Growth plate cartilage-targeting nanoparticles for pharmacological treatment of hypochondroplasia.

Hypochondroplasia (HCH) is a systemic cartilage disorder caused by gain-of-function mutations in FGFR3, resulting in overactivation of signaling and short stature. Pharmacological therapy remains the primary treatment but provides only partial symptomatic relief, as the avascular and alymphatic nature of growth plate cartilage severely limits drug delivery and accumulation. To address this challenge, we developed CT-CM-NPs, a drug delivery system coated with primary chondrocyte membranes and further modified with the collagen II-binding peptide WYRGRL. This design retains the inherent biological properties of native membranes while incorporating targeting capability, enabling efficient cartilage targeting and penetration. In vivo, CT-CM-NPs effectively delivered the Hedgehog pathway agonist Purmorphamine to the growth plate cartilage in an HCH mouse model, resulting in upregulated Hedgehog signaling, restored impaired ciliogenesis, improved chondrocyte phenotypes, and ultimately increased bone and body length. Collectively, these findings establish CT-CM-NPs as a promising and potentially translatable nanoplatform for the treatment of HCH.