Glioblastoma　multiforme　(GBM)　is　the　most　aggressive　brain　tumor.　There　is　a　pressing　need　to　develop　novel　treatment　strategies　due　to　the　poor　targeting　effect　of　current　therapeutics.　Here,　a　gold　cluster　coated　with　optimized　GBM-targeting　peptide　is　engineered,　namely　NA.　NA　can　efficiently　target　GBM　both　in　vitro　and　in　vivo.　Interestingly,　the　uptake　of　NA　significantly　sensitizes　GBM　cells　to　ferroptosis,　a　form　of　programmed　cell　death　that　can　bypass　the　tumor　resistance　to　apoptosis.　This　effect　is　exerted　through　regulating　the　HO-1-dependent　iron　ion　metabolism,　which　is　the　non-canonical　pathway　of　ferroptosis.　The　combined　treatment　of　a　ferroptosis　inducer　and　NA　profoundly　inhibited　tumor　growth　in　both　the　GBM　spheroid　model　and　a　syngeneic　mouse　model　with　enhanced　ferroptosis　levels　and　excellent　biosafety.　Importantly,　the　infiltration　of　tumoricidal　lymphocytes　is　also　significantly　increased　within　tumor.　Therefore,　NA　presents　a　potential　novel　nanomaterial-based　strategy　for　GBM　treatment.