Bone-targeted LNP delivering anti-sclerostin antibody mRNA restores bone mass in ovariectomy osteoporosis.

Osteoporosis is characterized by bone loss, leading to increased fracture risk. Current mRNA therapies face challenges in skeletal applications due to conventional lipid nanoparticles (LNPs) primarily accumulating in the liver. This hepatic tropism limits the therapeutic potential of mRNA for bone disorders. Targeting bone tissue directly with mRNA encoding osteoanabolic agents like anti-sclerostin antibodies could offer a more effective and safer treatment strategy by modulating sclerostin, a key negative regulator of bone formation.

Researchers engineered a bone-targeted mRNA nanocarrier, SA@LNP-D, by conjugating the Asp8 peptide (hydroxyapatite-binding) to LNPs via microfluidic synthesis. This system delivered anti-sclerostin antibody mRNA. In vitro, they assessed bone affinity and binding to hydroxyapatite and isolated bone. In vivo, they used a murine ovariectomy model of osteoporosis to evaluate systemic delivery of SA@LNP-D versus conventional LNP, measuring bone formation, resorption, and trabecular bone mass/microstructure.

In vitro experiments confirmed that Asp8-modified LNPs exhibited significant bone affinity, efficiently binding to hydroxyapatite and isolated bone. In vivo results demonstrated that SA@LNP-D effectively reduced hepatic sequestration, showing specific accumulation in bones via mineral-directed anchoring.

In a murine ovariectomy model of osteoporosis, systemic delivery of bone-targeted LNP (SA@LNP-D) showed a stronger therapeutic effect compared to conventional LNP, significantly restoring trabecular bone mass and microstructure. The targeted delivery system not only stimulated bone formation but also inhibited bone resorption, indicating a dual mechanism of action. This targeted approach achieved superior therapeutic outcomes for osteoporosis compared to non-targeted LNP delivery of the same mRNA payload.