Sonodynamic　therapy　(SDT)　has　the　advantages　of　high　penetration,　non-invasiveness,　and　controllability,　and　it　is　suitable　for　deep-seated　tumors.　However,　there　is　still　a　lack　of　effective　sonosensitizers　with　high　sensitivity,　safety,　and　penetration.　Now,　ultrasound　(US)　and　glutathione　(GSH)　dual　responsive　vesicles　of　Janus　Au-MnO　nanoparticles　(JNPs)　were　coated　with　PEG　and　a　ROS-sensitive　polymer.　Upon　US　irradiation,　the　vesicles　were　disassembled　into　small　Janus　Au-MnO　nanoparticles　(NPs)　with　promoted　penetration　ability.　Subsequently,　GSH-triggered　MnO　degradation　simultaneously　released　smaller　Au　NPs　as　numerous　cavitation　nucleation　sites　and　Mn2+　for　chemodynamic　therapy　(CDT),　resulting　in　enhanced　reactive　oxygen　species　(ROS)　generation.　This　also　allowed　dual-modality　photoacoustic　imaging　in　the　second　near-infrared　(NIR)　window　and　T1-MR　imaging　due　to　the　released　Mn2+,　and　inhibited　orthotopic　liver　tumor　growth　via　synergistic　SDT/CDT.　©　2020　Wiley-VCH　Verlag　GmbH　&　Co.　KGaA,　Weinheim