Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment
Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment
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DOI：
10.1021/jacs.2c02706
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发表时间：
2022-06-08
影响因子：
15
通讯作者：
Mitchell, Michael J.
中科院分区：
文献类型：
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作者：
Xue, Lulu;Gong, Ningqiang;Mitchell, Michael J.
用于靶向骨微环境的脂质纳米颗粒（LNP）制剂的开发对于核酸治疗应用（包括骨再生、癌症和造血干细胞疗法）具有显著的潜力。然而，由于几种生物屏障，如骨中的低血流量、血-骨髓屏障和药物与骨矿物质之间的低亲和力，将治疗剂递送至骨仍然是一个重大挑战，这导致骨微环境中的不利治疗剂量。在这里，我们构建了一系列的双膦酸盐（BP）类脂材料具有高亲和力的骨矿物质，作为一种手段，以克服生物屏障，有效地提供mRNA治疗骨微环境中的体内。在体外筛选配制成LNP的BP脂质样材料后，我们鉴定了一种先导BP-LNP制剂490 BP-C14，与不存在BP的490-C14 LNP相比，其在体内小鼠骨微环境中具有增强的mRNA表达和定位。此外，BPLNPs增强mRNA的递送和分泌的治疗性骨形态发生蛋白-2从骨微环境静脉内给药。这些结果证明了BP-LNP递送至骨微环境的潜力，其可潜在地用于一系列mRNA治疗应用，包括再生医学、蛋白质替代和基因编辑疗法。
The development of lipid nanoparticle (LNP) formulations for targeting the bone microenvironment holds significant potential for nucleic acid therapeutic applications including bone regeneration, cancer, and hematopoietic stem cell therapies. However, therapeutic delivery to bone remains a significant challenge due to several biological barriers, such as low blood flow in bone, blood-bone marrow barriers, and low affinity between drugs and bone minerals, which leads to unfavorable therapeutic dosages in the bone microenvironment. Here, we construct a series of bisphosphonate (BP) lipidlike materials possessing a high affinity for bone minerals, as a means to overcome biological barriers to deliver mRNA therapeutics efficiently to the bone microenvironment in vivo. Following in vitro screening of BP lipid-like materials formulated into LNPs, we identified a lead BP-LNP formulation, 490BP-C14, with enhanced mRNA expression and localization in the bone microenvironment of mice in vivo compared to 490-C14 LNPs in the absence of BPs. Moreover, BPLNPs enhanced mRNA delivery and secretion of therapeutic bone morphogenetic protein-2 from the bone microenvironment upon intravenous administration. These results demonstrate the potential of BP-LNPs for delivery to the bone microenvironment, which could potentially be utilized for a range of mRNA therapeutic applications including regenerative medicine, protein replacement, and gene editing therapies.