Plaque-Targeted Rapamycin Spherical Nucleic Acids for Synergistic Atherosclerosis Treatment.
Plaque-Targeted Rapamycin Spherical Nucleic Acids for Synergistic Atherosclerosis Treatment.
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DOI：
10.1002/advs.202105875
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发表时间：
2022-05
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动脉粥样硬化伴不稳定斑块是致死性心脑血管疾病的主要病理基础，可因斑块破裂导致急性死亡。由于动脉粥样硬化的全身性发生，斑块靶向药物递送以实现促进治疗仍然是主要挑战。本研究构建了一种能够在斑块中特异性积累以协同治疗动脉粥样硬化的雷帕霉素（RAP）球形核酸（SNA）结构。通过在脱氧核糖核酸（DNA）链的3 '端设计连续的硫代酸（PS），将多个疏水RAP共价接枝到PS片段上，形成两亲性的药物接枝DNA (RAP - DNA)， RAP - DNA依次自组装成胶束SNA （RAP - SNA）。此外，磷酸二酯DNA片段构成RAP‐SNA的外壳，使其能够与功能性siRNA（靶向凝集素样氧化低密度脂蛋白受体- 1，LOX‐1）进一步杂交，以获得药物共递送的SNA （LOX‐1/RAP‐SNA）。LOX‐1/RAP‐SNA含有两种活性成分，不仅能诱导强效自噬，减少病理性巨噬细胞的恶性凋亡，同时还能抑制LOX‐1介导的有害泡沫细胞的形成，实现协同治疗的效果。因此，LOX‐1/RAP‐SNA显著降低了动脉粥样硬化的进展并稳定了斑块，为协同靶向动脉粥样硬化治疗提供了一种新的策略。通过共价药物嫁接和超分子自组装，构建雷帕霉素（RAP）球形核酸（RAP‐SNA）与凝集素样氧化低密度脂蛋白受体- 1 (LOX‐1)siRNA杂交，获得药物共递送纳米制剂（LOX‐1/RAP‐SNA），该制剂通过诱导巨噬细胞的强自噬显著抑制异常细胞凋亡，同时抑制LOX‐1介导的泡沫细胞形成，从而产生协同抗动脉粥样硬化的效果。
Atherosclerosis with unstable plaques is the dominant pathological basis of lethal cardio‐cerebrovascular diseases, which can cause acute death due to the rupture of plaques. Plaque‐targeted drug delivery to achieve promoted treatment remains the main challenge because of the systemic occurrence of atheroma. Herein, a rapamycin (RAP) spherical nucleic acid (SNA) structure, capable of specifically accumulating in plaques for synergistic atherosclerosis treatment is constructed. By designing consecutive phosphorothioate (PS) at 3’ terminus of the deoxyribonucleic acid (DNA) strand, multiple hydrophobic RAPs are covalently grafted onto the PS segment to form an amphiphilic drug‐grafted DNA (RAP‐DNA), which successively self‐assembles into micellar SNA (RAP‐SNA). Moreover, the phosphodiester‐DNA segment constitutes the outer shell of RAP‐SNA, enabling further hybridization with functional siRNA (targeting lectin‐like oxidized low‐density lipoprotein receptor‐1, LOX‐1) to obtain the drug codelivered SNA (LOX‐1/RAP‐SNA). With two active ingredients inside, LOX‐1/RAP‐SNA can not only induce robust autophagy and decrease the evil apoptosis of the pathological macrophages, but also simultaneously prohibit the LOX‐1‐mediated formation of damageable foam cells, realizing the effect of synergistic therapy. As a result, the LOX‐1/RAP‐SNA significantly reduces the progression of atheroma and stabilizes the plaques, providing a new strategy for synergistically targeted atherosclerosis treatment. By covalently drug grafting and supramolecularly self‐assembling, a rapamycin (RAP) spherical nucleic acid (RAP‐SNA) is constructed to hybridize with lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) siRNA to obtain the drug codelivery nanoformulation (LOX‐1/RAP‐SNA), which significantly suppresses abnormal cell apoptosis by inducing robust autophagy of macrophages and simultaneously inhibits LOX‐1‐mediated foam cell formation, resulting in synergistic antiatherosclerosis efficacy.