A multifunctional nanoplatform delivering carbon monoxide and a cysteine protease inhibitor to mitochondria under NIR light shows enhanced synergistic anticancer efficacy

Photoactivated chemotherapy has attracted widespread attention due to its ability to circumvent the shortcomings of hypoxia in tumor tissues compared with traditional photodynamic therapy. In this work, novel multifunctional nanoplatform (1), Ru-inhibitor@TPPMnCO@N-GQDs, was designed and prepared, which was capable of mitochondria-targeted co-delivery of the cysteine protease inhibitor and carbon monoxide (CO) stimulated with an 808 nm near infrared (NIR) laser. Nanoplatform (1) was prepared by covalent attachment of a mitochondria-targeted CO donor (TPPMnCO) and a Ru(ii)-caged cysteine protease inhibitor (Ru-inhibitor) on the surface of fluorescent N-doped graphene quantum dots (N-GQDs). Nanoplatform (1) preferentially accumulated in the mitochondria of cancer cells and instantly delivered CO and the cysteine protease inhibitor upon 808 nm NIR light irradiation, thus damaging mitochondria and leading to significant in vitro and in vivo anticancer efficacy. In addition, nanoplatform (1) has good biocompatibility and did not exert any toxic side effects on mice during the period of treatment. The targeted subcellular mitochondrial co-delivery of CO and the cysteine protease inhibitor may provide new insights into CO and enzyme inhibitor combined therapies for cancer treatment.