Intracellular Self‐Assembled Fe(II)‐Aniline Mustard NPs for Self‐Enhanced Anti‐Tumor Chemo‐/Chemodynamic Therapy

Abstract The combination of chemodynamic therapy (CDT) with chemotherapy amplifies antitumor effects while mitigating toxicity and overcoming tumor cell resistance associated with chemotherapy. However, small molecule chemo‐/chemodynamic therapy drugs are prone to rapid efflux, and nanomedicines are limited by low tumor delivery rates. To address these challenges, a tumor‐targeted, intracellularly self‐assembled prodrug, TpyFe(II)‐FF‐AM‐cRGD is developed, for highly efficient and precise chemo‐/chemodynamic tumor therapy. Upon targeting cancer cells with elevated α v β 3 integrin expression, the prodrug undergoes glutathione reduction and self‐assembly into TpyFe(II)‐FF‐AM nanoparticles inside the tumor cells, thereby enhancing the local concentrations of both Fe(II) and aniline mustard (AM), as well as prolonging their retention time. Fe(II) induces the Fenton reaction to generate hydroxyl radicals, while hypoxia‐mediated release of AM not only causes DNA alkylation but also further elevates reactive oxygen species levels to amplify the CDT effect, thereby significantly enhancing coordinated therapeutic efficacy. This strategy improves the efficiency and specificity of traditional chemo‐/chemodynamic therapy while minimizing systemic toxicity, presenting a promising avenue for effective cancer treatment.