Tumor　hypoxic　microenvironment　contributes　to　AZD9291　(osimertinib)　resistance　in　non-small　cell　lung　cancer　(NSCLC).　Developing　hypoxia-triggered　theranostic　formulation　for　simultaneous　hypoxia　tumor　imaging　and　oxygen-independent　photothermal　therapy　(PTT)　will　be　an　effective　strategy　to　overcome　AZD9291　resistance　under　hypoxic　conditions.　Herein,　we　designed　and　synthesized　a　boron-dipyrromethene　(BODIPY)　dye-modified　chitosan　(CsB)　linked　through　a　hypoxia-responsive　azobenzene　group　and　fabricated　a　nanoplatform　CsBANs　self-assembled　by　CsB　and　AZD9291　to　achieve　hypoxia-responsive　imaging　and　synergistic　PTT/targeted　molecular　therapy.　CsBANs　exhibited　excellent　cellular　uptake　efficiency　and　hypoxia　imaging　capacity　either　in　two-dimensional　NSCLC　cell　cultures　under　hypoxia　or　in　multicellular　tumor　spheroids.　The　in　vitro　and　in　vivo　results　showed　that　the　photothermal　effects　of　BODIPY　and　AZD9291　could　induce　satisfactory　anticancer　effects　in　NSCLC　cell　lines　and　in　xenograft　mouse　model.　Hence,　this　work　presents　a　promising　hypoxia-activated　nanotheranostic　platform　to　deal　with　hypoxia-induced　AZD9291　resistance　and　for　other　hypoxia-related　diseases.　©　2022　Elsevier　Ltd