Provoking LysosomeDisruption via <i>In Situ</i> Engineered Double-NetworkAssemblies for Targeted Cancer Cell Death

Increasing evidence has demonstrated the critical role of lysosomes in tumor progression, as well as their involvement in drug resistance during cancer treatment. However, the exploitation of lysosome-targeting agents to inhibit malignant cell growth is still in high demand. Herein, we report an alkaline phosphatase (ALP)-responsive peptide-based precursor (C1) that selectively induced lysosome dysfunction in uveal melanoma cells via noncontact light manipulation. We demonstrated that C1 was dephosphorylated upon close contact with ALP-upregulated tumor cells, endocytosed, and accumulated in lysosomes. Further light irradiation facilitated the generation of two self-sorting components that self-assembled to form nanofibrils and nanorods, respectively. Mesoscale interactions between these two nanostructures triggered the formation of robust double-network assemblies within lysosomes, resulting in lysosomal membrane permeabilization and tumor cell death. By strategically utilizing ALP activity, light responsiveness, and lysosomal acidity in the design of a self-assembling precursor, we have developed double-network assemblies capable of selectively disrupting lysosomal membrane integrity and effectively inhibiting tumor cells. These findings provide valuable insights for the advancement of lysosome-targeting therapeutic agents.