Abstract
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. We report bone-targeting ionizable lipids featuring a robust piperazine backbone, which forms strong interactions with hydroxyapatite ([Ca5(PO4)3OH]), a key component of mineralized tissues. These lipids, conjugated with derivatives of bisphosphates, demonstrate biocompatibility and low toxicity in vitro and in vivo. Our findings demonstrate the role of a piperazine backbone of a novel ionizable lipid that presents a bisphosphonate group to facilitate bone delivery. This research illustrates the rational design of ionizable lipids for next-generation bone-targeting delivery systems.
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