Development of pathology-responsive Cu-based metal–phenolic nanonetworks for disease-modifying treatment of knee osteoarthritis

Objectives Knee osteoarthritis (KOA) is characterized by chronic inflammation, oxidative stress, and extracellular matrix (ECM) degradation, while current therapies mainly provide symptomatic relief. We developed a pathology-responsive copper-based metal-phenolic nanonetwork (Cu-BAI-BER) to co-deliver two phytochemicals and mitigate multiple pathological features of KOA. Methods Cu-BAI-BER was prepared by one-pot coordination-driven self-assembly and characterized by transmission electron microscopy, dynamic light scattering, X-ray diffraction, X-ray photoelectron spectroscopy, UV-vis spectroscopy, and Fourier-transform infrared spectroscopy. Its pH- and reactive oxygen species (ROS)-responsive release and radical-scavenging properties were evaluated in vitro . Therapeutic effects were assessed in IL-1β- or H2O2-stimulated ATDC5 chondrocytes and in a destabilization of the medial meniscus-induced mouse model of KOA. Results Cu-BAI-BER formed stable amorphous nanonetworks with a particle size of approximately 70 nm. The nanonetwork exhibited accelerated release under acidic and ROS-rich conditions and effectively scavenged multiple radical species. In chondrocytes, Cu-BAI-BER improved cell viability, reduced IL-1β, TNF-α, and IL-6 expression, restored Aggrecan and Collagen II levels, and suppressed MMP-3 and MMP-13 expression. Under oxidative stress, it reduced intracellular ROS and lipid peroxidation, preserved mitochondrial membrane potential, decreased malondialdehyde levels, and enhanced endogenous antioxidant defenses. In vivo , intra-articular administration alleviated cartilage damage and joint inflammation, improved histological outcomes, and restored ECM homeostasis. These protective effects were accompanied by increased Nrf2 expression and upregulation of its downstream antioxidant targets HO-1, NQO1, and SOD2. The formulation showed favorable biocompatibility in vitro and minimal systemic toxicity in vivo . Conclusions Cu-BAI-BER is a pathology-responsive nanonetwork that attenuates inflammation, oxidative stress, and ECM degradation in experimental KOA. It represents a promising disease-modifying nanomedicine candidate for KOA treatment.