Piperazine‐Derived Bisphosphonate‐Based Ionizable Lipid Nanoparticles Enhance mRNA Delivery to the Bone Microenvironment
Year: 2024
Type: article
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, 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 5 (PO 4 ) 3 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.
Institutions: University of Pennsylvania, Abramson Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,510
Funders: National Science Foundation, Foundation for the National Institutes of Health, University of Pennsylvania, National Institutes of Health, Vagelos Institute for Energy Science and Technology, University of Pennsylvania, National Institute of General Medical Sciences, National Institute of Dental and Craniofacial Research, Division of Chemical, Bioengineering, Environmental, and Transport Systems, Division of Chemistry, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: A data-driven drug delivery (4D) platform for probing and treating the chemoresistant bone marrow microenvironment, G1343596579, G185654730, G1946437514, G2141756727, MRI: Acquisition of a 400 MHz Nuclear Magnetic Resonance (NMR) Spectrometer for Chemistry and Energy Research and Education at the University of Pennsylvania, G2989883016, Graduate Research Fellowship Program(GRFP), G3459316302, G458626264, G5240105467, G5986892838, G6671297155, Computational Methods for Selective Catalysis, Targeting Nucleic Acid Junctions with Small Molecules, Targeting mechanical regulation of monocyte fate in head and neck cancer., G7805455597, CAREER: Nanoparticle mRNA and DNA Immunoengineering of Macrophages for Solid Tumor Targeting, Advanced Training at the Interface of Engineering and Oral-Craniofacial Sciences, mRNA lipid nanoparticles for pre-eclampsia
OpenAlex ID: W4403274864