Dual-wing butterfly prodrug-driven hybrid nanoassemblies for synergistic cancer immunotherapy

Oxaliplatin (OXA) has shown excellent potential in inducing immunogenic cell death and enhancing immunotherapy. However, the poor physicochemical properties of oxaliplatin make it difficult to achieve efficient synchronous delivery and synergistic immunotherapy with immune checkpoint inhibitors. To address this, we designed structurally optimized dual-wing butterfly prodrugs: oxaliplatin prodrug (POP) that enhances immunogenicity and reducible NLG919 homodimer (NSSN) that mitigates immunosuppression. Structural optimization of dual-wing butterfly prodrugs significantly enhanced lipid solubility compared to the parent drugs. It is worth noting that we assembled two dual-wing butterfly prodrugs, POP and NSSN, together into hybrid nanoassemblies (NAs), achieving advantages such as stable assembly, flexible dosing, and collaborative therapy. Dual-wing butterfly prodrug-driven hybrid NAs demonstrated enhanced antitumor efficacy and metastasis control in experimental models, with biocompatibility confirmed through biosafety evaluations. This work proposes a co-delivery strategy based on dual-wing butterfly prodrugs as a clinically translatable candidate.