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 T₂-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 T₂-weighted MRI of tumor. Both in vitro and in vivo 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 in vivo 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.