A hyaluronidase-responsive nano in micro depot improves chondrocyte-level teriparatide delivery for osteoarthritis treatment

Osteoarthritis (OA) is a common degenerative joint disease with a growing clinical burden. Current treatments mainly provide symptomatic relief and have limited ability to slow structural progression. Teriparatide (TP), a clinically approved parathyroid hormone analogue, has shown potential for protecting chondrocytes and supporting cartilage matrix homeostasis. However, its application in OA remains limited by poor intra-articular availability, including rapid joint clearance, limited access to cartilage, and insufficient exposure at the chondrocyte level. To address these barriers, we developed a nano-in-micro sequential intra-articular delivery system, TP@P-Lipo@HM. In this system, TP was loaded into FGL-modified cationic liposomes (~ 100 nm), which were then encapsulated within methacrylated hyaluronic acid (HAMA) microspheres (~ 150 μm). Rather than requiring a single carrier to simultaneously achieve prolonged joint retention and efficient cartilage transport, the two structural scales were assigned complementary functions: the microscale HAMA compartment served as a retained intra-articular depot and enabled hyaluronidase-responsive liberation of the nanoscale liposomes, whereas the released P-Lipo promoted cartilage-associated distribution and enhanced uptake by OA chondrocytes. In vitro and in vivo studies demonstrated that TP@P-Lipo@HM improved chondrocyte anabolic–catabolic homeostasis, reduced inflammation and apoptosis, preserved cartilage structure, and attenuated OA progression. Thus, this nano-in-micro architecture provides a sequential strategy that decouples joint retention from tissue/cellular delivery and offers a practical platform for improving the local delivery of TP in OA.