pH/H2O2 Cascade‐Responsive Nanoparticles of Lipid‐Like Prodrugs through Dynamic‐Covalent and Coordination Interactions for Chemotherapy

Abstract Traditional lipid nanoparticles (LNPs) suffer from low drug loading capacity (DLC), weak stability, and lack of responsiveness. Conventional approaches to address these issues involve the synthesis of lipid‐prodrug by incorporating responsive covalent linkers. However, such approaches often result in suboptimal sensitivity for drug release and undermine therapeutic effectiveness. Herein, the study reports a fundamentally different concept for designing lipid‐like prodrugs through boron–nitrogen (B‐N) coordination and dynamic covalent interaction. The 5‐fluorouracil‐based lipid‐like prodrugs, featuring a borate ester consisting of a glycerophosphoryl choline head and a boronic acid‐modified 5Fu/dodecanamine complex tail, are used to prepare pH/H 2 O 2 cascade‐responsive LNPs (5Fu‐LNPs). The 5Fu‐LNPs exhibit enhanced DLC and stability in a neutral physiological environment due to the B‐N coordination and enhanced hydrophobicity. In tumors, acidic pH triggers the dissociation of B‐N coordination to release prodrugs, which further responds to low H 2 O 2 concentrations to release drugs, showcasing a potent pH/H 2 O 2 ‐cascade‐responsive property. Importantly, 5Fu‐LNPs demonstrate greater antitumor efficiency and lower toxicity compared to the commercial 5Fu. These results highlight 5Fu‐LNPs as a safer and more effective alternative to chemotherapy. This work presents a unique LNP fabrication strategy that can overcome the limitations of conventional LNPs and broaden the range of intelligent nanomaterial preparation techniques.