Electron-permeable graphitic atomic barrier confers paradoxical enhancement of fibrosarcoma apoptosis by Ptzymes.

Fibrosarcoma, a highly invasive sarcoma with redundant apoptotic networks, exhibits profound resistance to conventional therapies. Platinum nanozymes (Ptzymes) combine DNA-damaging activity with catalytic redox modulation; however, their application is limited by uncontrolled catalytic activity and off-target toxicity. This design effectively suppresses Pt ion leakage while preserving catalytic activity, enabling more controlled oxidative stress modulation. Pt@G NPs exhibit enhanced cytotoxicity toward HT1080 fibrosarcoma cells (120%) compared with bare Ptzymes, while showing reduced cytotoxic responses in three normal cell lines (80%). Cellular uptake studies revealed clear cell type-dependent differences, with HT1080 cells displaying the highest Ptzymes internalization. Furthermore, transcriptomic analysis indicated that ROS-related pathways were more prominently altered in Pt@G-treated HT1080 cells compared with the Pt-treated group, accompanied by increased ROS levels and lipid peroxidation. These changes were accompanied by activation of apoptosis-related processes. In vivo, Pt@G NPs achieved effective suppression of HT1080 xenograft tumors with improved systemic tolerance, as evidenced by reduced inflammatory cytokine levels and preserved hepatic and renal function. Overall, this study demonstrates that graphitic shell-confined Ptzymes can modulate intracellular oxidative stress responses and enhance therapeutic performance, providing a promising strategy for balancing therapeutic efficacy and biosafety.