α-Lipoic acid: from a mitochondrial cofactor to a versatile platform for dynamic biomaterials and translational biomedicine.

Abstract

α-Lipoic acid (LA) is a naturally occurring small molecule possessing both endogenous cofactor activity and dynamic covalent polymerization capability. The 1,2-dithiolane ring in its structure enables both redox-responsive biological functions and ring-opening polymerization to yield polylipoic acid (PolyLA) with a dynamic disulfide backbone, bridging small-molecule medicinal chemistry and functional polymeric materials within a single molecular platform. This Review systematically outlines the full landscape of LA research, covering its chemical foundations, biological functions, polymer chemistry, and biomedical applications. We elaborate on the multi-pathway redox and anti-inflammatory network of LA and its reduced form, as well as their vital roles as mitochondrial cofactors in energy metabolism and insulin sensitivity. We then compare the mechanisms and applicable scenarios of various ring-opening strategies, dissect the origin of room-temperature PolyLA depolymerization, and summarize the corresponding stabilization strategies. Further, we propose a three-stage evolutionary framework for LA-based nanoscale delivery systems, ranging from physical encapsulation and chemical conjugation to the therapeutic self-carrier paradigm; we also systematically recapitulate their design rationales and mechanisms in treating tumors, nerve injury, diabetic complications, inflammatory diseases, and cardiovascular diseases. As for dynamic biomaterials, PolyLA-based adhesives and flexible sensors leverage dynamic disulfide bonds and carboxyl groups to achieve universal adhesion, tissue integration, self-healing, and recyclable properties. Finally, we identify the core bottlenecks hindering clinical translation and outline forward-looking outlooks for this field. By establishing an integrated framework that connects molecular structure to multifunctional applications of LA-based biomaterials, this Review highlights how interdisciplinary integration unlocks innovative research avenues and accelerates the clinical translation of LA-derived therapeutics and biomaterials.