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.

Emerging evidence has established artesunate (ART) as a potent anticancer candidate, yet its clinical utility remains constrained by rapid clearance and limited bioavailability. To overcome these limitations, we developed fatty chain-driven self-assembling nanoassemblies (NAs) as an innovative therapeutic platform. In contrast to conventional prodrug-based self-assembled nanoassemblies (PBSANs), our ART conjugates (ART-R) activate antitumor effects without requiring responsive modules, substantially streamlining drug design. In this study, we investigated the assembly behavior, stability, and antitumor efficacy of ART-R conjugates with varying side chain lengths: short (ART-C4), medium (ART-C8, ART-C12), and long (ART-C14, ART-C18). To prolong systemic circulation and achieve tumor-selective release, we engineered reduction-responsive sp-ART-R NAs via 2-Distearoyl-sn-glycero-3-phosphoethanolamine-disulfide bond-polyethylene glycol 2000 (DSPE-SS-PEG_2K) modification. Following comprehensive evaluation, sp-ART-C14 NAs with the optimal side chain length were selected, which exhibit the most suitable octanol-water partition coefficient (logP), good assembly capability, stability, cytotoxicity, as well as optimal pharmacokinetic behavior and tumor accumulation ability. In the 4T1 breast tumor model, sp-ART-C14 NAs also demonstrated excellent therapeutic efficacy. This study overcomes the limitations of traditional PBSANs, eliminates dependence on response modules, and provides a new drug delivery solution for ART.