Yoon Il-Chul, Xue Lulu, Chen Qinyuan, Liu Jingyi, Xu Junchao, Siddiqui Zain, Kim Dongyoon, Chen Bingling, Shi Qiangqiang, Laura Han Emily, Cherry Ruiz Mia, Vining Kyle H, Mitchell Michael J
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, United States.
Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, United States.
Angew Chem Int Ed Engl. 2025 Jan 15;64(3):e202415389. doi: 10.1002/anie.202415389. Epub 2024 Dec 13.
Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field, due in part to low local blood flow and poor interactions between drug carriers and bone material. Here we report bone-targeting ionizable lipids incorporating a piperazine backbone and bisphosphate moieties, which bind tightly with hydroxyapatite ([Ca(PO)OH]), a key component of mineralized tissues. These lipids demonstrate biocompatibility and low toxicity in both vitro and in vivo studies. LNP formulated with these lipids facilitated efficient cellular transfection and improved binding to hydroxyapatite in vitro, and targeted delivery to the bone microenvironment in vivo following systemic administration. Overall, our findings demonstrate the critical role of the piperazine backbone in a novel ionizable lipid, which incorporates a bisphosphonate group to enable efficient bone-targeted delivery, highlighting the potential of rational design of ionizable lipids for next-generation bone-targeting delivery systems.
利用信使核糖核酸脂质纳米颗粒进行核酸递送正在被开发用于靶向多种组织和细胞类型。然而，靶向递送至骨微环境在该领域仍然是一项重大挑战，部分原因是局部血流低以及药物载体与骨材料之间的相互作用不佳。在此，我们报告了一种含有哌嗪主链和双膦酸盐部分的骨靶向可电离脂质，其与矿化组织的关键成分羟基磷灰石（[Ca(PO)OH]）紧密结合。这些脂质在体外和体内研究中均表现出生物相容性和低毒性。用这些脂质配制的脂质纳米颗粒在体外促进了高效的细胞转染并改善了与羟基磷灰石的结合，并且在全身给药后在体内靶向递送至骨微环境。总体而言，我们的研究结果证明了哌嗪主链在一种新型可电离脂质中的关键作用，该脂质含有双膦酸盐基团以实现高效的骨靶向递送，突出了可电离脂质合理设计用于下一代骨靶向递送系统的潜力。
