Polypeptide-Based Theranostics with Tumor-Microenvironment-Activatable Cascade Reaction for Chemo-ferroptosis Combination Therapy

Nanoengineering of polymer-based therapeutic carriers is promising for precise cancer treatment. Herein, we report the fabrication of polypeptide vehicles encapsulated with anticancer drug of cisplatin (Pt drug) and Fe₃O₄ nanoparticles (denoted as Pt&Fe₃O₄@PP) as theranostics for <i>T</i>₂-weighted magnetic resonance imaging (MRI)-guided chemo-ferroptosis combination therapy. The number of Fe₃O₄ nanoparticles per polypeptide vehicle is well controlled by adjusting the added amount of Fe₃O₄ nanoparticles. The tumor microenvironment can trigger the release of Pt drug and Fe^2/3+, which could induce the intracellular cascade reaction to generate sufficient ^•OH for ferroptosis therapy. Moreover, the released Pt drug can cause the apoptosis of tumor cells. Meanwhile, the encapsulated Fe₃O₄ nanoparticles can also be used for <i>T</i>₂-weighted MRI of tumor. Both <i>in vitro</i> and <i>in vivo</i> results indicate that the reported Pt&Fe₃O₄@PP can efficiently inhibit cancer cell growth without causing significant systemic toxicity. Importantly, polypeptide vehicles could significantly reduce the side effect of free Pt drug <i>in vivo</i> and therefore improve the drug delivery efficacy. Our findings suggest that polypeptide-based theranostics with tumor-microenvironment-activatable cascade reaction have great potential in biomedical applications.