Activated　B　cell-like　diffuse　large　B-cell　lymphoma　(ABC-DLBCL)　is　the　most　aggressive　form　of　DLBCL,　with　a　significantly　inferior　prognosis　due　to　resistance　to　the　standard　R　CHOP　immunochemotherapy.　Survival　of　ABC-DLBCL　cells　addicted　to　the　constitutive　activations　of　both　canonical　and　noncanonical　NF　-KB　signaling　makes　them　attractive　therapeutic　targets.　However,　a　pharmaceutical　approach　simultaneously　targeting　the　canonical　and　noncanonical　NF　-KB　pathway　in　the　ABC-DLBCL　cell　is　still　lacking.　Peptide-conjugated　gold　nano　clusters　(AuNCs)　have　emerged　unique　intrinsic　biomedical　activities　and　possess　a　great　potential　in　cancer　theranostics.　Here,　we　demonstrated　a　Au25　nanocluster　conjugated　by　cell-penetrating　peptides　that　can　selectively　repress　the　growth　of　ABCDLBCL　cells　by　inducing　efficient　apoptosis,　more　efficiently　than　glutathione　(GSH)-conjugated　AuNCs.　The　mechanism　study　showed　that　the　cell-penetrating　peptides　enhanced　the　cellular　internalization　efficiency　of　AuNCs,　and　the　selective　repression　in　ABC-DLBCL　cells　is　due　to　the　inhibition　of　inherent　constitutive　canonical　and　noncanonical　NF　-KB　activities　by　AuNCs.　Several　NF　-KB　target　genes　involved　in　chemotherapy　resistance　in　ABC-DLBCL　cells,　including　anti-apoptotic　Bcl-2　family　members　and　DNA　damage　repair　proteins,　were　effectively　down-regulated　by　the　AuNC.　The　emerged　novel　activity　of　AuNCs　in　targeting　both　arms　of　NF　-KB　signaling　in　ABC-DLBCL　cells　may　provide　a　promising　candidate　and　a　new　insight　into　the　rational　design　of　peptide-conjugated　Au　nanomedicine　for　molecular　targeting　treatment　of　refractory　lymphomas.