Chemotherapy resistance hinders the successful clinical cancer therapy, because of the low sensitivity of drugs to resistant cancer cells. In resistant cancer cells, the mutant p53 possesses anti-apoptosis capability to tolerate chemotherapeutic drugs such as doxorubicin (DOX). Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables can deplete intracellular mutant p53. In this work, the black phosphorus nanosheets-based (BPN-sbased) drug delivery system integrated with PEITC can effectively decrease mutant p53 level in resistant cancer cells and realize multiple drug resistance (MDR) reversal. The intrinsic properties of BPNs could achieve synergistic photothermal/photodynamic/chemo-therapy of resistant cancer. Magnetic resonance imaging (MRI) is used to investigate the biodistribution of nanoparticles which confirmed the efficient accumulations of nano-particles at tumor sites. In vitro and in vivo anticancer experiments demonstrate the drug resistance tumor is effectively inhibited with minimal side effects by BPNs-based drug delivery system.