Nucleus-targeting Oxaplatin(IV) prodrug Amphiphile for enhanced chemotherapy and immunotherapy.

Platinum(II)-based drugs (Pt), which hinder DNA replication, are the most widely used chemotherapeutics. However, current Pt drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (Pt) prodrug amphiphile (C-OPt-RK), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (RK). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPt) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPt's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPt shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPt recruited more CD4 and CD8 T cells and reduced CD4 Foxp3 Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy.