Multifunctional DNA Tetrahedron for Alzheimer’s Disease Mitochondria-Targeted Therapy by MicroRNA Regulation

Abstract

The principal hallmark of Alzheimer’s disease (AD) is neuron mitochondrial dysfunction, whereas mitochondrial miRNAs potentially play important roles. Nevertheless, efficacious mitochondria organelle therapeutic agents for treatment and management of AD are highly advisable. Herein, we report a multifunctional DNA tetrahedron-based mitochondria-targeted therapeutic platform, termed tetrahedral DNA framework-based nanoparticles (TDFNs), which was modified with triphenylphosphine (TPP) for mitochondria-targeting, cholesterol (Chol) for crossing the central nervous system, and functional antisense oligonucleotide (ASO) for both AD diagnosis and gene silencing therapy. After injecting intravenously through the tail vein of 3 × Tg-AD model mice, TDFNs can both easily cross the blood brain barrier and accurately arrive at the mitochondria. The functional ASO could not only be detected via the fluorescence signal for diagnosis but also mediate the apoptosis pathway through knocking miRNA-34a down, leading to recovery of the neuron cells. The superior performance of TDFNs suggests the great potential in mitochondria organelle therapeutics.

An Enzymatically Activated and Catalytic Hairpin Assembly-Driven Intelligent AND-Gated DNA Network for Tumor Molecular Imaging

“…This indicates the distribution regions of tFNA-Hs and its ability to cross the blood–brain barrier, which aligns with previous findings (Figure S12B). The ex vivo imaging results revealed that tFNA-Hs exhibited predominant accumulation in both the tumor and liver following intravenous tail injection, which was consistent with the in vivo imaging findings (Figure J). In addition, the tumor tissue sections exhibited a distinct fluorescence signal, which was consistent with the results obtained from in vivo imaging (Figure K).…”

“…Moreover, microRNA (miRNA) represents a promising diagnostic biomarker for tumor detection. 27 However, the detection of miRNA remains challenging due to their intrinsic characteristics. 28 Additionally, enzyme-free amplification approaches like CHA 8 and hybridization chain reaction 6,16 have also been explored.…”

“…The aberrant expression and mislocalization of APE1 in cytoplasm have been observed in various malignancies. − Therefore, APE1, a highly expressed tumor-specific cytoplasmic target, was selected as the responsive target to minimize off-target signal leakage and enhance the discrimination ratio between cancerous and normal cells. Moreover, microRNA (miRNA) represents a promising diagnostic biomarker for tumor detection . However, the detection of miRNA remains challenging due to their intrinsic characteristics .…”

DNA nanotechnology-based nucleic acid delivery systems for bioimaging and disease treatment

“…121 Lately, Dong's group constructed tetrahedral DNA framework-based nanoparticles (TDFNs), where three vertices were modified with triphenylphosphine for mitochondria-targeting, cholesterol for crossing the blood–brain barrier, and functional ASO for gene silencing therapy. 122 TDFNs could effectively penetrate the neuron cells and target the mitochondria, recognizing intracellular miRNA-34a to generate fluorescence for the diagnosis of Alzheimer's disease, while the expression of miRNA-34a was knocked down by functional ASO for the anti-apoptosis regulation of neuron cells. Shi's group reported a vector-free programmable DNA spherical nanostructure for the effective treatment of ischemic stroke.…”