A Novel CRISPR/Cas9‐Encapsulated Biomimetic Manganese Sulfide Nanourchins for Targeted Magnetic Resonance Contrast Enhancement and Self‐Enhanced Chemodynamics‐Gene‐Immune Synergistic Tumor Therapy

Abstract CRISPR/Cas9 gene editing systems are widely studied in cancer therapy, however, it is still challenging to improve the gene editing efficiency and enhance the anticancer efficacy. Herein, a novel self‐assembled manganese sulfide nanourchin with CRISPR/Cas9 and hybrid membrane encapsulation (MCRT) is developed to highlight the synergistic mechanism of hydrogen sulfide (H 2 S) and CRISPR/Cas9 in cancer therapy. The special structure and cationic surface of nanourchins facilitate the loading of CRISPR/Cas9 with the large size and the encapsulation of erythrocyte‐tumor cell hybrid membrane, endowing the nanoplatform with long circulation and precise tumor targeting. MCRT with pH‐response can effectively decompose into H 2 S and Mn 2+ , and release CRISPR/Cas9 in acidic tumor microenvironment. H 2 S can up‐regulate intracellular hydrogen peroxide level by inhibiting the activity of catalase, which enables self‐enhanced chemodynamic therapy (CDT) of Mn 2+ . In addition, H 2 S can synergize with the released CRISPR/Cas9, co‐downregulating the level of intracellular anti‐apoptotic protein survivin, achieving self‐enhanced gene therapy. Furthermore, systemic delivery of MCRT displays significantly tumor magnetic resonance imaging (MRI) contrast enhancement. Importantly, H 2 S‐enhanced CDT‐gene therapy simultaneously induces immunogenic cell death and triggered a robust anti‐tumor immune response. Thus, MCRT has a potential application for the targeted MRI and self‐enhanced CDT‐gene‐immune synergistic tumor therapy.