Inducing　pyroptosis　in　cancer　cells　holds　great　potential　in　cancer　immunotherapy.　Lipopolysaccharide　(LPS)-sensing　noncanonical　pathways　are　an　important　mechanism　of　pyroptosis　to　eliminate　damaged　cells,　which　has　not　yet　been　explored　for　cancer　immunotherapy.　Here,　we　utilize　bacterial　outer　membrane　vesicles　(OMVs)　as　a　natural　LPS　carrier　to　trigger　a　noncanonical　pyroptosis　pathway　for　immunotherapy.　To　address　the　concern　of　systemic　toxicity,　molecule　engineered　OMVs　were　designed　by　equipping　DNA　aptamers　on　the　OMVs　(Apt-OMVs).　In　addition　to　improving　capacity　to　target　tumors,　Apt-OMVs　also　took　advantage　of　the　spherical　nucleic　acid　structure　to　shield　OMVs　against　nonspecific　immune　recognition　and　evade　immunogenicity.　The　selective　pyroptosis　enhanced　tumor　immunogenicity,　not　only　promoting　the　infiltration　of　effector　T　cells　but　also　reducing　the　amount　of　immunosuppressive　regulatory　T　cells,　which　remarkably　suppressed　tumor　growth.　This　work　reports　the　first　pyroptosis　inducer　by　the　noncanonical　pathway,　offering　inspiration　for　safe　and　efficient　pyroptosis-mediated　immunotherapy.　©　2023　American　Chemical　Society