Chemically tailored lipids mediate solid-phase RNA programming of mineralized microenvironments

The localized delivery of RNA therapeutics to mineralized tissue interfaces is limited by poor retention and rapid clearance at the target site. We report the development of a solid-phase transfection platform that functionalizes mineralized surfaces into bioactive nucleic acid reservoirs. Through the rational design and screening of a library of 21 piperazine-linked bisphosphonate ionizable lipids, we identified a lead formulation of bisphosphonate lipid nanoparticle (BP-LNP) that maximizes hydroxyapatite affinity without compromising transfection potency. Upon adsorption onto mineral substrates, these BP-LNPs resisted fluid removal and maintained surface-mediated, sustained delivery of encapsulated RNA cargo to adjacent cells. We demonstrated the versatility of this Mineralized Tissue-Targeting Expression System (MiTEX) composed of BP-LNPs in two therapeutic contexts: Cre recombinase mRNA-functionalized allogeneic bone grafts to genetically label de novo bone formation in vivo, and STAT3 siRNA delivery to reduce inflammation in human gingival explants. This platform provides a universal strategy for transforming inert calcium phosphate materials and tissues into locally bioactive RNA delivery systems for regenerative and immunomodulatory applications.