Recent Advances in Nanotechnology for Targeted Protein Degradation

Abstract Mutations or overexpression of proteins contribute to the pathogenesis and progression of numerous diseases, including cancers and neurodegenerative disorders. Traditional small-molecule inhibitors have played a crucial role in treating these diseases; however, they still face several limitations, such as off-target toxicity due to high required concentrations and the inability to inhibit undruggable proteins. Targeted protein degradation (TPD) technology, which operates via a catalytic degradation mechanism, has partially addressed these challenges. Nevertheless, its relatively large molecular weight often leads to issues such as poor solubility and low bioavailability, significantly hindering in vivo application. Nanotechnology offers a promising platform to overcome these obstacles. It can not only serve as a delivery system to transport TPD molecules to disease sites in response to various signals, thereby enhancing targeting specificity, but can also possess inherent TPD functionality. Through flexible structural design, nanotechnology enables the investigation of various factors influencing degradation efficiency, thereby providing theoretical guidance for developing more effective TPD strategies. This work highlights that nanotechnology, as a flexibly and precisely tunable multifunctional platform, facilitates the exploration of core mechanisms that dominate the protein degradation efficiency of TPD technology. The summarized research rules provide rational guidance for the design of high-efficiency TPD systems. Furthermore, this review systematically discusses the existing bottlenecks of current nano-TPD strategies, aiming to advance the construction of high-performance nano-TPD platforms and accelerate their clinical translation.