Chronic　lymphocytic　leukemia　(CLL)　is　still　incurable　by　conventional　chemotherapy　due　to　the　resistance　to　apoptosis.　We　have　previously　found　that　a　peptide-capped　gold　cluster　(Au25Sv9)　can　target　on　the　aberrant　oxidative　stress　in　CLL　cells　to　specially　inhibit　thioredoxin　reductase　(TrxR)　activity,　resulting　in　significant　apoptosis.　However,　the　required　doses　of　the　gold　cluster　for　inducing　apoptosis　are　high,　restricting　its　potential　for　further　applications.　Notably,　the　most　recent　studies　suggested　that　CLL　cells　overexpressed　antiapoptotic　BCL-2　protein　to　prevent　chemotherapy-induced　apoptosis,　indicating　that　BCL-2　could　be　a　promising　target　for　CLL　therapy.　Regrettably,　the　nonmitochondrial-targeted　Au25Sv9　has　little　effect　on　BCL-2.　In　this　study,　we　successfully　screened　a　modified　BADBH3　peptide　(B1P)　that　could　antagonize　BCL-2　protein　in　CLL　cells.　We　found　that　B1P　could　effectively　sensitize　MEC-1　cells　to　a　subliminal　dose　of　Au25Sv9.　To　simplify　the　treatment　regimen,　we　directly　fabricated　a　gold　cluster　capped　with　the　B1P　peptides　by　one-step　synthesis　to　integrate　the　BCL-2　antagonistic　activity　into　the　gold　the　cluster,　named　BGC.　We　already　found　that　low　doses　of　BGC　could　significantly　induce　more　apoptosis　in　MEC-1　cells　than　equivalent　doses　of　the　Au25Sv9　cluster　or　B1P　peptide　alone.　Mechanistically,　in　addition　to　the　inherent　inhibitory　effect　of　gold　clusters　on　TrxR　activity,　BGC　could　bind　to　BCL-2　on　mitochondria　and　activate　the　BCL-2　family-mediated　mitochondrial　apoptosis　cascade　more　effectively.　These　results　demonstrated　that　antagonizing　the　overexpressed　BCL-2　in　CLL　cells,　together　with　inhibiting　TrxR　simultaneously　by　a　single　gold　cluster,　is　a　promising　strategy　for　the　treatment　of　CLL　cells.　This　study　will　provide　a　paradigm　and　reference　for　the　development　of　functionalized　gold　clusters　with　rationally　designed　peptides,　and　opens　up　a　new　opportunity　for　the　treatment　of　CLL　in　clinical　settings.