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

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 (H2S) 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 H2S and Mn2+, and release CRISPR/Cas9 in acidic tumor microenvironment. H2S can up-regulate intracellular hydrogen peroxide level by inhibiting the activity of catalase, which enables self-enhanced chemodynamic therapy (CDT) of Mn2+. In addition, H2S 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, H2S-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.