Journal
CHEMICAL ENGINEERING JOURNAL
Volume 443, Issue -, Pages -Publisher
ELSEVIER SCIENCE SA
DOI: 10.1016/j.cej.2022.136428
Keywords
Nuclear DNA; Mitochondrial DNA; Cyclic GMP-AMP synthase-stimulator of inter-feron genes (cGAS; STING); Gastric cancer; Innate immunity
Categories
Funding
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer [2020B121201004]
- National Natural Science Foundation of China [82001948, 81971746]
- Guangdong Basic and Applied Basic Research Foundation [2022A1515010462]
- Guangdong Provincial Major Talents Project [2019JC05Y361]
- College Students' Innovative Entrepreneurial Training Plan Program [202012121020]
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This study constructed organic silica nanoparticles containing platinum nanoparticles and a photosensitizer, which can enhance the efficacy of immunotherapy in gastric cancer by activating signaling pathways.
Immune checkpoint inhibitors-based cancer immunotherapy is yielding great clinical benefit, but its efficacy is limited in gastric cancer (GC) by the lack of T-cell infiltration in the tumor microenvironment. Notably, activating the DNA-sensitive cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) signaling pathway could trigger innate immunity and recruitment of tumor-infiltrating lymphocytes. Herein, we constructed co-loaded platinum nanoparticles (Pt-NPs; chemo-prodrugs) and IR820 (photosensitizer) into hollow mesoporous organosilica nanoparticles (termed as HMON@IR820/Pt-NPs). The HMON@IR820/Pt-NPs exhibit appropriate size distribution, good biocompatibility, and generate reactive oxygen species under mild near infrared irradiation (0.7 W cm-2). Importantly, HMON@IR820/Pt-NPs efficiently enter GC cells and release loaded drugs. Pt-NPs can trigger H2O2 decomposition to O2, enhancing photodynamic efficiency. Furthermore, IR820 could enter into mitochondria, then induce mitochondria oxidative stress disorder, resulting in the releasing of oxidative mitochondrial DNA (mitoDNA). Meanwhile, this oxidative process also allowed for oxidation of Pt(0) to cytotoxic Pt(II), resulting in the dysfunction of nuclear DNA (nDNA). Dual-damage to nDNA and mitoDNA activates the c-GAS/STING pathway, stimulating innate immunity, including a primary anti-tumor effect and recruitment of CD8+ T cells, enhancing cross-presentation inside dendritic cells, and sustaining lethality in distant tumors. In summary, HMON@IR820/Pt-NPs have the potential to improve immunotherapy efficacy in GC.
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