Multifunctional copper-light synergistic prodrug nanosystems for specific reprogramming of tumour immunogenic endoplasmic reticulum stress.

Abstract

Inducing lethal endoplasmic reticulum (ER) stress is a key initiative to counteract tumour resistance and induce anti-tumour immunity. However, conventional ER stress inducers are largely limited by hypoxia and off-target effects to induce tumour-lethal ER stress. Here, we encapsulated Cu-bridged eosin Y (CuBY) in ER-targeting peptide (pardaxin)-modified mesoporous silica and successfully constructed an oxygen-independent multifunctional copper-light synergistic prodrug nanosystems (MP@CuBY). MP@CuBY is activated to the "on" state within the glutathione-overexpressing tumour microenvironment, causing copper and BY release. Interestingly, released copper can drive oxygen-independent cascade reactions in situ in the ER, resulting in the production of highly toxic O₂-• and •OH. The BY released can produce ¹O₂ in situ in the ER under laser irradiation. Therefore, type I and type II reactive oxygen species (ROS) generated by MP@CuBY in situ in the ER specifically reprogramed tumour immunogenic ER stress, which significantly activated systemic anti-tumour immunity and long-term immune memory, as well as ensured satisfactory efficacy in synergistically eradicating spinal metastases in conjunction with α-PD-L1 antibody. In conclusion, the well-designed MP@CuBY may represent an advanced design for anti-tumour prodrug nanosystems, providing a novel copper-light synergistic strategy for the specific activation of lethal tumour ER stress.