Zn2+-mediated siRNA-doxorubicin self-assembled nanoparticles amplify Immunogenic cell death via aggravating redox dyshomeostasis for cancer therapy

Immunogenic cell death (ICD), instigated by reactive oxygen species (ROS), has emerged as an efficacious strategy for augmenting the immunogenicity of tumor cells. However, the effects of ICD are severely diminished by elevated levels of glutathione (GSH) within tumor cells to maintaining intracellular redox homeostasis. To address this, the novel carrier-free self-assembled nanoparticles are designed to aggravating redox dyshomeostasis by reducing GSH and increasing ROS levels. The nanoparticles (ZDS NPs) were established by the self-assembly of zinc ions (Zn²⁺), doxorubicin (DOX) and Nrf2 siRNA. The ZDS NPs exhibited the ultra-high entrapment efficiency of DOX (99%) and siRNA (89%), and the releases of DOX and siRNA were both pH-dependent owing to the cleavage of coordinate and hydrogen bonds under acidic conditions. Following the endocytosis of ZDS NPs by tumor cells, redox homeostasis was significantly disrupted, DOX and Zn²⁺ enhanced the production of ROS via activating cGAS/STING pathway, whereas siRNA reduced GSH levels by decreasing the expression of Nrf2 protein. This further promoted a stronger ICD effect with elevated secretion of ATP, HMGB1, CRT, thereby inducing the maturation of DCs and activating a more robust anti-tumor immunity. This study presents a novel approach for the synergistic enhancement of ICD in cancer immunotherapy.