Bioimaging　guided-radiotherapy　is　widely　investigated　as　one　of　the　mainstream　cancer　theranostic　strategies　for　precision　medicine.　Nevertheless,　background　noise　with　“always-on”　imaging　signal　and　inadequate　tumor　enrichment　restrict　disease　diagnosis　and　therapy.　Here,　a　nanogapped　gold　nanoparticles　(AuNNPs)–silver　sulfide　(Ag2S)　vesicle　(Ve)　is　designed　as　a　“biological　switch”　through　the　self-assembly　of　pH-responsive　polymer　thiolated　polystyrene-co-poly(4-vinylpyridine)　grafted　AuNNPs　and　Ag2S　quantum　dots　(QDs).　The　AuNNPs–Ag2S　Ve　exhibits　quenched　NIR-II　fluorescence　(FL)　and　enhanced　photoacoustic　signals　initially,　which　can　be　specifically　activated　by　an　acidic　environment　to　release　Ag2S　QDs　and　“turn　on”　NIR-II　FL　signal　in　the　second　near-infrared　(NIR-II,　950–1700　nm)　window.　Besides,　the　strategy　of　disease-located　NIR-II　imaging　guided　cancer　therapy　can　remarkably　enhance　the　therapeutic　efficacy　of　radiotherapy,　as　well　as　minimize　side　effects.　Such　an　intelligent　nanoplatform　with　the　ability　of　stimulus　activated　NIR-II　imaging　guided　radiotherapy　shows　great　promise　to　precision　biomedicine　in　the　future.　©　2022　Wiley-VCH　GmbH.