Mitochondria-targeting multi-metallic ZnCuO nanoparticles and IR780 for efficient photodynamic and photothermal cancer treatments

• TPP-ZC-IR-PNPs specifically targeted the mitochondria and avoided lysosomes. • Zn-doped Cu NPs are effective in inducing the ROS generation upon laser irradiation. • The photothermal and photodynamic therapy synergistically induced enhanced apoptosis and tumor suppression in vivo. Chemo-resistance has pushed cancer treatment to the boundary of failure. This challenge has encouraged scientists to look for nanotechnological solutions. In this study, we have taken this goal one step further without depending on chemotherapy. Specifically, hybrid metal, polymer, and lipid nanoparticles that formed an IR780-a photosensitizer and Zinc copper oxide incorporated nanoparticle (ZCNP) nanoparticles were utilized in a combined photothermal and photodynamic therapy. Through the mediation of triphenylphosphonium (TPP) as a mitochondria-targeting moiety, TPP-conjugated polymer-lipid hybrid nanoparticles containing ZCNP/IR-780 significantly enhanced cellular uptake by cancer cells and selectively targeted the mitochondria, which improved the induction of apoptosis. In tumor-bearing mice, the nanoparticles were detected predominantly in tumors rather than in the other principle organs, which did not show notable signs of toxicity. Both in vitro and in vivo results demonstrated a great improvement in photothermal and photodynamic efficacy in combination when compared to either one individually, and a significant inhibition of tumor growth was observed with the combined therapies. In summary, this study describes an effective mitochondria-targeting nanocarrier for the treatment of cancer using combined photothermal and photodynamic therapies.