The　development　of　efficient　and　versatile　theranostic　agents　based　on　a　single　molecule　for　sonodynamic　therapy　(SDT)　of　hypoxic　tumor　remains　a　formidable　challenge.　Herein,　we　present　a　spatiotemporally　controllable　oxygen-releasing　nanoliposomal　sonosensitizer　(PcA-PFO@FLPs)　based　on　a　multifunctional　phthalocyanine　derivative,　which　integrates　dual-modality　imaging　guidance　for　enhanced　SDT　of　hypoxic　tumors.　The　perfluoropentadecyl　ether　oxygen　reservoir　enables　PcA-PFO@FLPs　to　exhibit　ultrasound-responsive　oxygen　release,　enhancing　reactive　oxygen　species　(ROS)　generation　at　both　solution　and　cellular　levels,　thereby　demonstrating　potent　sonodynamic　activity　(IC50　=　1.55　μM)　against　4　T1　cells.　Notably,　the　nanosonosensitizer　maintains　comparable　ROS　production　efficiency　in　hypoxic　and　normoxic　cancer　cells.　This　robust　ROS　generation　not　only　triggers　mitochondrial　membrane　depolarization　(89.5　%　of　depolarization　rate)　and　apoptosis　but　also　induces　iron-free　ferroptosis　through　lipid　peroxidation　accumulation　and　glutathione　depletion　(65　%　of　depletion).　In　vivo　fluorescence　and　photoacoustic　imaging　confirmed　tumor-selective　retention　with　rapid　renal　clearance,　enabling　efficient　tumor　suppression　in　murine　models　while　maintaining　biosafety.　Thus,　this　work　establishes　a　new　paradigm　for　developing　versatile　nanosonosensitizers　for　SDT　of　hypoxic　tumors.　©　2025　Elsevier　B.V.