As the backbone of tumor therapy, chemotherapy is prone to tumor resistance due to its apoptotic pathway. Ferroptosis, as an effective form of non-apoptotic cell death, can overcome chemotherapy apoptosis-induced resistance. Therefore, the combination of chemotherapy and ferroptosis is a highly promising tumor treatment strategy. However, high glutathione (GSH) and insufficient intracellular iron content in the tumor environment limit the efficiency of ferroptosis-mediated anticancer. Not only that, simultaneous intracellular delivery of iron sources, ferroptosis inducers, and chemotherapeutic agents remains a major challenge. Here, we constructed a self-assembled nano prodrug system to co-deliver iron sources, ferroptosis inducers, and anti-cancer drugs for combined ferroptosis and chemotherapy. In the tumor microenvironment, high levels of GSH triggered redox-responsive disulfide bonding, which induced the disassembly of this nano prodrug system (PFSH@HCPT), releasing hydroxycamptothecin (HCPT), honokiol (HNK) and ferrocene (Fc). HCPT induced cell death via apoptosis and Fc triggered the Fenton reaction, which induced ferroptosis. HNK inhibited the activity of glutathione peroxidase 4 (GPX4) to enhance ferroptosis, and on the other hand, it further induced cell death via apoptosis. Meanwhile, the combined strategy of HNK-mediated resistance and ferroptosis-induced resistance mechanism further overcame the resistance of HCPT and significantly improved the therapeutic efficacy. This nano prodrug system realized the “multi-machine integrated” therapeutic efficacy and showed great therapeutic potential, which may open up a new way for effective cancer treatment.

Photothermal therapy (PTT) has been widely used in the treatment of tumors, but its efficacy is greatly limited by the inability of precise drug delivery and the increase of heat shock proteins (HSPs) caused by high temperature. This article describes a therapeutic strategy to enhance PTT with starvation therapy in conjunction with ferroptosis mechanism. A nanoparticle platform ZIF-8@GA was constructed by wrapping together glucose oxidase (GOX) and gold nanospheres (AuNPs) loaded with dihydroartemisinin (DHA) with zeolitic imidazolate framework-8 (ZIF-8). This platform can take advantage of the micro-environment of osteosarcoma (OS) cells, featuring low pH and high reactive oxygen species (ROS), for precision drug delivery. GOX can effectively catalyze glucose to produce gluconic acid and H₂O₂, and DHA can also induce ROS production in OS cells. ROS produced by GOX and DHA can further generate lipid peroxidation (LPO) and lead to ferroptosis of OS cells. At the same time, ROS and LPO produced can inhibit the expression of HSPs, thereby increasing the therapeutic effect of PTT. In vitro experiments show that the nanoparticles are pH and ROS responsive. 1 μg/mL GOX combined with 0.2 μg/mL DHA promotes ferroptosis of OS cells, and increases the killing effect of near-infrared (NIR) on OS cells. Further in vivo experiments showed that the nano drug-delivery platform combined with PTT can effectively inhibit the growth of OS cells. Meanwhile, this study provides a new idea for the treatment of OS with biomaterials combined with various treatment methods.