The　efficacy　and　biosafety　of　sonodynamic　therapy　(SDT)　are　closely　related　to　the　properties　of　sonosensitizers.　Inorganic　sonosensitizers　with　high　chemical　stability　and　low　dark　toxicity　are　generally　limited　by　slow　metabolism　and　accumulation　in　vivo.　Combined　treatment　strategies　by　inducing　more　redox　imbalance　are　expected　to　improve　the　efficacy　of　sonodynamic　antitumor　therapy.　Herein,　we　report　the　development　of　ultra-small　iron-doped　zinc　oxide　nanoparticles　(FZO　NPs)　to　achieve　synergistic　sono-chemodynamic　therapy　and　low　accumulation　in　vivo.　The　surface　of　FZO　NPs　with　diameter　of　5　nm　was　modified　with　3-aminopropyltriethoxysilane　and　polyethylene　glycol　600　to　obtain　FZO-ASP　with　good　aqueous　stability.　FZO-ASP　with　iron　doping　could　trigger　Fenton　reaction　and　induce　ferroptosis　in　cancer　cells.　With　the　assistance　of　ultrasonic　energy,　FZO-ASP　demonstrated　enhanced　inhibitory　effects　on　proliferation　of　various　cancer　cells　and　murine　breast　tumor　growth　than　undoped　counterpart.　In　addition,　FZO-ASP　injected　intravenously　could　be　effectively　excreted　in　vivo　and　showed　no　obvious　cumulative　toxicity　to　the　treated　mice.　Hence,　this　type　of　ultra-small　iron-doped　zinc　oxide　nanoparticles　could　serve　as　a　safe　and　efficient　sonosensitizer　agent　for　synergistic　sono-chemodynamic　cancer　therapy.　©　2023　Elsevier　B.V.