部浓度。为了解决这个问题，我们设计了一种可注射的羧甲基壳聚糖氧化右旋糖酐水凝胶（LIRA@CMCS-OD），通过动态希夫碱键来局部递送LIRA。该水凝胶具有良好的可注射性、组织粘附性、生物相容性和ph反应性药物释放动力学。体外研究表明LIRA@CMCS-OD抑制牙龈卟啉单胞菌生长，有效清除人牙周韧带细胞（hPDLCs）细胞内ROS，有力促进hPDLCs成骨分化。在糖尿病牙周炎大鼠模型中，局部应用LIRA@CMCS-OD可显著改善牙龈炎症和牙齿活动，促进牙槽骨再生，并显示出良好的生物安全性。通过实现持续的局部药物释放和协调协同“抗菌-抗氧化-成骨保护”机制，这种装载lira的可注射水凝胶为糖尿病牙周炎提供了一种有效而安全的治疗策略。

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引用次数: 0

New-generation advanced Nano-PROTACs as potential therapeutic agents in cancer therapy 新一代先进的纳米protacs作为潜在的治疗药物在癌症治疗中

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-04 DOI: 10.1016/j.jconrel.2026.114673

Jingjuan Zhang , Yongzheng Li , Huiyuan Jin , Peizhen Yang , Huan Min , Jian Song , Yingqiu Qi

Proteolysis targeting chimeras (PROTACs) are catalytic degraders that eliminate pathogenic proteins via the ubiquitin-proteasome system (UPS). Building on this mechanism, nano-engineered PROTACs (Nano-PROTACs) integrate PROTACs with rationally designed nanomaterials to create an emerging therapeutic platform for cancer. This integrative approach preserves the core capability of PROTACs to precisely degrade pathogenic proteins through the UPS, and also confers multiple therapeutic advantages including enhanced tissue targeting, improved membrane permeability, and controlled drug release, thereby significantly improving cancer therapeutic efficacy while effectively reducing systemic toxicity. This review provides a comprehensive overview of recent advances in Nano-PROTACs for cancer therapy, with a particular focus on the design strategies enabled by nanomaterial-based delivery systems, along with the applications in monotherapy and synergistic therapies. In addition, the therapeutic advantages and existing challenges of Nano-PROTACs are critically discussed, while delineating their potential future clinical applications, providing critical insights to the understanding of this emerging technology and offering novel perspectives for future development of precision therapeutics.

蛋白水解靶向嵌合体（PROTACs）是通过泛素-蛋白酶体系统（UPS）消除致病性蛋白的催化降解剂。基于这一机制，纳米工程PROTACs （Nano-PROTACs）将PROTACs与合理设计的纳米材料相结合，创造了一个新兴的癌症治疗平台。这种综合方法既保留了PROTACs通过泛素-蛋白酶体系统精确降解致病蛋白的核心能力，又具有增强组织靶向性、改善膜通透性、控制药物释放等多种治疗优势，从而在有效降低全身毒性的同时显著提高肿瘤治疗效果。本文综述了纳米protacs用于癌症治疗的最新进展，特别关注基于纳米材料的递送系统的设计策略，以及在单药治疗和协同治疗中的应用。此外，本文还对纳米protacs的治疗优势和存在的挑战进行了批判性的讨论，同时描述了其潜在的未来临床应用，为理解这一新兴技术提供了关键的见解，并为未来精确治疗的发展提供了新的视角。

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引用次数: 0

ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice apoe导向的CpG纳米免疫佐剂改善小鼠阿尔茨海默病样病理。

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-04 DOI: 10.1016/j.jconrel.2026.114687

Xin Huang , Yan-Yun Sun , Yi-Ren Qin , Hong Chen , Ting-Ting Pan , Song-Song Zhao , Qian Cai , Xiao-Shuo Zhang , Xiao-Dong Nie , Lei Feng , Hua Hu , Yong Tang , Pei-Zhuo Zhang , Zhi-Yuan Zhong , Jie Li , Li Lu , Feng-Hua Meng , Quan-Hong Ma

Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.

toll样受体9 （TLR9）在中枢神经系统的小胶质细胞和神经元中均有表达，是阿尔茨海默病（AD）的一个有希望的治疗靶点。虽然小胶质细胞或神经元的TLR9激活可以发挥神经保护作用，改善AD病理和保持认知功能，但CpG寡脱氧核苷酸（odn），合成激动剂，不能穿过血脑屏障（BBB）。为了克服这个问题，我们开发了tNCpG，一种载脂蛋白E （ApoE）功能化的聚合物纳米载体，用于脑靶向递送CpG ODNs。APP/PS1转基因小鼠过度表达人类突变体APP/PS1，广泛用于临床前研究的AD小鼠模型，从4 月龄开始，每两周静脉注射tNCpG，持续3 个月。tNCpG在特异性靶向小胶质细胞和神经元的同时实现了高效的脑递送。tNCpG治疗增强了小胶质细胞对Aβ斑块的募集和吞噬，抑制了Aβ的产生，同时促进了其降解，改善了血脑屏障的完整性和Aβ的外排。总的来说，这些作用显著减少了脑Aβ负荷、神经炎症和神经变性，从而挽救了认知缺陷。我们的研究建立了通过tNCpG靶向激活TLR9作为AD的一种疾病改善治疗策略。

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引用次数: 0

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。

{"title":"Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury","authors":"Mitsue Hibino, Yukari Muramatsu, Hideyoshi Harashima, Yuma Yamada","doi":"10.1016/j.jconrel.2026.114682","DOIUrl":"10.1016/j.jconrel.2026.114682","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose-induced liver damage is a serious clinical issue primarily caused by mitochondrial dysfunction in hepatocytes. Coenzyme Q<sub>10</sub> (CoQ<sub>10</sub>) 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 CoQ<sub>10</sub> 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 CoQ<sub>10</sub>-loaded nanocarriers on APAP-induced liver injury (AILI). Three types of CoQ<sub>10</sub>-loaded mitochondrial-targeted nanocarriers (CoQ<sub>10</sub>-MITO-Porter) of different particle sizes (50, 100, 200 nm) and CoQ<sub>10</sub>-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 CoQ<sub>10</sub> delivery efficiency were evaluated systematically. The 50-nm CoQ<sub>10</sub>-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 CoQ<sub>10</sub>-LP. These results highlight the importance of systematic evaluation of nanocarrier physicochemical properties to achieve effective mitochondrial delivery of CoQ<sub>10</sub> 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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114682"},"PeriodicalIF":11.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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