Purpose Current chemotherapy fails to offer a desirable efficacy in clinical treatment against breast cancer due to the extensive multi-drug resistance. In this study, we developed dual sensitization anti-resistant nanoparticles to treat refractory breast cancer, aiming to benefit from photodynamic therapy and chemotherapy. Methods Hyaluronic acid (HA) derivative and photosensitizer chlorin e6 (Ce6) derivative were synthesized and confirmed by mass spectrometry. These derivatives and the chemotherapy agent paclitaxel were incorporated into nanoparticles by an emulsion-solvent evaporation method. The prepared nanoparticles were characterized by dynamic laser scattering, atomic force microscopy, and high performance liquid chromatography (HPLC). The efficacy and mechanisms of the nanoparticles, both in vitro and in vivo, were investigated by flow cytometry, confocal/fluorescence microscopy, and a high-content screening system. Results The prepared dual sensitization anti-resistant nanoparticles were round with a diameter of ~ 100 nm, exhibiting high encapsulation efficiency for the anticancer agent paclitaxel. The nanoparticles demonstrated a robust inhibitory effect against drug-resistant breast cancer cells by enhanced uptake, synergistic effect of photodynamic therapy and chemotherapy, and apoptosis-inducing via multiple pathways. In vivo efficacy, biocompatibility and safety were further confirmed acceptable in tumor-bearing mice. Conclusion The prepared dual sensitization anti-resistant nanoparticles were promising to treat refractory breast cancer with a controllable treatment site and minimal side effects.