Piperazine‐derived bisphosphonate‐based ionizable lipid nanoparticles enhance mRNA delivery to the bone microenvironment

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.