Provoking Lysosome Disruption via In Situ Engineered Double-Network Assemblies for Targeted Cancer Cell Death

Area of Science:

• Biochemistry
• Nanotechnology
• Oncology

Background:

• Lysosomes play a crucial role in tumor progression and cancer drug resistance.
• Targeting lysosomes for cancer therapy is an area of high demand but limited success.
• Developing selective lysosome-targeting agents remains a significant challenge.

Purpose of the Study:

• To design and synthesize an alkaline phosphatase (ALP)-responsive peptide-based precursor (C1) for targeted cancer therapy.
• To investigate the selective induction of lysosome dysfunction in uveal melanoma cells using light manipulation.
• To develop a self-assembling system for disrupting lysosomal membrane integrity and inhibiting tumor growth.

Main Methods:

• Synthesis of an ALP-responsive peptide precursor (C1).
• Demonstration of selective dephosphorylation, endocytosis, and lysosomal accumulation in ALP-upregulated tumor cells.
• Light-induced self-assembly of C1 into double-network assemblies (nanofibrils and nanorods) within lysosomes.
• Investigation of lysosomal membrane permeabilization and subsequent tumor cell death.

Main Results:

• C1 selectively accumulated in lysosomes of tumor cells upon ALP-mediated dephosphorylation.
• Light irradiation triggered the formation of self-sorted nanofibrils and nanorods within lysosomes.
• The interaction of these nanostructures formed robust double-network assemblies, leading to lysosomal membrane permeabilization.
• Significant inhibition of tumor cell growth was observed.

Conclusions:

• A novel double-network assembly system was developed by utilizing ALP activity, light responsiveness, and lysosomal acidity.
• This system effectively disrupts lysosomal membrane integrity and selectively inhibits tumor cells.
• The findings offer valuable insights for advancing lysosome-targeting therapeutic agents in cancer treatment.