Radiotherapy　(RT)　utilizes　the　non-invasive　and　high　penetration　X-ray　as　the　energy　source　to　eliminate　deep-seated　tumors.　The　efficacy　of　RT　can　be　optimized　by　designing　effective　radiosensitizers　and　synergizing　with　other　treatment　methods.　Glutathione　(GSH)-responsive　radio-sensitizing　nanovesicles　are　designed　with　size-transformability　via　self-assembly　of　gold-manganese　oxide　Janus　nanoparticles　(JNPs)　encapsulating　the　near-infrared　fluorescence　(NIR)　dye　(IR1061).　In　the　presence　of　GSH,　JNP　vesicles　(Ves)　dissociate　into　smaller　gold　(Au)　NPs　and　manganese　ion　(Mn2+)　that　not　only　penetrate　into　the　deeper　layers　of　the　tumor　but　also　deplete　the　GSH　and　trigger　chemodynamic　therapy　(CDT)　through　a　Fenton-like　reaction,　which　augments　the　efficacy　of　RT.　In　addition,　the　IR1061　released　from　the　disintegrated　nanostructures　fluoresces　in　the　NIR-II　window,　and　along　with　photoacoustic　(PA)　and　magnetic　resonance　imaging　(MRI)　enables　high　precision　tumor　detection.　The　combination　of　JNP　Ve　and　X-ray　irradiation　achieves　multimodal　image-guided　ablation　of　subcutaneous　as　well　as　deep-seated　tumors　in　murine　models.　Therefore,　this　novel　multimodal　image-guided　RT/CDT　therapeutic　platform　is　a　promising　strategy　in　high-precision　tumor　therapy.　©　2021　Wiley-VCH　GmbH