Programmed initiation and enhancement of cGAS/STING pathway for tumour immunotherapy via tailor-designed ZnFe2O4-based nanosystem

Abstract

The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway has been a promising target for anticancer immunity, but rationally activating and enhancing this pathway in tumour cells is critical. Herein, a glutathione sensitive ZnFe₂O₄-based nanosystem is developed to programmatically initiate and enhance the STING signalling pathway in tumour cells. The prepared ZnFe₂O₄ nanoparticles were coated with cancer cell membrane (CCM), which enabled the nanosystem target tumour cells. In tumour cells, ZnFe₂O₄ nanoparticles could be disintegrated by responding to high level glutathione, and the released Fe³⁺ generated reactive oxygen species to induce the DNA leakage into the cytoplasm to stimulate cGAS. Then Zn²⁺ promoted cGAS-DNA phase separation to intensify the cGAS enzymatic activity. In addition, the low dose encapsulation of paclitaxel (PTX) acting as an antimitotic agent (ZnFe₂O₄-PTX@CCM) ensured the sustained activation of cGAS/STING pathway. The in vitro and in vivo results confirmed that ZnFe₂O₄-PTX@CCM elevated the cGAS/STING activity, promoted dendritic cell maturation, increased cytotoxic T lymphocyte and natural killer cells infiltration, eventually inhibiting the tumour progress and postoperative recurrence. This study provided feasible references on constructing STING activation nanosystem for tumour immunotherapy.