Two-photon phototriggering of ROS storm in ruthenium(II) coordinated carbon nitride for robust cancer immunotherapy

The use of Ru(II) polypyridine complexes for photodynamic therapy is receiving much attention. Despite their promising properties, these compounds are associated with a poor excitation in the biological spectral window, a highly reduced or complete loss of the therapeutic effect under hypoxic conditions, and no immune response, limiting their application. To overcome all these limitations, herein, the coordination of Ru(II) polypyridine complexes to graphitic carbon nitride nanosheets for oxygen-self-sufficient two-photon photodynamic immunotherapy is presented. The conjugates were found with an exceptionally strong two-photon absorption and could self-sufficiently produce an ROS storm consisting of ^•O₂^-, ^•OH, and ¹O₂. Upon two-photon irradiation, the nanomaterial induced cell death in hypoxic monolayer cancer cells and multicellular tumor spheroids by a combination of apoptosis, paraptosis, ferroptosis, and immunogenic cell death. The nanomaterial was found with a strong tumor growth inhibition against the primary and secondary distant tumor in a melanoma-bearing mouse model through activation of the immune system.