Engineering Bone-Targeted LNP Delivery of Anti-Sclerostin Antibody mRNA for the Treatment of Osteoporosis.

Messenger RNA (mRNA) therapy represents a transformative platform in regenerative medicine, but its application to skeletal disorders remains limited by the pronounced hepatic tropism of conventional lipid nanoparticle (LNP) delivery systems. To redirect the distribution of biomolecules to bone tissue, we developed a bone-targeting mRNA nanocarrier (SA@LNP-D) through microfluidic synthesis followed by surface conjugation of the Asp8 peptide (binding to hydroxyapatite). This system enables efficient expression of anti-sclerostin antibody mRNA in bone tissue, thereby achieving therapeutic effects for osteoporosis treatment. Our in vitro experimental results have demonstrated that LNP modified with bone-targeting peptides exhibits significant bone affinity and can efficiently bind to hydroxyapatite and isolated bone. Furthermore, the in vivo results confirmed that SA@LNP-D effectively reduces hepatic sequestration and specifically accumulates in bones through mineral-directed anchoring. In a murine ovariectomy model of osteoporosis, systemic delivery of bone-targeted LNP demonstrated a stronger therapeutic effect compared to conventional LNP. It not only stimulated bone formation but also inhibited bone resorption, thereby significantly restoring trabecular bone mass and microstructure. Together, this work establishes a targeted, nonhepatic mRNA delivery strategy that offers a safe and effective therapeutic option for osteoporosis and related skeletal conditions.