Surface charge accumulation of functionalized carbonized polymer dots selectively induces lysosomal membrane permeabilization of breast cancer cells

Abstract

Lysosomal membrane permeabilization (LMP) has become an attractive strategy in tumor therapy. However, non-specific cytotoxicity caused by LMP remains a challenge; whether lysosomal-dependent autophagy process affected by lysosomal damage is still unclear. Here, we provide a carbonized polymer dots (CPDs)-based lysosomal targeted nano-strategy that mediates specific cytotoxicity to breast cancer cells by inducing LMP and disruption of autophagy degradation. CPDs functionalized via covalent conjugation with PpIX modified cathepsin D (CTSD) specific substrate peptide (CPDs-PP) were designed to achieve the selectivity to breast cancer cells. The effects and underlying mechanism of CPDs-PP on lysosomal membrane integrity and autophagic flux were determined. CPDs-PP with pH-dependent protonation and CTSD-responsive surface positive charge accumulation property at specific pH were obtained. Conversion of CPDs-PP to CPDs-P and ratiometric green–red fluorescence switching were observed in breast cancer cells with high expression of CTSD. It has been confirmed that CPDs-PP induced LMP and autophagic flux blockage of breast cancer cells. Lysosomal lipid accumulation was demonstrated to be the potential mechanism. CPDs-PP-induced LMP exhibited selective cytotoxicity to adherent tumor cells and tumor spheres, which was furtherly enhanced by spatiotemporal controlled lysosomal specific photodamage. This strategy offers promise for utilization of lysosome-targeting nanocarriers for anti-cancer pro-drugs and drug delivery systems.