| Autor: |
Kang Qian, Xiaoyan Bao, Yixian Li, Pengzhen Wang, Qian Guo, Peng Yang, Shuting Xu, Fazhi Yu, Ran Meng, Yunlong Cheng, Dongyu Sheng, Jinxu Cao, Minjun Xu, Jing Wu, Tianying Wang, Yonghui Wang, Qiong Xie, Wei Lu, Qizhi Zhang |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
ACS nano. 16(7) |
| ISSN: |
1936-086X |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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