Engineered Cyanobacteria-Hydrogel Microecological System for Oxygen Reprogramming Synergizes Immunomodulation With Anabolism in Osteoarthritis Therapy.

Osteoarthritis remains a major clinical challenge due to its complex pathophysiology involving chronic inflammation and progressive cartilage degradation. Current treatments largely fail to address the dual demands of synovial anti-inflammation and cartilage anabolism, particularly under the critical yet often overlooked influence of oxygen zonation within articular tissues. In this study, we propose a novel microorganism oxygen metabolism engineering strategy using an injectable cyanobacteria-laden hydrogel (R-alga) that enables light-dependent dynamic oxygen regulation to mimic native physiological oxygen gradients. Under infrared ray (red) light irradiation, cyanobacteria within R-alga efficiently produce oxygen via photosynthesis, specifically targeting and alleviating hypoxia in the inflamed synovial region. This process significantly suppresses the aberrant expression of HIF-1α in macrophages, ameliorates their metabolic dysfunction, and effectively scavenges ROS, ultimately inducing macrophage polarization toward an pro-regenerative phenotype. In the absence of light, cyanobacteria within R-alga actively consume oxygen through respiration, creating and maintaining a physiologically relevant hypoxic microenvironment in the cartilage defect area. This environment stabilizes HIF-1α expression in chondrocytes, activates the HIF-1α-DOT1L signaling axis, and significantly enhances the biosynthesis of key cartilage matrix components, thereby facilitating cartilage repair. Collectively, the microorganism oxygen metabolismengineering strategy offers a breakthrough for precise control of the osteoarthritis microenvironment and therapy.