Osteosarcoma is a highly aggressive bone tumor with limited treatment options because of its drug resistance and tumor heterogeneity. In this study, we developed a multifunctional nanomaterial, P-FeO@Pal@HM, combining porous FeO nanoparticles, the DNA intercalator palmatine, and a hybrid membrane coating derived from osteosarcoma cells and tumor-associated endothelial cells. The FeO core facilitates a Fenton-like reaction, generating reactive oxygen species (ROS) to enhance DNA damage, whereas palmatine (Pal) inhibits RRM2 (ribonucleotide reductase regulatory subunit M2) expression, blocking DNA repair and inducing apoptosis. The hybrid membrane coating provides precise targeting of both tumor and endothelial cells, thus addressing the challenge of tumor heterogeneity. Under low-temperature photothermal conditions, the Fenton-like reaction is further enhanced, boosting ROS production and increasing cytotoxicity. This nanomaterial also modulates the immune microenvironment by promoting M1 macrophage polarization, thereby amplifying the antitumor immune response. P-FeO@Pal@HM demonstrated superior therapeutic efficacy to conventional treatments, significantly reducing tumor volume and inducing apoptosis with minimal toxicity to normal tissues. This innovative approach offers a promising strategy to overcome drug resistance, improve tumor targeting, and enhance treatment outcomes in osteosarcoma. The multifunctional design of P-FeO@Pal@HM highlights its potential as an advanced therapeutic platform in osteosarcoma.