Abstract: Acute myeloid leukemia (AML), characterized by rapid progression, therapeutic resistance, and high relapse rates, remains a critical threat to patient survival. The complex leukemic microenvironment often diminishes the efficacy of conventional monotherapies and single-target approaches. Drug delivery strategies based on microenvironment characteristics and multi-mechanism synergy are expected to have better therapeutic effects on AML. Therefore, we developed a biomimetic supramolecular nanoparticle (Fe-GA@CM) through homologous targeting strategy and metal-polyphenol coordination for co-delivery of gambogic acid (GA) and Fe³⁺. The particle size, zeta potential, and release performance of the system were characterized. Furthermore, the efficacy and mechanism of action of this system in treating AML was explored. The results showed that the particle size of the nano system was approximately 270 nm and positively charged. After being specifically taken up by AML cells, it is reduced by high concentrations of glutathione in the tumor microenvironment and released Fe²⁺ and GA in a responsive manner. The combination therapy for AML is achieved by inducing ferroptosis with Fe²⁺ and inhibiting glycolysis in AML cells with GA. In summary, the formulated Fe-GA@CM provides novel ideas for targeted therapy and combination therapy for AML.