The　therapeutic　effectiveness　of　photothermal　therapy　(PTT)　is　limited　by　heat　tolerance　and　PTT-induced　inflammation,　which　increases　the　risk　of　tumor　metastasis　and　recurrence.　Ferroptosis　combined　with　PTT　can　achieve　significant　therapeutic　effects.　In　this　work,　we　designed　self-healing　photothermal　nanotherapeutics　to　achieve　effective　PTT　with　triple-amplified　ferroptosis　and　cascade　inflammation　inhibition　after　photothermal　treatment.　After　the　ferroptosis-inducing　ability　of　mangiferin　(MF)　was　first　elucidated,　the　nanocomplex　PFeM,　coordinated　by　Fe3+　and　MF　with　polyvinylpyrrolidone　(PVP)　modification,　was　prepared　by　a　one-pot　self-assembly　method.　PFeM　with　laser　irradiation　could　induce　intensified　ferroptosis　by　integrating　the　functions　of　MF　to　deactivate　glutathione　peroxidase　4,　Fe3+/Fe2+　to　generate　lethal　reactive　oxygen　species　via　the　Fenton　reaction,　and　the　photothermal　effect　to　amplify　ferroptosis.　More　importantly,　the　released　MF　could　achieve　cascade　inflammation　inhibition,　thereby　reversing　the　proinflammatory　microenvironment　caused　by　PTT.　The　in　vivo　antitumor　and　anti-inflammatory　effects　of　PFeM　were　further　confirmed　in　a　4T1　tumor-bearing　mouse　model.　This　study　expounding　the　ferroptosis-inducing　effects　of　MF　and　utilizing　the　strategy　of　chelating　MF　with　iron　ions　can　provide　a　new　idea　for　developing　photothermal　nanoagents　with　clinically　convertible　safety　ingredients　and　a　green　preparation　process　that　improve　efficacy　and　reduce　adverse　reactions　during　PTT.　©　2024　American　Chemical　Society.