Brain‐Penetration and Neuron‐Targeting DNA Nanoflowers Co‐Delivering miR‐124 and Rutin for Synergistic Therapy of Alzheimer's Disease

Abstract

tau hyperphosphorylation, mitochondrial dysfunction and oxidative stress, and neuroinflammatory response. [3] Among them, the amyloid theory that focuses on excessive deposition of β-amyloid (Aβ) has been extensively studied with wide acceptance. [4] In this theory, imbalance of Aβ metabolism and catabolism in the central nervous system (CNS) has been regarded as the main reason for AD-like pathology. [5] Aβ is the product of a proteolytic process of a transmembrane protein, amyloid precursor protein (APP), by β-secretase 1 (BACE1, β-site APP cleavage enzyme 1) and the γ-secretase. [6] The overgeneration and abnormal aggregation of Aβ 1-42 can cause the collapse of dendritic spines and neuronal loss, induce oxidative stress, and promote inflammatory by activating microglia, which in turn exacerbates the pathogenesis of AD. [7] Several strategies focus on blocking Aβ aggregation and alleviating Aβ-mediated neurotoxicity have been developed, including aggregation inhibition, copper chelation, Aβ photo-oxidation, fibril thermal dissociation, and Aβ degradation. [8] However, many Aβ targeting pharmacological treatments failed to slow down genitive decline or improve global functioning in phase 3 clinical trials although with definite efficacy at animal model. [9] Besides the pathological discrepancy between real clinical patient and AD animal model, [10] another important reason is that AD is a multifactorial disease and therapy targeting Aβ alone is far more enough. [11] Despite significant Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid β generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.

Hemin-incorporating DNA nanozyme enabling catalytic oxygenation and GSH depletion for enhanced photodynamic therapy and synergistic tumor ferroptosis

“…The DF were prepared according to our previous report [39], in which the circular DNA template was first ligation by T4 ligase, followed by rolling circle amplifications (Fig. 1A).…”

“…Recently, we and other groups have demonstrated that DNA nanoflower (DF) is a type of highly robust nanocarrier to deliver functional nucleic acids [39,40]. DF is a spherical porous DNA nanostructure formed by rolling circle amplification (RCA).…”

Imine-Linked Covalent Organic Framework Modulates Oxidative Stress in Alzheimer’s Disease

“…The BBB-crossing ability of SC@COF-T5 was assessed by using an in vitro BBB model based on brain endothelial cell lines, in which bEnd.3 cells were cultured in the upper chambers of a transwell dish, and SVG cells were at the bottom of the upper chambers (Figure C). After 5 days, transendothelial electrical resistance (TEER) was measured to be higher than 200 ohm·cm 2 , which suggested that the BBB model was established successfully. − Then, RB-modified SC@COF and SC@COF-T5 were added into the apical chamber, and the concentrations of the two nanoparticles were detected after 12, 18, and 24 h of the addition. The permeability of SC@COF-T5 significantly increased compared to that without T5 modification (Figure D), demonstrating that the KLVFF peptide can improve BBB penetration efficiency by bonding RAGE, the receptor for advanced glycation end products.…”

MicroRNA-22-3p ameliorates Alzheimer’s disease by targeting SOX9 through the NF-κB signaling pathway in the hippocampus

“…Studies have confirmed that in the brain tissue or serum of AD patients, many miRNAs have been identified as down-regulated and thought to be involved in the formation of senile plaques and neurofibrillary tangles [ 11 ]. Some brain-enriched miRNAs, such as miR-124, miR-125b, and miR-132 [ 12 – 14 ], have been revealed to show therapeutic effects on AD. In our previous study, we investigated the changes of miRNA levels in serum of AD patients and found that miR-22-3p was significantly down-regulated [ 15 ].…”