Black phosphorus (BP) nanosheets with excellent features have been broadly employed for cancer therapy. BPs in blood were known to form BP nanomaterial-corona complexes, yet not explored their biological effects. In this study, BPs as delivery vehicles loaded with doxorubicin (DOX) (BP-DOX) by electrostatic interaction had been successfully prepared for photothermal/chemotherapy with a tumor inhibition rate of 81.47% more than the rates of BPs (69.50%) and free DOX (51.91%) in the Hela-bearing mice model by a pH/photo-responsive controlled drug release property. Then, in vivo experiments demonstrated that the treatment of healthy mice with BPs led to mild inflammation in the body and oxidative stress in the liver and lung which caused cell apoptosis. In vitro studies further showed that oxidative stress and metabolic disorders could be induced by BPs in A549, HepG2, Beas-2B, and LO2 cells. Lastly, the RGD peptide-conjugated red blood cell (RBC) membrane-coated BPs (RGD-RBC@BP) was prepared by lipid insertion and co-ultrasound methods for efficient photo-thermal therapy (PTT) cancer via a tumor-targeted strategy. RGD-RBC@BP showed positive biocompatibility, photo-thermal properties, and increased cellular uptake by Hela cells benefited by the long circulation property of RBC and RGD peptides. Pharmacokinetics and bio-distribution study of RGD-RBC@ BP were found to prolong circulation time and tended to accumulate in the tumors, which overexpression alpha nu beta 3 integrin rather than livers after intravenous injection 24 h in vivo. After 808 nm laser irradiation, RGD-RBC@BP nanoparticles exhibited a better PTT than PEGylated BPs (BP-PEG). The active-targeting strategy of biomimetic nanomaterials based on the tumor microenvironment have been proved to have favorable biological prospects in cancer PTT.