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.