From metabolic node to smart building block: α-Ketoglutarate-empowered biomaterials for programmable cell fate.

α-Ketoglutarate serves as a metabolic node in tricarboxylic acid cycle. In recent years, its role has expanded far beyond that of an energy supplier, emerging as a crucial regulator that programs cell fate by modulating the epigenetic landscape, delaying cellular aging, and maintaining immune homeostasis. However, the clinical translation of AKG has been severely hindered by the inherent pharmacokinetic deficiencies of its monomeric form, such as low bioavailability, short in vivo half-life, and poor tissue targeting. This review proposes a paradigm shift: redefining AKG from a mere "therapeutic molecule" to a "smart building block" for AKG-empowered biomaterials. The core of this concept lies in leveraging AKG's intrinsic functional groups to directly participate in biomaterial synthesis through covalent bonds, thereby integrating it as an intrinsic component of the material framework. This achieves a leap from "passive transportation" to "active construction." The review systematically delineates the main biological effects of AKG and evaluates three progressive engineering strategies for AKG-empowered biomaterials: from protected "cargo," to functionally synergistic "adjuvant," and ultimately to the material "framework" itself. Emphasis is placed on the significant application prospects of these intelligent materials in fields such as bone and cartilage regeneration, soft tissue repair, immune homeostasis regulation, and enhanced oncotherapy through specific cell fate programming. Finally, current challenges are addressed, and an outlook on future directions is provided. This review aims to offer a blueprint for bridging the gap from basic biology to advanced material design, promoting the establishment of a new paradigm: "metabolism-guided materialization of cell fate programming."