肽
神经保护
胆碱能的
高磷酸化
线粒体
细胞生物学
化学
生物化学
药理学
生物
激酶
神经科学
作者
Kan Qian,Xiaoyan Bao,Yixian Li,Pengzhen Wang,Qin Guo,Peng Yang,Shuting Xu,Fazhi Yu,Ran Meng,Yunlong Cheng,Dongyu Sheng,Jinxu Cao,Min-Jun Xu,Jing Wu,Tianying Wang,Yonghui Wang,Qiong Xie,Wei Lü,Qizhi Zhang
出处
期刊:ACS Nano
[American Chemical Society]
日期:2022-07-15
卷期号:16 (7): 11455-11472
被引量:20
标识
DOI:10.1021/acsnano.2c05795
摘要
Mitochondrial dysfunction in neurons has recently become a promising therapeutic target for Alzheimer’s disease (AD). Regulation of dysfunctional mitochondria through multiple pathways rather than antioxidation monotherapy indicates synergistic therapeutic effects. Therefore, we developed a multifunctional hybrid peptide HNSS composed of antioxidant peptide SS31 and neuroprotective peptide S14G-Humanin. However, suitable peptide delivery systems with excellent loading capacity and effective at-site delivery are still absent. Herein, the nanoparticles made of citraconylation-modified poly(ethylene glycol)-poly(trimethylene carbonate) polymer (PEG-PTMC(Cit)) exhibited desirable loading of HNSS peptide through electrostatic interactions. Meanwhile, based on fibroblast growth factor receptor 1(FGFR1) overexpression in both the blood–brain barrier and cholinergic neuron, an FGFR1 ligand-FGL peptide was modified on the nanosystem (FGL-NP(Cit)/HNSS) to achieve 4.8-fold enhanced accumulation in brain with preferred distribution into cholinergic neurons in the diseased region. The acid-sensitive property of the nanosystem facilitated lysosomal escape and intracellular drug release by charge switching, resulting in HNSS enrichment in mitochondria through directing of the SS31 part. FGL-NP(Cit)/HNSS effectively rescued mitochondria dysfunction via the PGC-1α and STAT3 pathways, inhibited Aβ deposition and tau hyperphosphorylation, and ameliorated memory defects and cholinergic neuronal damage in 3xTg-AD mice. The work provides a potential platform for targeted cationic peptide delivery, harboring utility for peptide therapy in other neurodegenerative diseases.
科研通智能强力驱动
Strongly Powered by AbleSci AI