期刊
THERANOSTICS
卷 11, 期 17, 页码 8587-8604出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.62572
关键词
Mitochondria-targeted; Oxygen and nitric oxide codelivery; Reverse immunosuppression; Sonodynamic therapy; Immune response
资金
- Youth Foundation of Jiangsu province [BK20180699]
- National Science Foundation for Post-doctoral Scientists of Jiangsu Province, China [1601018A]
- National Natural Science Foundation of China [81803439]
- China Postdoctoral Science Foundation [2017M611792]
- Nanjing Medical Science and Technique Development Foundation [QRX17048, ZKX19014]
This study developed mitochondria-targeted nanoparticles to co-deliver oxygen and nitric oxide for enhancing sonodynamic therapy and reversing immunosuppression in the tumor microenvironment. The nanoparticles showed promising results in inhibiting tumor growth, promoting immunogenic cell death, and enhancing immune response both in vitro and in vivo. The findings provide a simple strategy to improve cancer immunotherapy by combining sonodynamic therapy with oxygen and nitric oxide delivery.
Background: Sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate antitumor immune responses for immunotherapy. However, the hypoxic and immunosuppressive tumor microenvironment limits its therapeutic efficacy and suppresses immune response. Methods: In this study, mitochondria-targeted and ultrasound-responsive nanoparticles were developed to co-deliver oxygen (O-2) and nitric oxide (NO) to enhance SDT and immune response. This system (PIH-NO) was constructed with a human serum albumin-based NO donor (HSA-NO) to encapsulate perfluorodecalin (FDC) and the sonosensitizer (IR780). In vitro, the burst release of O-2 and NO with US treatment to generate reactive oxygen species (ROS), the mitochondria targeting properties and mitochondrial dysfunction were evaluated in tumor cells. Moreover, in vivo, tumor accumulation, therapeutic efficacy, the immunosuppressive tumor microenvironment, immunogenic cell death, and immune activation after PIH-NO treatment were also studied in 4T1 tumor bearing mice. Results: PIH-NO could accumulate in the mitochondria and relive hypoxia. After US irradiation, O-2 and NO displayed burst release to enhance SDT, generated strongly oxidizing peroxynitrite anions, and led to mitochondrial dysfunction. The release of NO increased blood perfusion and enhanced the accumulation of the formed nanoparticles. Owing to O-2 and NO release with US, PIH-NO enhanced SDT to inhibit tumor growth and amplify immunogenic cell death in vitro and in vivo. Additionally, PIH-NO promoted the maturation of dendritic cells and increased the number of infiltrating immune cells. More importantly, PIH-NO polarized M2 macrophages into M1 phenotype and depleted myeloid-derived suppressor cells to reverse immunosuppression and enhance immune response. Conclusion: Our findings provide a simple strategy to co-deliver O-2 and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.
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