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.

Tumor sentinel lymph node (SLN) metastasis plays a vital role in tumor staging and therapeutic decision-making process. However, precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes. Herein, we report three novel IR820-fatty acid (FA) conjugates (IR-OA, IR-LA, and IR-PA) for precise lymphatic metastasis illumination and primary tumor diagnosis. The IR-FA conjugates are able to non-covalently bound to albumin in vivo, and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin (BSA) in vitro. Moreover, the BSA-IR-FA conjugates display large Stokes shift (> 120 nm), dramatically improving in vivo imaging resolution. Among them, IR-PA demonstrates distinct advantage over IR-OA, IR-LA, and IR-maleimide (MAL) (fluorescent probe previously reported by our group) in terms of fluorescence quantum yield, photostability, and imaging resolution. As a result, IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location. Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.

Self-engineered small-molecule prodrug-nanoassemblies have emerged as promising nanomedicines for cancer treatment. Modular design of prodrug molecules is crucial to guarantee the favorable assembly stability, tumor-specific prodrug activation, and satisfactory antitumor effect. However, too much attention has been paid to the pharmacophores and chemical linkages in prodrug molecules while neglects the vital roles of nonpharmacological moieties. Herein, we found that iso-carbon fatty acids with different number, position, and cis-trans configuration of double bonds dramatically affect the nanoassembly feature and drug delivery fates of thioether-linked paclitaxel prodrug-nanoassemblies. Particularly, the number and cis-trans configuration of double bonds in fatty acid moieties not only dominate the self-assembly ability and colloidal stability of prodrugs, but also exert significant influences on the pharmacokinetics, prodrug activation, and antitumor activity of prodrug-nanoassemblies. Finally, oleic acid with one cis double bond stands out as the optimal nonpharmacological moiety for thioether-linked paclitaxel prodrug-nanoassemblies. This study elucidates the crucial roles of nonpharmacological moieties in prodrugs, and provides new insights into the modular design of prodrug-based nanomedicines for cancer therapy.