Inflammation is involved in many human pathologies, including osteoarthritis (OA). Hydrogen (H 2 ) is known to have anti-inflammatory effects; however, the bioavailability of directly administered H 2 gas is typically poor. Herein, a local delivery system that can provide a high therapeutic concentration of gaseous H 2 at inflamed tissues is proposed. The delivery system comprises poly(lactic-co-glycolic acid) microparticles that contain magnesium powder (Mg@PLGA MPs). Mg@PLGA MPs that are intra-muscularly injected close to the OA knee in a mouse model can act as an in situ depot that can evolve gaseous H 2 continuously, mediated by the cycle of passivation/activation of Mg in body fluids, at a concentration that exceeds its therapeutic threshold. The analytical data that are obtained in the biochemical and histological studies indicate that the proposed Mg@PLGA MPs can effectively mitigate tissue inflammation and prevent cartilage from destruction, arresting the progression of OA changes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)