Lu An, Xu Zhiyi, Zhao Zhixia, Yan Yi, Jiang Linxia, Geng Jing, Jin Hongwei, Wang Xiangyu, Liu Xiaoyan, Zhu Yuanjun, Shi Yujie, Liu Lihong, Dai Huaping, Wang Jian-Cheng
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Department of Pharmacy, Clinical Trial Research Center, China-Japan Friendship Hospital, Beijing, 100029, China.
Adv Sci (Weinh). 2024 Dec;11(47):e2405406. doi: 10.1002/advs.202405406. Epub 2024 Oct 30.
Mitochondrial permeability transition pore (mPTP) opening is a key hallmark of injured type II alveolar epithelial cells (AECIIs) in idiopathic pulmonary fibrosis (IPF). Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a "double braking" strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D-lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D-lipid and MCU targeting siRNA (siMCU) are co-assembled to form stable 3D-LNP/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D-lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage-associated molecular patterns (DAMPs) release and suppressing epithelial-to-mesenchymal transition (EMT) process in bleomycin-induced A549 cells. In vivo results revealed that 3D-LNP/siMCU NPs effectively ameliorated collagen deposition, pro-fibrotic factors secretion, and fibroblast activation in bleomycin-induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3-based formulation, optimized Opt-MC3/siRNA NPs with incorporating 3D-lipid as the fifth component, showed superior therapeutic efficacy against PF due to their enhanced stability and higher gene silencing efficiency. Overall, the nanomedicine containing 3D-lipid and siMCU will be a promising and potential approach for IPF treatment.
线粒体通透性转换孔（mPTP）开放是特发性肺纤维化（IPF）中II型肺泡上皮细胞（AECIIs）损伤的关键标志。抑制AECIIs中的mPTP开放被认为是一种潜在的IPF治疗方法。在此，提出了一种针对mPTP的“双重制动”策略，即通过具有3D结构的环孢素A（CsA）衍生的可电离脂质（3D-脂质）结合亲环蛋白D（CypD）以及小干扰RNA（siRNA）下调线粒体钙单向转运体（MCU）的表达来治疗IPF。3D-脂质与靶向MCU的siRNA（siMCU）共同组装，与辅助脂质一起形成稳定的3D-LNP/siMCU纳米颗粒（NPs）。体外实验结果表明，这些纳米颗粒通过3D-脂质与CypD结合以及siRNA下调MCU表达，有效抑制了mPTP开放，从而减少了损伤相关分子模式（DAMPs）的释放，并抑制了博来霉素诱导的A549细胞中的上皮-间质转化（EMT）过程。体内实验结果显示，3D-LNP/siMCU纳米颗粒有效改善了博来霉素诱导的肺纤维化（PF）小鼠模型中的胶原沉积、促纤维化因子分泌和成纤维细胞活化。此外，与基于商业化MC3的制剂相比，优化后的包含3D-脂质作为第五种成分的Opt-MC3/siRNA纳米颗粒，由于其增强的稳定性和更高的基因沉默效率，对PF表现出更好的治疗效果。总体而言，含有3D-脂质和siMCU的纳米药物将是一种有前景的潜在IPF治疗方法。
