Nanotechnology Advances Proteolysis Targeting Chimeras (PROTACs): Transition From Basic Research to Clinical Application
Xupeng Mu, Chenpeng Mu, Mengxue Wang, Meng Chen, Huimin Liu, Haibin Lu
Abstract
Proteolysis Targeting Chimeras (PROTACs) have been extensively explored for the targeted degradation of disease-associated proteins due to their therapeutic ability to modulate proteins that are difficult to target by conventional small molecules, showing vast potential in treating refractory diseases such as cancer and neurodegenerative disorders. However, the clinical application of PROTACs is limited by their large molecular weight, low solubility, poor permeability, and the "hook effect". Fortunately, the rapid advancement of nanotechnology offers new strategies to overcome some of the key challenges faced by traditional PROTAC technologies, potentially facilitating their clinical translation. In this review, we outline the mechanisms of action of PROTACs and explore their potential clinical significance, along with the main challenges in delivering these compounds. Additionally, we comprehensively summarize recent advancements in nanotechnology for enhancing the delivery efficiency of PROTAC drugs and discuss the limitations of current strategies and future perspectives. In conclusion, this review aims to deepen researchers' understanding of this strategy, thereby advancing the clinical translation of PROTAC drugs and providing more effective strategies for treating complex, refractory diseases.