文献类型：期刊文献

英文题名：Bone-Targeting Nucleic Acid Delivery Polymer Vector for Effective Therapy of Bone Metastasis

作者：Li, Zejuan[1,2];Xiao, Xiao[3];Pu, Xu[1];Yang, Xingsen[1];Shi, Junqiu[1,2];He, Shisheng[3];Du, Jianzhong[2,3,4,5];Zhu, Yunqing[1]

机构：[1]Tongji Univ, Sch Mat Sci & Engn, Dept Polymer Mat, Shanghai 201804, Peoples R China;[2]Tongji Univ, Dept Gynaecol & Obstet, Shanghai Key Lab Anesthesiol & Brain Funct Modulat, Clin Res Ctr Anesthesiol & Perioperat Med,Translat, Shanghai 200434, Peoples R China;[3]Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Orthopaed, Shanghai 200072, Peoples R China;[4]Tongji Univ, Sch Mat Sci & Engn, Key Lab Adv Civil Engn Mat, Minist Educ, Shanghai 201804, Peoples R China;[5]East China Univ Sci & Technol, Sch Mat Sci & Engn, Shanghai 200237, Peoples R China

年份：2025

卷号：19

期号：17

起止页码：17014

外文期刊名：ACS NANO

收录：;EI(收录号：20251718310055);WOS:【SCI-EXPANDED(收录号:WOS:001474285300001)】；

基金：This research was supported by the National Natural Science Foundation of China (22175131, 22335005, 21925505, and 82372442), the National Key R&D Program of China (2022YFC2402900), Innovation Program of Shanghai Municipal Education Commission (2023ZKZD28), and the Interdisciplinary Collaborative Research Project of Tongji University (2023-2-YB-03) and Tongcheng Youth Research and Development Fund (CPCIF-RA-0104). J.D. is a recipient of National Science Fund for Distinguished Young Scholars. The nude mice, syringes, breast, skeletal, and cellular components included in Scheme 1, TOC graphic, and Figure 6A were selected from BioRender's authorized element library.

语种：英文

外文关键词：nucleic acid; delivery vector; polyamidoamines; alendronic acid; bone targeting; bone metastases

摘要：Bone diseases, such as bone metastases, pose significant therapeutic challenges due to the distinct physiological environment of skeletal tissues, which complicates the targeted delivery of nucleic acid therapeutics. Existing delivery systems, including lipid nanoparticles (LNP) and polyethylenimine (PEI), struggle to achieve precise bone targeting effectively. To address this issue, we developed a polymer-based bone-targeting bioreducible nucleic acid delivery vector, poly[alendronic acid-co-(N,N '-bis(acryloyl)cystamine-co-4-amino-1-butanol)] (ALN-Pabol), which incorporates alendronic acid (ALN) for precise bone targeting. The ALN-Pabol exhibited a hydroxyapatite binding rate of 91.1%, significantly outperforming nontargeted Pabol/miRNA (73.5%) and commercial systems such as PEI/miRNA (58.3%) and Lipofectamine 2000/miRNA (64.7%). In vivo fluorescence imaging demonstrated its superior skeletal accumulation compared to nontargeted controls. In a murine breast cancer bone metastasis model, ALN-Pabol/miRNA polyplex reduced bone tumor weight by 79.1% relative to PBS controls and 36.8% compared to LNP/miRNA. Mechanistically, the polyplex dissociates in the high-glutathione tumor microenvironment, releasing therapeutic miRNA to suppress cancer cell proliferation and promote apoptosis. Simultaneously, ALN inhibits osteoclast activity, significantly mitigating osteolytic damage. Micro-CT analysis revealed near-complete restoration of bone volume and trabecular architecture to healthy levels. This work establishes ALN-Pabol as a highly promising delivery vector for bone-targeted gene therapy, bridging critical gaps in skeletal disease treatment and expanding potential applications in bone regeneration and cancer therapy.