pH-gated aggregation of Cu-phycocyanin nanoparticles for precise induction of lysosomal membrane permeabilization and synchronized multimodal tumor cell death.

Abstract

Lysosomal membrane permeabilization (LMP) mediated by pH-responsive materials has demonstrated considerable potential in tumor therapy. However, tumor cells exhibit a pronounced adaptive capacity to remodel lysosomal pH, thereby resisting LMP induction by pH-responsive materials and ultimately compromising therapeutic efficacy. To overcome this limitation, we engineered proton-driven π-π stacked copper-phycocyanin nanoparticles (CuPC NPs) designed to selectively promote LMP in tumor cells through their aggregation within acidic lysosomes. Mechanistically, aggregated CuPC NPs directly engage the RIPK3/p-MLKL signaling axis to trigger LMP, thereby orchestrating the synergistic activation of necroptosis, ferroptosis, and cuproptosis. Due to the coordinated induction of multimodal cell death, these pH-responsive CuPC NPs effectively inhibit primary breast tumor growth and suppress pulmonary metastasis. Collectively, our study establishes a strategy for precise modulation of lysosomal function to enhance antitumor efficacy and provides valuable insights into the development of lysosome-targeted nanotherapeutics for tumor treatment.