Co-delivery of PROTAC and siRNA via novel liposomes for the treatment of malignant tumors.

Schematic representation of co-delivery liposomes for the treatment of malignant tumors. [Display omitted] • Efficient co-loading of PROTAC and siRNA into novel liposomes. • Enhancement of PROTAC drug solubility and endocytosis via a novel lipid nanodelivery system. • Synergistic action of PROTAC and siRNA for enhanced degradation of BCL-xL target protein. • Augmented tumor therapeutic effects through synergistic interaction of PROTAC and siRNA. Targeted elimination of damaged or overexpressed proteins within the tumor serves a pivotal role in regulating cellular function and restraining tumor cell growth. Researchers have been striving to identify safer and more effective methods for protein removal. Here, we propose the synergistic employment of a small molecule degrading agent (PROTAC) and siRNA to attain enhanced protein clearance efficiency and tumor therapeutic effects. Co-delivery liposomes were prepared to facilitate the efficient encapsulation of PROTAC and siRNA. Specifically, the cationic liposome significantly improved the solubility of the insoluble PROTAC (DT2216). The cationic polymer (F-PEI) achieved efficient encapsulation of the nucleic acid drug, thereby promoting endocytosis and enhancing the therapeutic impact of the drug. Both in vivo and in vitro experiments demonstrated remarkable degradation of target proteins and inhibition of tumor cells by the co-delivery system. In conclusion, the co-delivery liposomes furnished a nano-delivery system proficient in effectively encapsulating both hydrophilic and hydrophobic drugs, thereby presenting a novel strategy for targeted combination therapy in treating tumors. [ABSTRACT FROM AUTHOR]