The　clinical　efficacy　of　epidermal　growth　factor　receptor-tyrosine　kinase　inhibitors　(EGFR-TKIs)-based　targeted　molecular　therapies　(TMT)　is　inevitably　hampered　by　the　development　of　acquired　drug　resistance　in　non-small　cell　lung　cancer　(NSCLC)　treatment.　Sonodymanic　therapy　(SDT)　is　a　promising　new　cancer　treatment　approach,　but　its　effects　are　restricted　by　tumor　hypoxia.　Herein,　a　nanoplatform　fabricated　by　erlotinib-modified　chitosan　loading　sonosensitizer　hematoporphyrin　(HP)　and　oxygen-storing　agent　perfluorooctyl　bromide　(PFOB),　namely　CEPH,　was　developed　to　deliver　HP　to　erlotinib-sensitive　cells.　CEPH　with　ultrasound　could　alleviate　hypoxia　inside　the　three-dimensional　multicellular　tumor　spheroids,　suppress　NSCLC　cell　growth　under　normoxic　or　hypoxic　condition,　and　enhance　TMT/SDT　synergistic　effects　through　elevated　production　of　reactive　oxygen　species,　decrease　of　mitochondrial　membrane　potential,　and　down-regulation　of　the　expression　of　the　proteins　EGFR,　p-EGFR,　and　HIF-1α.　Hence,　CEPH　could　be　a　potential　nanoplatform　to　improve　the　efficacy　of　oxygen-dependent　SDT　and　overcome　hypoxia-induced　TMT　resistance　for　enhanced　synergistic　TMT/SDT.　©　2021　Elsevier　Ltd