Nano-Proteolysis Targeting Chimeras (Nano-PROTACs) in Cancer Therapy

Abstract

Yue Song,1,* Qing-Qing Dong,2,* Yi-Ke Ni,3 Xiao-Ling Xu,3 Chao-Xiang Chen,3 Wei Chen2 1Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, People’s Republic of China; 2ICU, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China; 3Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang Province, 310015, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Ling Xu; Chao-Xiang Chen, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, 310015, People’s Republic of China, Email [email protected]; [email protected]: Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have the capability to induce specific protein degradation. While playing a revolutionary role in effectively degrading the protein of interest (POI), PROTACs encounter certain limitations that impede their clinical translation. These limitations encompass off-target effects, inadequate cell membrane permeability, and the hook effect. The advent of nanotechnology presents a promising avenue to surmount the challenges associated with conventional PROTACs. The utilization of nano-proteolysis targeting chimeras (nano-PROTACs) holds the potential to enhance specific tissue accumulation, augment membrane permeability, and enable controlled release. Consequently, this approach has the capacity to significantly enhance the controllable degradation of target proteins. Additionally, they enable a synergistic effect by combining with other therapeutic strategies. This review comprehensively summarizes the structural basis, advantages, and limitations of PROTACs. Furthermore, it highlights the latest advancements in nanosystems engineered for delivering PROTACs, as well as the development of nano-sized PROTACs employing nanocarriers as linkers. Moreover, it delves into the underlying principles of nanotechnology tailored specifically for PROTACs, alongside the current prospects of clinical research. In conclusion, the integration of nanotechnology into PROTACs harbors vast potential in enhancing the anti-tumor treatment response and expediting clinical translation. Keywords: Proteolysis-targeting chimeras, nanotechnology, delivery, linker, designing principles

Keywords

• proteolysis-targeting chimeras
• nanotechnology
• delivery
• linker
• designing principles