Bin Cui, Min Wen, Chao Zhang, Yufeng Zheng, Zhaojun Jia
ABSTRACT Hypoxic microenvironments in damaged or diseased tissues, arising primarily from inadequate or compromised vasculature, represent a critical yet often underappreciated limitation in contemporary regenerative medicine and oxygen‐reliant therapeutics such as photodynamic/sonodynamic therapy and chemotherapy/radiotherapy. Biomaterials‐based oxygen supplementation offers a promising yet underexplored strategy to alleviate or reverse local hypoxia insults. However, it remains an arduous challenge to controllably deliver and precisely replenish oxygen in accordance with the spatiotemporal demands of specific tissues. Addressing this challenge requires a thorough understanding of oxygen‐ and hypoxia‐centered pathophysiology, accurate monitoring and simulation of hypoxic conditions, and advances in the development of intelligent, designer oxygen‐delivering biomaterials. This review systematically examines fundamental theories, strategic advances, and emerging trends in precision oxygen therapy mediated by functional biomaterials. It begins by revisiting the physiopathological roles of oxygen and hypoxia, as well as strategies for hypoxia mimicry. Thereafter, the design rationale, fabrication techniques, and mechanisms of action of state‐of‐the‐art oxygen‐carrying/‐generating materials are compiled and discussed. Subsequently, bioadaptive, tissue/disease‐specific applications of these oxygenating materials are discussed, with emphasis on precision regeneration and targeted therapeutics. Finally, existing challenges and potential opportunities, from fundamental research to clinical translation, are critically assessed to spur future development. This review would be instrumental in guiding the design and utilization of self‐oxygenating biomaterials for advancing tissue engineering and disease therapy.