Cartilage-adhesive/penetrating pH-responsive polyphenol-glucosamine nanoparticles alleviate osteoarthritis by matrix remodeling and immune regulation.

Osteoarthritis (OA) is a chronic, whole-joint degenerative disease that ultimately leads to joint deformity and permanent loss of function. Chondrocyte dysfunction secondary to inflammatory responses and oxidative stress impedes the regenerative remodeling of cartilage. Here, a kind of cartilage-adhesive/penetrating self-assembled nanoparticles (GE NPs) are constructed through multiple dynamic covalent and non-covalent interactions between epigallocatechin gallate (EGCG) and glucosamine (GlcN). The hydrogen bonding interactions between GE NPs and the cartilage surface mediate their prolonged retention within the joint cavity. The optimized particle size allows GE NPs to readily penetrate the fibrous matrix of cartilage, facilitating deep tissue delivery. GE NPs reverse OA progression by scavenging reactive oxygen species (ROS) and regulating macrophage polarization, thereby establishing an anti-inflammatory microenvironment and rescuing chondrocytes from apoptosis. Simultaneously, pH-responsive GlcN release promotes the synthesis and secretion of proteoglycans, thereby enhancing cartilage matrix regeneration in the inflammatory microenvironment. In vivo experiments demonstrate that GE NPs facilitate cartilage regeneration and alleviate OA progression within one month. Overall, this cartilage-adhesive, deeply penetrating, and pH-responsive nanoplatform for the co-delivery of GlcN and EGCG represents a synergistic approach to OA treatment.