Photothermal therapy combined with chemotherapy based on nanomedicine has been considered a promising strategy for improving therapeutic efficacy in a tumor. However, nanomedicine can be easily cleared by the immune system without specific surface engineering modifications, thus affecting the ultimate efficacy. Herein, multifunctional biomimetic nanoparticles (Bio-RBCm@PDA@MSN-DOX) with enhanced long circulation and targeting ability are constructed by coating large pore-sized mesoporous silica (MSN) with polydopamine (PDA) layers in a biotin modified red blood cell membrane (Bio-RBCm) for efficient chemo/photothermal synergistic therapy. It is demonstrated that Bio-RBCm@PDA@MSN-DOX presents high photothermal conversion efficiency (40.17%) and enhanced capability to accelerate the release of the anticancer drug (doxorubicin, DOX), thus showing a good synergistic therapeutic effect in cell experiments. More importantly, with the assistance of the biotin and RBC membrane, Bio-RBCm@PDA@MSN-DOX can successfully evade immune clearance and effectively target transport to HeLa tumor sites, finally accomplishing up to 98.95% tumor inhibition with negligible side effects to normal tissues. This multilayer structure presents a valuable model for future therapeutic applications with safe and effective tumor chemotherapy and photothermal therapy.