Injectable, Reactive Oxygen Species-Responsive Collagen Hydrogel for Peptide-Directed and On-Demand Nanotherapy of Osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by chronic inflammation and cartilage loss. However, disease-modifying treatments are still unavailable, and even promising nanomaterials are hindered by rapid clearance and poor targeting. Herein, we reported a peptide-modified and reactive oxygen species (ROS) responsive collagen hydrogel (CSH-AuNCs-CIITP) that coupled environmental adaptability with molecular precision for spatiotemporally regulated cartilage regeneration. Gold nanoclusters were functionalized with a type II collagen-targeting peptide (CIITP) for cartilage affinity and encapsulated within a ROS-cleavable disulfide-crosslinked collagen hydrogel (CSH), yielding an injectable, self-healing system with enhanced mechanical integrity and enzymatic stability. The hydrogel achieves ROS-triggered, on-demand release of therapeutic nanoclusters within the OA microenvironment. In vitro, this hydrogel system promoted BMSCs chondrogenesis and macrophage M2 polarization. In vivo, it facilitated preliminary integration and repair with robust matrix restoration. This ROS-activated cartilage-targeting platform integrates nano-bio interactions, dynamic covalent chemistry, and microenvironmental modulation. It achieves precise cartilage targeting, prolonged intra-articular retention, and spatiotemporally regulated bioactivity, culminating in superior anti-inflammatory and chondroregenerative outcomes, offering a promising strategy for nanomaterial-enabled osteoarthritis therapy.