AbstractLiposome, a widely used drug delivery system (DDS), still shows several disadvantages such as dominant clearance by liver and poor target organ deposition. To overcome the drawbacks of liposomes, we developed a novel red blood cell (RBC)–liposome combined DDS to modulate the tumor accumulation and extend the blood circulation life of the existing liposomal DDS. Here, RBCs, an ideal natural carrier DDS, were utilized to carry liposomes and avoid them undergo the fast clearance in the blood. In this study, liposomes could either absorbed onto RBCs’ surface or fuse with RBCs’ membrane by merely altering the interaction time at 37°C, while the interaction between liposome and RBCs would not affect RBCs’ characteristics. In thein vivoantitumor therapeutic efficacy study, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes attached onto RBCs’ surfaces exhibited lung targeting effect (via RBC-hitchhiking approach) and reduced clearance in the liver, while DPPC liposomes fused with RBCs had prolong blood circulation up to 48 h and no enrichment in any organ. Furthermore, 20 mol% of DPPC liposomes were replaced with pH-sensitive phospholipid 1,2-dioleoyl-Sn-glycero-3-phosphoethanolamine (DOPE) as it could respond to the low pH tumor microenvironment and then accumulate in the tumor. The DOPE attached/fusion RBCs showed partial enrichment in lung and about 5–8% tumor accumulation, which were significantly higher than (about 0.7%) the conventional liposomal DDS. Thus, RBC–liposome composite DDS is able to improve the liposomal tumor accumulation and blood circulation and shows the clinical application promises of using autologous RBCs for antitumor therapy.