Artificial Chlorella Biohybrids for Alleviation of Cartilage Degeneration in Osteoarthritis

ABSTRACT Osteoarthritis (OA), one of the most common chronic joint diseases, is characterised by cartilage imbalance and disruption of the cartilage extracellular matrix. In this study, we observed impaired mitophagy and glucose metabolism disorders in OA chondrocytes, which exacerbated cartilage degeneration. And we unveil Chlorella , a natural microorganism that appeared more than two billion years ago, as an efficient regulator of both mitophagy and glucose metabolism in OA chondrocytes. Chlorella activates mitophagy and rescues mitochondrial function. More importantly, Chlorella inhibits glycolysis and reprograms glucose metabolism in chondrocytes, leading to the remodelling of chondrocyte homeostasis and alleviation of cartilage degeneration both in vitro and in vivo. As a proof of concept, we constructed a photothermal Chlorella biohybrid (Ch@P) that induced articular thermal stimulation under near‐infrared irradiation and significantly strengthened the protection against cartilage degeneration in DMM mouse models of OA. Ch@P activates the AMPK‐Sirt1 signalling pathway to restore mitochondrial homeostasis and energy metabolism in chondrocytes. Furthermore, HSP70 is also activated to regulate chondrocyte homeostasis due to articular thermal stimulation. Our study unveils the activity of natural Chlorella in chondrocyte homeostasis by activating mitophagy and reprogramming glucose metabolism and identifies an artificial Chlorella biohybrid as a promising therapeutic option for OA treatment.