Abstract

Combination therapy with topoisomerase I and PARP inhibitors is promising for cancer treatment, yet its efficacy is often limited by mismatched pharmacokinetics and inefficient co-delivery. Here, we report a phospholipid-based single-molecule dual-drug conjugate, CNPC, in which camptothecin (CPT) and niraparib (NI) are covalently integrated into a choline glycerophosphate scaffold through redox-responsive linkers. The CNPC, enabled by their amphiphilic phospholipid architecture, spontaneously self-assemble in aqueous solution into stable supramolecular nanotubes (CNPC-NT) of ∼100 nm with a high overall drug loading of ∼46%. The CNPC-NT preserve the active lactone form of CPT, remain stable in plasma-related media, yet rapidly respond to high glutathione levels to simultaneously release both drugs. In vitro, CNPC-NT enhances DNA damage, apoptosis, and tumor cell killing compared with the parental CPT nanotubes. In vivo, CNPC-NT prolongs blood circulation with a longer half-life than liposomes, achieves effective tumor accumulation, and shows the strongest antitumor efficacy with good tolerability. This work establishes a phospholipid dual-drug strategy for synchronous combination therapy and provides a molecular design principle for self-assembling nanomedicines with stimulus-responsive release.