Two-dimensional (2D) nanosheets as carriers have shown promising potential for surface-displaying or loading various drugs. Nevertheless, developing sheet-like materials themselves into an immunoregulator has never been realized so far. In this study, we take advantage of the immunoregulatory effects of rare earth elements themselves and develop water-soluble erbium-dysprosium 2D nanosheets (2D NSs). Such 2D NSs can target lymph nodes and activate macrophages to improve vaccine efficacy in mice significantly. Transcriptome analysis further reveals that six critical molecules (Msr1, Ccr2, Serpinb9, Klrk1, Klrd1, Klrc1) closely correlate with 2D NS-mediated immunoregulation in vivo. For the first time, the present work realizes a proof-of-concept for designing immunoregulatory 2D NSs and shows a promising potential of 2D NSs for improving the immunoprophylaxis/immunotherapy of vaccines.This journal is © The Royal Society of Chemistry.