A ROS-Responsive nanoparticle for nuclear gene delivery and autophagy restoration in Parkinson's disease therapy

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2025-04-15 DOI:10.1016/j.biomaterials.2025.123345

Limin Zhai , Yifei Gao , Hao Yang , Haoyuan Wang , Beining Liao , Yuxue Cheng , Chao Liu , Jingfeng Che , Kunwen Xia , Lingkun Zhang , Yanqing Guan

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引用次数: 0

Abstract

Parkinson's disease (PD) is characterized by the pathological aggregation of α-synuclein (α-syn) and neuroinflammation. Current gene therapies face challenges in nuclear delivery and resolving pre-existing α-syn aggregates. Here, we developed glucose-and trehalose-functionalized carbonized polymer dots (GT-PCDs) loaded with plasmid DNA (pDNA) for targeted gene delivery and autophagy restoration. The GT-PCDs@pDNA nanoparticles exhibit reactive oxygen species (ROS)-responsive behavior, enabling efficient nuclear entry under oxidative stress conditions. Both in vitro and in vivo studies demonstrated that GT-PCDs@pDNA effectively silenced SNCA gene expression, reduced α-syn aggregates, and restored autophagic flux by promoting transcription factor EB (TFEB) nuclear translocation. Moreover, GT-PCDs@pDNA enhanced blood-brain barrier (BBB) permeability via glucose transporter 1 (Glut-1)-mediated transcytosis, significantly improving motor deficits and reducing neuroinflammation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. This multifunctional nanocarrier system offers a promising strategy for combined gene therapy and autophagy modulation in neurodegenerative diseases.

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用于帕金森病治疗的核基因传递和自噬修复的ros响应纳米颗粒

帕金森病（PD）以α-突触核蛋白（α-syn）的病理聚集和神经炎症为特征。目前的基因治疗在核传递和解决预先存在的α-syn聚集方面面临挑战。在这里，我们开发了葡萄糖和海藻糖功能化的碳化聚合物点（GT-PCDs），装载质粒DNA (pDNA)，用于靶向基因传递和自噬恢复。GT-PCDs@pDNA纳米颗粒表现出活性氧（ROS）响应行为，能够在氧化应激条件下有效进入核。体外和体内研究均表明，GT-PCDs@pDNA通过促进转录因子EB （TFEB）核易位，有效地沉默SNCA基因表达，降低α-syn聚集，恢复自噬通量。此外，GT-PCDs@pDNA通过葡萄糖转运蛋白1 （Glut-1）介导的胞吞作用增强血脑屏障（BBB）的通透性，在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中显著改善运动缺陷并减少神经炎症。这种多功能纳米载体系统为神经退行性疾病的基因治疗和自噬调节联合治疗提供了一种很有前景的策略。

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来源期刊

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.