Harnessing the HMnO2 nanoparticles as the DNA injury amplifier to improve the OXA-based trans-artery infusion chemotherapy

Oxaliplatin (OXA) serves as a key chemotherapeutic agent in trans-arterial infusion chemotherapy (TAIC) for liver cancer. However, its clinical efficacy is frequently limited by several factors: suboptimal tumor uptake, systemic detoxification mediated by glutathione (GSH), and the activation of cellular DNA repair mechanisms. Herein, we present a hollow MnO₂ nanoparticle loaded with OXA, the PEI-HMnO₂@OXA, to improve the TAIC effect of OXA. The acidic tumor microenvironment facilitated the release of OXA and triggered PEI-HMnO₂ to generate free radicals. When coupled with GSH depletion, this cascade culminated in significant DNA damage. Moreover, the PEI-HMnO₂ showed a synergistic effect with OXA by blocking multiple DNA repair genes. On the other hand, by leveraging the enhanced permeability and retention effect of the nano-sized structure, 10-100 times greater tumor uptake and a more pronounced inhibitory effect by TAIC are achieved compared with intravenous or single-drug treatment. Meanwhile, the PEI-HMnO₂@OXA enabled real-time MRI monitoring of drug distribution and tumor state, facilitating the treatment guidance. Comprehensive experiments using different cell lines, mouse and rabbit models, and patient-derived HCC OXA-sensitive/resistant organoids were conducted to clarify the tumor-inhibiting effects of PEI-HMnO₂@OXA, providing novel insights into cancer management.