Although　novel　molecular　targeted　drugs　have　been　recognized　as　an　effective　therapy　for　non-small　cell　lung　cancer　(NSCLC)　harboring　epidermal　growth　factor　receptor　(EGFR)　activating　mutations,　their　efficacy　fails　to　meet　the　expectation　due　to　the　acquired　resistance　in　tumors.　Up-regulation　of　the　anti-apoptotic　protein　Survivin　was　shown　to　contribute　to　the　resistance　to　EGFR　tyrosine　kinase　inhibitors　(TKI)　in　EGFR　mutation–positive　NSCLC.　However,　the　unorganized　tumor　blood　vessels　impeded　drug　penetration　into　tumor　tissue.　The　resulting　insufficient　intracellular　drug/gene　delivery　in　drug-resistant　cancer　cells　remarkably　weakened　the　drug　efficacy　in　NSCLC.　In　this　work,　a　multi-functional　drug　delivery　system　AP/ES　was　developed　by　using　anti-EGFR　aptamer　(Apt)-modified　polyamidoamine　to　co-deliver　erlotinib　and　Survivin-shRNA.　Chloroquine　(CQ)　was　used　in　combination　with　AP/ES　to　normalize　tumor　vessels　for　sufficient　drug/gene　delivery　to　overcome　drug　resistance　in　NSCLC　cells.　The　obtained　AP/ES　possessed　desired　physicochemical　properties,　good　biostability,　controlled　drug　release　profiles,　and　strong　selectivity　to　EGFR-mutated　NSCLC　mediated　by　Apt.　CQ　not　only　enhanced　endosomal　escape　ability　of　AP/ES　for　efficient　gene　transfection　to　inhibit　Survivin,　but　also　showed　strong　vessel-normalization　ability　to　improve　tumor　microcirculation,　which　further　promoted　drug　delivery　and　enhanced　drug　efficacy　in　erlotinib-resistant　NSCLC　cells.　Our　innovative　gene/drug　co-delivery　system　in　combination　with　CQ　showed　a　promising　outcome　in　fighting　against　erlotinib　resistance　both　in　vitro　and　in　vivo.　This　work　indicates　that　normalization　of　tumor　vessels　could　help　intracellular　erlotinib/Survivin-shRNA　delivery　and　the　down-regulation　of　Survivin　could　act　synergistically　with　erlotinib　for　reversal　of　erlotinib　resistance　in　EGFR　mutation-positive　NSCLC.　Statement　of　Significance:　NSCLC　patients　who　benefited　from　EGFR-TKIs　inevitably　developed　acquired　resistance.　Previous　research　focused　on　synthesis　of　new　generation　of　molecular　targeted　drugs　that　could　irreversibly　inhibit　EGFR　with　a　particular　gene　mutation　to　overcome　drug　resistance.　However,　they　failed　to　inhibit　EGFR　with　other　gene　mutations.　Activation　of　bypass　signaling　pathway　and　the　changes　of　tumor　microenvironment　are　identified　as　two　of　the　mechanisms　of　acquired　resistance　to　EGFR-TKIs.　We　therefore　constructed　multifunctional　gene/drug　co-delivery　nanocomplexes　AP/ES　co-formulated　with　chloroquine　that　could　target　the　both　two　mechanisms.　We　found　that　chloroquine　not　only　enhanced　endosomal　escape　ability　of　AP/ES　for　efficient　gene　transfection　to　inhibit　Survivin,　but　also　showed　strong　vessel-normalization　ability　to　improve　tumor　microcirculation,　which　further　promoted　drug　delivery　into　tumor　tissue　and　enhanced　drug　efficacy　in　erlotinib-resistant　NSCLC.　©　2018　Acta　Materialia　Inc.