Tetrahedral framework nucleic acids inhibit A[beta]-mediated ferroptosis and ameliorate cognitive and synaptic impairments in Alzheimer's disease

• Published in: Journal of nanobiotechnology 2024-11, Vol.22 (1)
• Main Authors: Tan, Lu, Xie, Jiazhao, Liao, Chenqi, Li, Xiaoguang, Zhang, Weiyun, Cai, Changchun, Cheng, Liming, Wang, Xiong
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Apoptosis; Care and treatment; Complications and side effects; Health aspects; Nanoparticles; Nucleic acids
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-024-02963-x

Ferroptosis represents a nonapoptotic type of programmed cell death induced by excessive intracellular iron accumulation. Ferroptosis is an essential driver of the pathogenesis of Alzheimer's disease (AD). Tetrahedral framework nucleic acids (tFNAs) are a novel type of nanoparticle with superior antiapoptotic capacity and excellent biocompatibility. However, the effect of tFNAs on A[beta] triggered ferroptosis, cognitive and synaptic impairments in AD remains unknown. N2a cells were treated with A[beta] combined with/without tFNAs. Cell viability and levels of Fe.sup.2+, lipid peroxidation, MDA, LDH, and GSH were examined. RNA sequencing was applied to explore dysregulated ferroptosis related genes. Seven-month-old APP/PS1 mice were intranasally administrated with tFNAs for two weeks. Fluorescence imaging was used to detect the tFNAs distribution in the brain. Novel object recognition (NOR) test followed by Morris water maze (MWM) was used to test the learning and memory performance of mice. Golgi staining, Western blot, and immunofluorescence staining were used to examine synaptic plasticity. tFNAs promoted cell viability and GSH levels, reduced the levels of Fe.sup.2+, lipid peroxidation, MDA, and LDH in N2a cells treated with A[beta]. RNA sequencing revealed that tFNAs reversed the promotive effect of A[beta] on ferroptosis driver Atf3 gene and suppressive effect on ferroptosis suppressors Rrm2 and Furin genes. Fluorescence imaging confirmed the brain infiltration of tFNAs. tFNAs rescued synaptic and memory impairments, and ferroptosis in seven-month-old APP/PS1 mice. Collectively, tFNAs inhibited A[beta]-mediated ferroptosis and ameliorated cognitive and synaptic impairments in AD mice. tFNAs may serve as novel option to deal with AD.