Engineering　functional　nanomaterials　to　have　both　high　therapeutic　efficacy　and　minimal　side-effects　has　become　a　promising　strategy　for　next-generation　cancer　treatments.　Herein,　an　adenosine　triphosphate　(ATP)　depletion　and　reactive　oxygen　species-enhanced　combination　chemotherapy　platform　is　introduced　whereby　therapeutic　samarium　(Sm3+)　ions　and　(−)-epicatechin　(EC)　are　integrated　via　a　metal-phenolic　network　(SmIII-EC).　The　independent　pathway　between　Sm3+　and　EC　can　achieve　a　synergistic　therapeutic　effect　through　the　mitochondrial　dysfunction　process.　SmIII-EC　nanoparticles　cause　a　significant　reduction　of　viability　of　C26　murine　colon　carcinoma　cells　while　with　lower　systemic　toxic　effects　on　normal　cell　lines.　SmIII-EC　nanoparticles　are　used　to　directly　compare　with　a　clinic　anticancer　drug　5-fluorouracil.　SmIII-EC　nanoparticles　not　only　decrease　the　tumor　volume　but　also　do　not　affect　the　body　weight　of　mice　and　normal　organs,　showing　significant　advantages　over　clinic　counterpart.　These　facts　suggest　that　SmIII-EC　nanoparticles　represent　a　clinically　promising　candidate　for　colon　cancer　treatment　with　a　targeted　therapeutic　effect　and　minimum　side　toxicity.　©　2018　WILEY-VCH　Verlag　GmbH　&　Co.　KGaA,　Weinheim