High-Throughput Screening Strategy and Metal–Organic Framework-Based Multifunctional Controlled-Release Nanomaterial for Osteoarthritis Therapy

Osteoarthritis (OA) is a prevalent degenerative disease that lacks effective therapy. Oxidative stress is one of the major factors contributing to OA; however, treatments targeting oxidative stress are still lacking. In the current study, we established an oxidative stress-induced cell death model in chondrocytes in vitro and screened drugs that may suppress oxidative stress-induced cell death. Ethyl gallate (EG) was identified as the most potent drug against oxidative stress-induced cell death out of more than 600 drugs in the natural product library. Application of drugs without an appropriate delivery system for OA therapy may have drawbacks such as low bioavailability, short action time, and poor efficacy. Herein, poly-His6-zinc assembly (PZA), a pH-responsive metal–organic framework (MOF) loaded with EG (EG@PZA) was designed for OA therapy. It was demonstrated that EG@PZA may have the lysosome escape property, which dramatically increases the utilization of EG. Furthermore, EG@PZA showed enhanced release capability of EG in the acidic microenvironment. In vitro and in vivo studies demonstrated that EG@PZA effectively suppresses oxidative stress-induced extracellular matrix degradation, ferroptosis, and senescence in chondrocytes and also ameliorates OA in the destabilization of the medial meniscus (DMM) mouse model in vivo. Together, the current study showed that EG@PZA may become a potential controlled-release nanomaterial for effective OA therapy.