Biomimetic Nanoregulators Mediated Tyrosine Hydroxylase mRNA and Stimulator of Interferon Genes Antagonist Codelivery for Synergistic Therapy on Parkinson's Disease
Degeneration of dopaminergic neurons in substantia nigra and neuroinflammation caused by microglia is one of the basic pathological features of Parkinson's disease (PD). Currently, therapeutic strategies that enhance dopaminergic neuronal function while simultaneously mitigating neuroinflammation hold great promise but face significant challenges in clinical application. To address these challenges, we developed a neuron-derived exosome biomimetic multifunctional nanoregulator codelivered tyrosine hydroxylase (TH) mRNA and stimulator of interferon genes (STING) antagonist. This nanoregulator system simultaneously delivers TH mRNA to enhance dopaminergic neuronal function and activity while incorporating the STING antagonist H-151 to promote microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, effectively suppressing neuroinflammation. Both in vitro and in vivo studies demonstrate that via mRNA therapy can precisely target and regulate dopamine (DA) synthesis, and that combined anti-inflammatory treatment effectively enhances this effect, significantly alleviating motor dysfunction in PD mice. Our findings present an effective approach for the development of PD medications and the advanced delivery of mRNA nanomedicines. This innovative nanoregulator represents a promising therapeutic strategy for managing neuroinflammation and improving dopaminergic neuronal function in PD by merging mRNA-based gene therapy with neuroinflammation modulation, addressing DA deficiency at its root and overcoming the current treatment obstacles in PD.
基金:
National Natural Science Foundation of China [82171935]; National Natural Science Foundation of China [2024J010027]; Natural Science Foundation of Fujian Province [2023Y9009]; Joint Funds for the Innovation of Science and Technology Fujian Province [2024ZD01002]; Major Science and Technology Project of Fujian Provincial Health Commission
第一作者机构:[1]Capital Med Univ, Beijing Tiantan Hosp, Dept Ultrasound, Beijing 100070, Peoples R China[2]Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China
通讯作者:
通讯机构:[4]Capital Med Univ, Xuanwu Hosp, Dept Radiol & Nucl Med, Beijing 100053, Peoples R China[5]Fujian Med Univ, Sch Basic Med Sci, Fujian Prov Key Lab Brain Aging & Neurodegenerat, Fuzhou 350122, Fujian, Peoples R China
推荐引用方式(GB/T 7714):
Yang Lizhi,Li Shuo,Hou Chao,et al.Biomimetic Nanoregulators Mediated Tyrosine Hydroxylase mRNA and Stimulator of Interferon Genes Antagonist Codelivery for Synergistic Therapy on Parkinson's Disease[J].ACS NANO.2025,19(38):33734-33748.doi:10.1021/acsnano.5c00694.
APA:
Yang, Lizhi,Li, Shuo,Hou, Chao,Zhang, Yukang,Cheng, Linggang...&Zhang, Wei.(2025).Biomimetic Nanoregulators Mediated Tyrosine Hydroxylase mRNA and Stimulator of Interferon Genes Antagonist Codelivery for Synergistic Therapy on Parkinson's Disease.ACS NANO,19,(38)
MLA:
Yang, Lizhi,et al."Biomimetic Nanoregulators Mediated Tyrosine Hydroxylase mRNA and Stimulator of Interferon Genes Antagonist Codelivery for Synergistic Therapy on Parkinson's Disease".ACS NANO 19..38(2025):33734-33748