The enhanced permeability and retention (EPR) effect of tumors is much more complex than initially defined, and it alone is not sufficient for targeted delivery of nanosized agents. Meanwhile, poor tumor penetration is another major challenge for the treatment of solid tumors using nanoparticles. Development of delivery systems for SN38, the active metabolite of CPT-11 in human and a very potent anticancer molecule, has become an attractive research area. PEGx -p(HEMASN38)y (x and y are viable), a prodrug synthesized by using polyethylene glycol (PEG) as initiator and SN38 as monomer through atom transfer radical polymeration (ATRP) method, is previously reported. Using PEG2.4K -p(HEMASN38)3K as a model prodrug, herein an active-targeted strategy decorated with cys-arg-gly-asp-lys (CRGDK), a peptide specifically binds to neuropilin-1 overexpressed by tumor vessels and tumor cells, is successfully established to further improve the delivery and efficacy of SN38. CRGDK-functionalized PEG2.4K -p(HEMASN38)3K (C-SN38) nanoparticles and nonfunctionalized control (B-SN38) are prepared with two distinct sizes, 30 and 100 nm. Their physiochemical and biological characteristics are investigated in vitro and in vivo with multiple tumor models. It is demonstrated for the first time that CRGDK functionalization can be a promising strategy for efficient delivery of SN38, and C-SN38 is a potent drug candidate for the treatment of neuropilin-1 overexpressing tumors.