Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, P. R. China.
Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
Small. 2022 Jul;18(30):e2203182. doi: 10.1002/smll.202203182. Epub 2022 Jun 30.
Alzheimer's disease (AD), as a progressive and irreversible brain disorder, remains the most universal neurodegenerative disease. No effective therapeutic methods are established yet due to the hindrance of the blood-brain barrier (BBB) and the complex pathological condition of AD. Therefore, a multifunctional nanocarrier (Rapa@DAK/siRNA) for AD treatment is constructed to achieve small interfering RNA of β-site precursor protein (APP) cleaving enzyme-1 (BACE1 siRNA) and rapamycin co-delivery into the brain, based on Aleuria aurantia lectin (AAL) and β-amyploid (Aβ)-binding peptides (KLVFF) modified PEGylated dendrigraft poly-l-lysines (DGLs) via intranasal administration. Nasal administration provides an effective way to deliver drugs directly into the brain through the nose-to-brain pathway. AAL, specifically binding to L-fucose located in the olfactory epithelium, endows Rapa@DAK/siRNA with high brain entry efficiency through intranasal administration. KLVFF peptide as an Aβ targeting ligand and aggregation inhibitor enables nanoparticles to bind with Aβ, inhibit Aβ aggregation, and reduce toxicity. Meanwhile, the release of BACE1 siRNA and rapamycin is confirmed to reduce BACE1 expression, promote autophagy, and reduce Aβ deposition. Rapa@DAK/siRNA is verified to improve the cognition of transgenic AD mice after intranasal administration. Collectively, the multifunctional nanocarrier provides an effective and potential intranasal avenue for combination therapy of AD.
阿尔茨海默病（AD）是一种进行性和不可逆的脑疾病，仍然是最普遍的神经退行性疾病。由于血脑屏障（BBB）的阻碍和 AD 的复杂病理状况，尚未建立有效的治疗方法。因此，构建了一种用于 AD 治疗的多功能纳米载体（Rapa@DAK/siRNA），通过鼻腔给药，基于金顶侧耳凝集素（AAL）和β-淀粉样蛋白（Aβ）结合肽（KLVFF）修饰的聚乙二醇化树枝状大分子多聚赖氨酸（DGLs），将β-位点前体蛋白（APP）裂解酶-1（BACE1）siRNA 和雷帕霉素共递送至大脑。鼻腔给药通过鼻脑途径为将药物直接递送至大脑提供了一种有效方法。AAL 特异性结合位于嗅上皮的 L-岩藻糖，使 Rapa@DAK/siRNA 通过鼻腔给药具有高的脑内进入效率。KLVFF 肽作为 Aβ 靶向配体和聚集抑制剂，使纳米颗粒能够与 Aβ 结合，抑制 Aβ 聚集，降低毒性。同时，证实了 BACE1 siRNA 和雷帕霉素的释放可以减少 BACE1 的表达，促进自噬，并减少 Aβ 的沉积。经鼻腔给药后，Rapa@DAK/siRNA 被证实可以改善转 AD 小鼠的认知能力。总的来说，多功能纳米载体为 AD 的联合治疗提供了一种有效的、有潜力的鼻腔途径。
