UNLABELLED: In recent years, indocyanine green (ICG) encapsulated in different kinds of nano-carriers have been developed to overcome its short lifetime in vivo and non-selectivity in cancer cells. However, these nanoparticles are still easily recognized and captured by the reticuloendothelial system (RES) and the low singlet oxygen quantum (0.08) of ICG inevitably leads to a limited efficacy of phototherapy. To overcome these limitations, a novel oxygen self-enriched biomimetic red blood cell (RBC) was developed by cloaking albumin nanoparticles which contained ICG and perfluorocarbon (PFC) with RBC membranes. Due to the high oxygen capacity of PFC, the oxygen self-enriched nanoparticles can enhance photodynamic therapy (PDT) by generating more singlet oxygen (O). After successfully coated RBC membranes onto nanoparticles, the novel oxygen self-enriched biomimetic RBCs remained the characteristics of photothermal therapy (PTT) and enhanced PDT in vitro. Importantly, it can effectively reduce immune clearance in macrophage cells (RAW264.7) and significantly prolong blood circulation time, achieving high accumulation in tumor. In addition, the tumor growth was effectively inhibited after intravenous injection to tumor-bearing mice. Altogether, this oxygen self-enriched RBCs with long circulation time and high oxygen capacity as natural RBCs provide a new strategy to design biomimetic nano-system for clinical cancer phototherapy treatment. STATEMENT OF SIGNIFICANCE: Near-infrared (NIR) dyes encapsulated in nanocarriers have been achieved great interest in cancer phototherapy treatment. However, the low singlet oxygen (O) quantum of NIR dyes and short circulation time of nanoparticles lead to unsatisfactory efficacy, limiting their applications. In this study, a novel oxygen self-enriched biomimetic red blood cell (bio-RBC) was developed to produce fluorescence, imaging-guided for photothermal therapy (PTT) and enhanced photodynamic therapy (PDT). It was composed of RBC membranes and albumin nanoparticles (IPH) which contained indocyanine green (ICG) and perfluorocarbon (PFC). After RBC membranes successfully being coated on nanoparticles, bio-RBC can effectively reduce immune clearance in macrophage cells and achieve longer circulation time in vivo, due to the protein retention in RBC membranes. In addition, PFC with high oxygen capacity can provide more oxygen to generate more O and dissolve O to enhance its life-time, enhancing PDT cancer treatment. In summary, the novel bio-RBC with longer lifetime and higher oxygen capacity as natural RBCs can significantly accumulate on tumor and effectively enhance phototherapy. It could serve as a novel strategy to overcome the problems of NIR dyes encapsulated nanoparticles, promising for future clinical application.