Background:　Treatment　multiple　tumors　by　immune　therapy　can　be　achieved　by　mobilizing　both　innate　and　adaptive　immunity.　The　programmed　death　ligand　1　(PD-L1;　or　CD274,　B7-H1)is　a　critical　“don＇t　find　me”　signal　to　the　adaptive　immune　system.　Equally　CD47　is　a　critical　“don＇t　eat　me”　signal　to　the　innate　immune　system　and　a　regulator　of　the　adaptive　immune　response.　Method:　Both　of　CD47　and　PD-L1　are　overexpressed　on　the　surface　of　cancer　cells　to　enable　to　escape　immune-surveillance.　We　designed　EpCAM　(epithelial　cell　adhesion　molecule)-targeted　cationic　liposome　(LPP-P4-Ep)containing　si-CD47　and　si-PD-L1　could　target　high-EpCAM　cancer　cells　and　knockdown　both　CD47　and　PD-L1　proteins.　Findings:　Efficient　silencing　of　CD47　and　PD-L1　versus　single　gene　silencing　in　vivo　by　systemic　administration　of　LPP-P4-Ep　could　significantly　inhibited　the　growth　of　solid　tumors　in　subcutaneous　and　reduced　lung　metastasis　in　lung　metastasis　model.　Target　delivery　of　the　complexes　LPP-P4-Ep　increased　anti-tumor　T　cell　and　NK　cell　response,　and　release　various　cytokines　including　IFN-γ　and　IL-6　in　vivo　and　in　vitro.　Interpretation:　This　multi-nanoparticles　showed　significantly　high-EpCAM　tumor　targeting　and　lower　toxicity,　and　enhanced　immune　therapeutic　efficacy.　Our　data　indicated　that　dual-blockade　tumor　cell-specific　innate　and　adaptive　checkpoints　represents　an　improved　strategy　for　tumor　immunotherapy.　Fund:　This　research　supported　by　the　Ministry　of　Science　and　Technology　of　the　People＇s　Republic　of　China　(grant　number　2015CB931804);　the　National　Natural　Science　Foundation　of　China　(NSFC,　grant　numbers　81703555,　U1505225　and　81773063),　and　the　China　Postdoctoral　Science　Foundation　(grant　number　2017　M620268).　©　2019