Prodrug nanoassemblies offer an innovative approach to drug delivery, but their lysosomal entrapment often impairs drug release. Notably, tertiary amine structures can undergo protonation reactions, thereby facilitating lysosomal escape through the proton sponge effect. In this study, we developed three novel paclitaxel prodrug nanoassemblies (PTX-SS-NO NPs, PTX-SS-CC NPs and PTX-SS-NC NPs) featuring distinct heterocyclic tertiary amine structures to investigate structure-activity relationships in lysosomal escape and drug delivery. Among them, PTX-SS-NC NPs demonstrated excellent lysosomal escape capability, enabling rapid drug release into the cytosol. Systematic evaluation revealed that the PTX-SS-NC NPs exhibited optimized pharmacokinetics and significant tumor accumulation, further contributing to their strong antitumor efficacy. Our findings establish heterocyclic tertiary amines as crucial design elements for overcoming lysosomal entrapment and optimizing chemotherapeutic prodrug nanoassemblies.

Heterocyclic tertiary amine  /  Lysosomal escape  /  Proton sponge effect  /  Paclitaxel prodrug nanoassemblies  /  Modular design  /  Stimuli-responsive  /  Drug delivery  /  Cancer therapy