Cancer cell membrane biomimetic mesoporous silica nanotheranostics for enhanced Ferroptosis-mediated immuogenic cell death on Gastric cancer

Selective induction of ferroptosis of cancer cells would be a promising approach to trigger immunogenic cell death (ICD) and sequentially potentiate immunotherapy. Actually, the efficiency to produce toxic lipid peroxides (LPO) and deplete glutathione (GSH) at the tumor site plays a key role in inducing ferroptosis. Herein, a cancer targeted cascade nanosystem (CCM@Mn@MSN-Pt(IV), CMnMPt) was constructed for synergistic chemo-dynamic and chemotherapy by conjugating Mn ions-doped mesoporous silica nanoparticles (Mn@MSN) and cisplatin prodrug (Pt(IV)), with cancer cell membrane cloaking. Owing to the bio-mimetic surface functionali-zation, the immune escape and homologous targeting behaviors of CMnMPt would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, intracellular GSH would be depleted attributed to the bio-degradation of Mn@MSN and reduced of Pt(IV), resulting in Mn2+ release and cisplatin transform (from Pt(IV) to Pt(II)). Subsequently, generated Pt(II)) could damage nuclear DNA, and further acti-vate nicotinamide adenine dinucleotide phosphate oxidases (NOXs) to enhance downstream H2O2 levels. Additionally, Mn2+ ions could catalyze H2O2 into highly reactive hydroxyl radical (center dot OH), which results in a further increase in LPO content. In summary, CMnMPt could induce ferroptosis-mediated ICD, and recruit cytotoxic T lymphocytes cells, offering potential clinical applications to facilitate anti-tumor immunotherapy.