Cobalt Oxide Nanoparticle-Synergized Strategy Manipulating Autophagy, Ubiquitin-Proteasome and Photothermal Therapy for Enhanced Anticancer Therapeutics

Abstract

How to effectively enable both protein degradation pathways, which include autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS), with photothermal therapy synergistically for enhanced anticancer treatment in vivo remains a big challenge. Cobalt oxide nanoparticles (Co3O4 NPs) have attracted great interests for their biological application, including potential use for anticancer treatment although their exact mechanisms are still poorly understood. Here, we firstly report on the synergistic use of Co3O4 NPs as autophagy inhibitor, chemosensitizer and photosensitizer to manipulate protein degradation pathways (ALP and UPS) and photothermal therapy for enhanced anticancer treatments both in vitro and in vivo . Co3O4 NPs are found to block autophagic flux to induce autophagosome accumulation and lysosomal functions damage by inhibiting the lysosomal proteolytic activity and reducing the intracellular ATP level. Notably, Co3O4 NPs can further sensitize proteasome inhibitor Carfilzomib (Cfz) to promote autophagic substrates and ubiquitinated protein accumulation with increased endoplasmic reticulum stress for enhanced cancer inhibition. More importantly, taking advantages of the excellent photothermal conversion efficiency, Co3O4 NPs can further serve as photothermal sensitizer for photothermal therapy, which synergistically enhanced the anticancer efficacy of Cfz both in vitro and in vivo . This novel nanomaterial-synergized anticancer strategy synergistically manipulating autophagy, ubiquitin-proteasome system and photothermal therapy may potentially serve in more effective therapeutics against cancer.