Composition-engineered copper-doped ZIF-8 nanoplatform for oxidative stress regulation and ferroptosis suppression in osteoarthritis

Composition-engineered Cu-doped ZIF-8 was designed for OA therapy. • Cu@ZIF-8 reduced oxidative stress and lipid peroxidation in chondrocytes. • Cu@ZIF-8 suppressed ferroptosis and preserved ECM homeostasis. • Intra-articular Cu@ZIF-8 attenuated OA progression in rats. Engineering metal–organic framework (MOF)-based materials with tunable composition and biological function offers a promising strategy for regulating pathological oxidative microenvironments. Herein, a composition-engineered copper-doped zeolitic imidazolate framework-8 nanoplatform, Cu@ZIF-8, was designed to modulate oxidative stress-associated lipid peroxidation and chondrocyte ferroptosis for osteoarthritis (OA) therapy. The incorporation of copper into the ZIF-8 framework enabled homogeneous elemental distribution while preserving the crystalline structure and high specific surface area of the MOF platform. In H 2 O 2 - and RSL3-induced chondrocyte injury models, Cu@ZIF-8 reduced intracellular ROS accumulation, alleviated lipid peroxidation, preserved mitochondrial membrane potential, restored GPX4/SLC7A11 expression, and maintained extracellular matrix homeostasis. Mechanistic studies suggested that Cu@ZIF-8-mediated ferroptosis suppression was associated, at least in part, with modulation of p38 MAPK/AKT signaling. In a surgically induced rat OA model, intra-articular administration of Cu@ZIF-8 attenuated cartilage degeneration, reduced oxidative and ferroptosis-related damage, and showed no apparent systemic toxicity under the tested conditions. This study establishes a composition-engineered MOF nanoplatform that links copper-doped ZIF-8 design with oxidative stress regulation, ferroptosis suppression, and cartilage protection, providing a materials-design strategy for OA microenvironment modulation. Download: Download high-res image (110KB) Download: Download full-size image