Liposomal and Polymeric Drug Delivery of Creatine: Exploring a Multifaceted Molecule for Neurodegenerative Diseases and Beyond.

Creatine (Cr), best known as a sports supplement, is increasingly recognized for its multifaceted biological functions and broad therapeutic potential. Through its roles in cellular energy homeostasis, mitochondrial function, oxidative stress reduction, and neuroinflammation modulation, Cr has shown therapeutic potential in neurodegenerative diseases (NDs), cancer, and other disorders of energy metabolism. For NDs specifically, the application of Cr may be hindered by poor bioavailability, high dose requirements, and, most importantly, its limited ability to efficiently cross the blood-brain barrier (BBB). Advances in nanotechnology-based drug delivery systems have introduced new approaches that may help address these limitations by improving pharmacokinetics, facilitating BBB penetration, enabling targeted drug delivery, and supporting controlled drug release. Among these platforms, liposomes and polymer-based systems have been widely studied because of their favorable biocompatibility, safety profiles, and translational potential. These delivery strategies have mainly been evaluated in preclinical studies and in models of diseases other than NDs. This review examines the therapeutic potential of Cr in NDs by integrating current knowledge of its biological functions with developments in liposomal and polymeric drug delivery systems that may facilitate brain delivery and improve therapeutic outcomes. Recent studies of Cr-based formulations, Cr analogues, phosphocreatine, and other nanocarrier systems have provided insights into different approaches for improving Cr delivery and expanding its therapeutic applications. Furthermore, it summarizes recent progress in Cr-based nanomedicine, identifies current translational challenges, and highlights future research directions to advance Cr-based therapies, particularly for NDs, with potential applications in cancer and other energy metabolism-related disorders.