Injectable polysaccharide hydrogel microspheres integrated with BPNS-ZnO nanocomposites restore redox homeostasis and protect cartilage in osteoarthritis.

Abstract

Osteoarthritis (OA) is a progressive whole-joint disease driven by a persistent inflammatory-oxidative microenvironment that fuels cartilage destruction and osteochondral remodeling, while effective disease-modifying interventions remain scarce. Here, an injectable microsphere platform (HM@BPZn) is engineered by incorporating electronically coupled BPNS-ZnO hybrid nanosheets into a dual-polysaccharide network of methacrylated hyaluronic acid and gallic acid-grafted chondroitin sulfate. Interfacial electronic redistribution within the BPNS-ZnO hybrids enables active modulation of the pathological joint microenvironment. HM@BPZn suppresses reactive oxygen species accumulation and NF-κB signaling in macrophages, reducing inflammatory mediator production and promoting pro-resolving polarization. In inflamed chondrocytes, HM@BPZn activates the Keap1-Nrf2 pathway, upregulates antioxidant effectors including HO-1 and NQO1, and restores matrix homeostasis by suppressing catabolic markers while enhancing anabolic and lubrication-associated phenotypes. Transcriptomic profiling further verifies coordinated rewiring of inflammatory and antioxidant signaling networks. In an ACLT-induced OA model, intra-articular delivery of HM@BPZn markedly mitigates synovitis, preserves proteoglycan-rich cartilage, and attenuates pathological subchondral bone remodeling and osteophyte formation. These findings establish HM@BPZn as an injectable microenvironment-regulating platform for disease-modifying OA treatment.