Mitochondria-specific gadolinium (III) porphyrinate as efficient ROS generator for MRI visualization and sonodynamic-immunotherapy of deep localized tumors

Conventional sonodynamic therapy (SDT) is still limited in conquering localized tumors owing to its low reactive oxygen species (ROS)-based therapeutic effect and undesirably inhibiting effect of immunosuppressive tumor microenvironment (ITM). In this study, we reasonably designed a new sonosensitizer, gadolinium (III) porphyrinate (GdPorP), which could efficiently produce ROS upon ultrasound irradiation and specifically accumulate in mitochondria. The GdPorP-based mitochondria-specific sonodamage could induce high-efficiency cell apoptosis and cascade to producing large-scale immunogenic cell death. After GdPorP systematically delivered together with the indoleamine 2,3-dioxygenase (IDO) inhibitor by a pH-sensitive nanomedicine, the localized liver tumor was specifically mapped by the "switching-on" MRI. And the nanomedicine could not only efficiently suppress the progression of primary liver tumors but also simultaneously boost the systematic antitumor immune effect via the inhibition of ITM. The GdPorP-approved sonodynamic-immunotherapy (SDIT) has thereby been established as a new paradigm for upgrading the efficacy of cancer SDT.