Engineering “Trojan Horse” disguised by cancer cell membranes for mitochondrial targeting and amplified immunotherapy

Abstract

As the most promising strategy for cancer treatment, immunotherapy has attracted much attention, but its treatment effect is still blocked by the deficient immune response efficiency. In light of the significant role of mitochondria in cell metabolism, it has been considered to be a promising target to amplify immune response. In this report, a mitochondria-targeted nanodrug (UCNP@COF@FeCO/TPP@CM, UCFT@CM), camouflaged by cancer cell membrane (CM), was designed to realize cascade target and enhance immune response, further achieving the synergistic therapy of photodynamic therapy (PDT), CO gas therapy and immunotherapy. With the assistance of CM, the nanodrug exhibited significant enhancement on homologous targeting. After endocytosis, UCFT@CM would accumulate in mitochondria and realize controlled release of CO and enhanced PDT relying on the characteristics of mitochondria, further leading to serious mitochondrial oxidative stress and amplified immunotherapy. In addition, we verified that a new immune signal related to mitochondrial oxidative stress, mitochondrial transcription factor A (TFAM), is strongly associated with immunogenic cell death (ICD). Taken together, the sequenced targeting treatment makes full use of characteristics of mitochondria and provides a new approach for precisely targeting organelle to enhance the immune response.