Stimuli-triggered　release　and　alleviating　resistance　of　iridium(III)-based　drugs　at　tumor　sites　remains　challengeable　for　clinical　hepatoma　therapy.　Herein,　a　doxorubicin@iridium-transferrin　(DOX@IrTF)　nanovesicle　was　synthesized　by　carboxylated-transferrin　(TF)　and　doxorubicin-loaded　amphiphilic　iridium-amino　with　quaternary　ammonium　(QA)　groups　and　disulfide　bonds.　The　QA　groups　enhanced　photophysical　properties　and　broadened　production　capacity　of　photoinduced-reactive　oxygen　species　(ROS),　while　the　disulfide-bridged　bonds　regulated　oxidative　stress　levels　through　reacting　with　glutathione　(GSH);　simultaneously,　modification　of　TF　improved　recognition　and　endocytosis　of　the　nanovesicle　for　tumor　cells.　Based　on　in　-vitro　results,　a　controlled-release　behavior　of　DOX　upon　a　dualresponsiveness　of　GSH　and　near-infrared　ray　(NIR)　irradiation　was　presented,　along　with　high-efficiency　generation　of　ROS.　After　an　intravenous　injection,　the　nanovesicle　was　targeted　at　tumor　sites,　realizing　TF-navigated　photoacoustic　imaging　guidance　and　synergistic　chemotherapy-photodynamic　therapy　under　NIR/GSH　stimulations.　Overall,　newly-synthesized　DOX@Ir-TF　nanovesicle　provided　a　potential　in　subcutaneous　hepatocellular　carcinoma　therapy　due　to　integrations　of　targeting　delivery,　dual　-stimuli　responsive　release,　synergistic　therapy　strategy,　and　real　-time　monitoring.　(c)　2024　Published　by　Elsevier　B.V.　on　behalf　of　Chinese　Chemical　Society　and　Institute　of　Materia　Medica,　Chinese　Academy　of　Medical　Sciences.