The　circulating　tumor　cells　(CTCs)　existing　in　cancer　survivors　are　considered　the　root　cause　of　cancer　metastasis.　To　prevent　the　devastating　metastasis　cascade　from　initiation,　we　hypothesize　that　a　biodegradable　nanomaterial　loaded　with　the　abortifacient　mifepristone　(MIF)　and　conjugated　with　the　epithelial　cell　adhesion　molecule　antibody　(aEpCAM)　may　serve　as　a　safe　and　effective　cancer　metastatic　preventive　agent　by　targeting　CTCs　and　preventing　their　adhesion-invasion　to　vascular　intima.　It　is　demonstrated　that　MIF-loaded　mesoporous　silica　nanoparticles　(MSN)　coated　with　aEpCAM　(aE-MSN-M)　can　specifically　target　and　bind　colorectal　cancer　cells　in　either　cell　medium　or　blood　through　EpCAM　recognition　proven　by　quantitative　flow　cytometric　detection　and　free　aEpCAM　competitive　assay.　The　specific　binding　results　in　downregulation　of　the　captured　cells　and　drives　them　into　G0/G1　phase　primarily　attributed　to　the　effect　of　aEpCAM.　The　functional　nanoparticles　significantly　inhibit　the　heteroadhesion　between　cancer　cells　and　endothelial　cells,　suggesting　the　combined　inhibition　effects　of　aEpCAM　and　MIF　on　E-selectin　and　ICAM-1　expression.　The　functionalized　nanoparticles　circulate　in　mouse　blood　long　enough　to　deliver　MIF　and　inhibit　lung　metastasis.　The　present　proof-of-concept　study　shows　that　the　aE-MSN-M　can　prevent　cancer　metastasis　by　restraining　CTC　activity　and　their　adhesion-invasion　to　vascular　intima.　Mesoporous　silica　nanoparticles　(MSN)　loaded　with　abortifacient　mifepristone　(MIF)　and　coated　with　EpCAM　antibody　(aE-MSN-M)　can　specifically　target　and　bind　colorectal　cancer　cells　in　blood　through　EpCAM　recognition,　and　interfere　with　the　adhesion　of　circulating　tumor　cells　to　vascular　endothelium　by　the　combined　effects　produced　by　EpCAM　antibody　and　MIF　in　one　nanoparticle　delivery　system.　Collectively,　the　aE-MSN-M　entity　produces　inhibition　of　cancer　metastasis　in　vivo.　©　2016　WILEY-VCH　Verlag　GmbH　&　Co.　KGaA,　Weinheim.