Although　epidermal　growth　factor　receptor　tyrosine　kinase　inhibitors　(EGFR-TKIs)-based　molecular　targeted　therapy　are　proved　to　be　effective　in　the　treatment　of　non-small　cell　lung　cancer　(NSCLC)　with　EGFR　mutation,　its　efficacy　is　limited　by　the　acquired　drug　resistance.　The　combination　of　EGFR-TKIs　with　photodynamic　therapy　(PDT)　has　been　explored　to　combat　NSCLC　with　promising　synergistic　results.　However,　hypoxic　tumor　microenvironment　is　associated　with　the　development　of　EGFR-TKIs　resistance　and　severely　limits　the　efficacy　of　PDT.　Here,　we　synthesized　an　aptamer　modified　fluorinated　dendrimer　(APF)　as　a　drug　carrier　and　prepared　nanocomplexes　APFHG　by　encapsulation　of　gefitinib　(Gef)　and　hematoporphyrin　(Hp).　APF　has　good　oxygen-carrying　capacity,　high　drug　entrapment　efficiency,　and　could　release　Gef　and　Hp　in　response　to　intracellular　pH.　APF　can　specifically　recognize　EGFR-positive　NSCLC　cells　and　effectively　improve　the　tumor　hypoxic　microenvironment　due　to　the　targeting　effect　of　aptamer　and　the　good　oxygen-carrying　capacity　of　the　fluorinated　dendrimer.　Under　the　laser　irradiation,　APFHG　can　significantly　increase　the　production　of　the　intracellular　reactive　oxygen　species　and　produce　a　synergistic　therapeutic　effect　in　inhibition　of　cellular　growth　and　induction　of　cell　cycle　arrest　and　apoptosis　on　both　Gef-sensitive　and　Gef-resistant　EGFR-mutant　NSCLC　cells　through　PDT/molecular　targeted　therapy.　This　work　indicates　that　fluorinated　dendrimer　could　be　a　potent　drug　delivery　platform　to　overcome　hypoxia-related　resistance　and　the　co-delivery　of　EGFR-TKI　and　photosensitizer　by　the　fluorinated　dendrimer　could　be　a　promising　therapeutic　approach　for　reversal　of　EGFR-TKIs　resistance　in　EGFR　mutation-positive　NSCLC.