Acute　lymphoblastic　leukemia　(ALL)　is　an　aggressive　malignancy.　Adults　with　ALL　have　more　than　50%　relapse　rates.　We　have　previously　validated　that　overexpression　of　nucleophosmin　(NPM)　is　involved　in　the　multidrug　resistance　(MDR)　development　during　ALL;　and　a　synthetically　engineered　recombinant　NPM　binding　protein　(NPMBP)　has　been　developed　in　our　group;　NPMBP　and　doxorubicin　(DOX)　can　be　conjugated　in　a　nanoparticle-based　drug　delivery　system　named　DOX-PMs-NPMBP　to　counteract　MDR　during　ALL.　Here,　we　evaluated　the　antileukemia　potential　of　DOX-PMs-NPMBP　in　resistant　ALL　cells.　This　study　demonstrates　that　DOX-PMs-NPMBP　significantly　enhances　chemosensitivity　to　DOX　in　ALL　cells.　Despite　at　variable　concentrations,　both　resistant　and　primary　ALL　cells　from　relapsed　patients　were　sensitive　to　DOX-PMs-NPMBP.　In　detail,　the　half　maximal　inhibitory　concentration　(IC50)　values　of　DOX-PMs-NPMBP　were　between　1.6-　and　7.0-fold　lower　than　those　of　DOX　in　cell　lines　and　primary　ALL　cells,　respectively;　and　apoptotic　cells　ratio　was　over　2-fold　higher　in　DOX-PMs-NPMBP　than　DOX.　Mechanistically,　p53-driven　apoptosis　induction　and　cell　cycle　arrest　played　essential　role　in　DOX-PMs-NPMBP-induced　anti-leukemia　effects.　Moreover,　DOX-PMs-NPMBP　significantly　inhibited　tumor　growth　and　prolonged　mouse　survival　of　ALL　xenograft　models;　and　no　systemic　toxicity　occurrence　was　observed　after　treatment　during　follow-up.　In　conclusion,　these　data　indicate　that　DOX-PMs-NPMBP　may　significantly　exert　growth　inhibition　and　apoptosis　induction,　and　markedly　improve　DOX　antileukemia　activity　in　resistant　ALL　cells.　This　novel　drug　delivery　system　may　be　valuable　to　develop　as　a　new　therapeutic　strategy　against　multidrug　resistant　ALL.