Tumor　hypoxia　is　a　common　feature　of　the　tumor　microenvironment　and　has　been　regarded　as　one　of　the　key　factors　in　driving　the　emergence　of　drug　resistance　in　solid　tumors.　To　surmount　the　hypoxia-associated　drug　resistance,　we　fabricated　the　novel　multifunctional　liposomal　complexes　(ACLEP)　that　could　co-deliver　oxygen　and　molecular　targeted　drug　to　overcome　the　hypoxia-induced　drug　resistance　in　lung　cancer.　The　ACLEP　were　fabricated　with　liposomes　anchored　with　anti-EGFR　aptamer-conjugated　chitosan　to　co-administrate　erlotinib　and　PFOB　to　EGFR-overexpressing　non-small-cell　lung　cancer.　Our　results　showed　that　the　ACLEP　possessed　desired　physicochemistry,　good　biostability　and　controlled　drug　release.　The　entrapped　PFOB　in　nanoparticle　facilitated　the　uptake　of　ACLEP　in　either　normoxia　or　hypoxic　condition.　Comparing　to　those　nanoparticles　loading　erlotinib　alone,　our　innovative　oxygen/therapeutic　co-delivery　system　showed　a　promising　outcome　in　fighting　against　hypoxia-evoked　erotinib　resistance　both　in　vitro　and　in　vivo.　Hence,　this　work　presents　a　potent　drug　delivery　platform　to　overcome　hypoxia-induced　chemotherapy　resistance.　(C)　2017　Elsevier　Ltd.　All　rights　reserved.