Despite　significant　advances　in　diverse　cancer　treatment　methods,　chemotherapy　remains　the　primary　approach,　and　the　development　of　chemoresistance　is　still　a　persistent　problem　during　treatment.　Here,　we　developed　a　derivative　of　the　natural　product　mangiferin　as　a　carrier　for　delivering　chemotherapeutic　drug,　aiming　to　overcome　drug　resistance　through　a　distinctive　four-pronged　strategy,　including　modulation　of　inflammatory　tumor　microenvironment　(TME),　induction　of　ferroptosis,　deep　tumor　penetration,　and　the　combinatory　anticancer　effects.　After　clarifying　the　promotion　effects　of　the　cancer　associated　fibroblasts　(CAFs)　in　chemoresistance,　and　leveraging　our　previous　elucidation　of　the　anti-inflammatory　and　ferroptosis-inducing　ability　of　mangiferin,　we　synthesized　mangiferin　amphiphile　(MMF)　and　developed　a　self-assembled　carrier-free　nanomedicine,　named　MP,　through　the　self-assembly　of　MMF　and　the　representative　chemotherapeutic　drug　paclitaxel　(PTX).　MP　possessed　a　particle　size　of　approximately　68　nm　with　compact　filamentous　nanostructures.　MP　demonstrated　efficient　tumor-targeting　and　deep　tumor　penetration　abilities.　Furthermore,　MP　effectively　suppressed　glutathione　peroxidase　4　(GPX4)　expression　to　induce　ferroptosis,　mitigated　the　activation　of　IL-6/STAT3　pathway　to　deactivate　CAFs　within　the　inflammatory　TME,　and　exhibited　robust　anti-cancer　effects　against　PTX-resistant　breast　cancer　both　in　vitro　and　in　vivo.　This　mangiferin　derivative　represents　a　promising　“all-in-one”　nanocarrier　for　delivering　chemotherapeutic　drugs,　offering　a　green,　safe,　and　convenient　self-assembled　carrier-free　nanomedicine　to　effectively　overcome　drug　resistance.　©　2024　Elsevier　B.V.