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Biomaterials, due to their functional and structural diversity, hold significant clinical translation potential to meet various needs in OA management. However, the development of biomaterial scaffold strategies must align closely with advancements in the understanding of OA pathophysiology. This review revisits the interplay between aging, hypoxic microenvironments, and OA progression from a novel perspective. It details the aging\u2010related phenotypes characterized by impaired autophagy and inflammation in various OA\u2010affected tissues and introduces NDRG\u2010mediated hypoxia regulation mechanisms that function independently of the hypoxia\u2010inducible factor (HIF) family. Additionally, it systematically summarizes biomaterial scaffold strategies for OA treatment, including hydrogels, nanoparticles, microneedles, and exosomes. These strategies, inspired by new insights, aim to enhance drug bioavailability, reduce systemic effects, prolong therapeutic duration, and ameliorate the adverse microenvironment of OA through multiple modes of action. 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