Ferroptosis　is　a　newly　detected　iron-dependent　form　of　regulated　cell　death.　Sono-photodynamic　therapy　(SPDT)　can　generate　reactive　oxygen　species　(ROS)　and　induce　cell　death　under　light　and　ultrasound.　Due　to　the　complexity　of　tumor　physiology　and　pathology,　single-modality　often　fails　to　achieve　a　satisfactory　therapeutic　effect.　The　development　of　a　formulation　platform　with　integration　of　multiple　therapeutic　modalities　using　a　simple　and　convenient　method　is　still　a　challenge.　Here,　we　report　the　facile　construction　of　a　ferritin-based　nanosensitizer　FCD　by　co-encapsulating　chlorin　e6　(Ce6)　and　dihydroartemisinin　(DHA)　in　horse　spleen　ferritin,　and　was　employed　for　synergistic　ferroptosis　and　SPDT.　Ferritin　in　FCD　can　release　Fe3+　under　acidic　conditions　and　Fe3+　can　be　reduced　to　Fe2+　in　the　presence　of　glutathione　(GSH).　The　Fe2+　can　react　with　hydrogen　peroxide　(H2O2)　to　produce　harmful　hydroxyl　radicals.　Furthermore,　a　large　amount　of　ROS　can　be　generated　via　the　reaction　of　Fe2+　with　DHA　and　by　simultaneously　irradiation　of　FCD　with　both　light　and　ultrasound.　More　importantly,　the　depletion　of　GSH　by　FCD　could　decrease　glutathione　peroxidase　4　(GPX4)　and　increase　lipid　peroxidation　(LPO)　levels,　thereby　inducing　ferroptosis.　Therefore,　by　integrating　the　advantageous　GSH-depletion　capacity,　ROS　generation　ability,　and　ferroptosis　induction　capability　into　one　single　nanosystem,　FCD　can　serve　as　a　promising　platform　for　combined　chemo-sono-photodynamic　therapy　of　cancer.　©　2023　The　Royal　Society　of　Chemistry.