Screening of Zwitterionic Liposomes with Red Blood Cell‐Hitchhiking and Tumor Cell‐Active Transporting Capability for Efficient Tumor Entrance

Abstract The active transport of nanoparticles into the solid tumor through cell transcytosis has shown great promise in cancer nanomedicine, but it is challenging to develop efficient active transporting nanomedicines with the potential for clinical translation. Here, a type of tertiary amine oxide (TAO)‐containing zwitterionic liposomal nanocarriers is developed that can hitchhike red blood cells (RBCs) to tumor blood vessels and enter solid tumors through transcytosis. To boost the active‐transporting capability, a library of the TAO liposomes (TAOLs) with different chemical structures and particle sizes is constructed and screened by their stability and active transporting capability. Two types of TAOLs are identified that can induce efficient tumor cell transcytosis through rapid macropinocytosis and endoplasmic reticulum/Golgi‐involved exocytosis. It is found that these zwitterionic TAOLs can hitchhike RBCs to gain long blood circulation, get off the cell at the tumor site, effectively enter the tumor through transcytosis, and infiltrate the whole tumor. The chemotherapeutic drug‐loaded liposomes can stop the tumor progression of mice bearing human hepatocellular carcinoma HepG2 cells, exhibiting superior antitumor activity compared to the traditional liposomal drug. This study demonstrates a strategy to construct effective active transporting liposomal nanomedicines for efficient tumor entrance.