Highly efficient and long-acting split-and-mix proteolysis targeting chimera based on self-assembled polylactic acid.

Proteolysis targeting chimera (PROTAC) technology has received extensive attention due to its "event-driven" mechanism of action. However, existing chimera molecules tend to have higher molecular weight and higher polar surface area and exhibit lower druggable properties. In order to effectively improve the bioavailability, circulation time and other proprietary drug parameters of "chimera molecules", we combine the characteristics of nanotechnology and chimera technology, and propose the strategy of "Split-and-Mix" proteolysis degradation (SM-PROTAC) technology. However, both peptide- and liposome-based SM-PROTAC showed suboptimal in vivo efficiency. Hence, in this study, we incorporated Polylactic acid (PLA), an FDA-approved biomedical material, as the self-assembled matrix for SM-PROTAC to enhance in vivo effectiveness. PLA-based SM-PROTACs successfully degrade model targets including BRD4, ERα, and CDK4 in cellular assays and display more obvious tumor inhibition in vivo in female mice with a lower target ligand content (~1/10 of small molecule PROTAC controls) and long-term therapeutic potential (1 injection per three days vs 1 injection every day). In summary, PLA-based SM-PROTACs demonstrate promising drug characteristics and present obvious advantages in low-dose and long-term applications, providing additional insights into the pharmaceutical potential of the SM-PROTAC strategy.