Lipid-modulating hyaluronic acid hydrogel promotes chondrogenesis of osteoarthritis progenitor cells for weight-bearing cartilage repair.

Mechanical injury and aging both contribute to cartilage defects that accelerate osteoarthritis (OA) progression. Emerging evidence indicates that nutritional microenvironmental factors, particularly lipid bioavailability, modulate progenitor cell chondrogenesis. Our RNA-seq analysis of OA/normal chondroprogenitors and chondrocyte revealed a pivotal role of lipid metabolism in chondrogenic differentiation. Functional validation using OA cartilage derived progenitor cells (OA-CPCs) demonstrated enhanced chondrogenesis under high-glucose/low-lipid conditions. We subsequently fabricated a lipid-blocking, hyaluronic acid-based hydrogel (AHA-MA-RGD-EPL@GW1100, AMARE@G) with injectable, self-healing and anti-bacterial properties for cartilage repair in the weight-bearing region of in rabbit knee. In the AMARE@G hydrogel group, we observed regenerated cartilage with smooth surface, abundant type II collagen and proteoglycan, and minimal fibrotic type I collagen. This integrated approach synergizes metabolic regulation with biomaterial innovation to achieve functional cartilage restoration in load-bearing areas, demonstrating translational potential for cartilage repair and OA intervention.