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Theranostics 2021; 11(17):8587-8604. doi:10.7150/thno.62572 This issue Cite

Research Paper

Mitochondria-targeted and ultrasound-responsive nanoparticles for oxygen and nitric oxide codelivery to reverse immunosuppression and enhance sonodynamic therapy for immune activation

Changwei Ji^1,#, Jingxing Si^2,3,#, Yan Xu⁴, Wenjing Zhang⁴, Yaqian Yang⁴, Xin He¹, Hao Xu⁴, Xiaozhou Mou^2,3✉, Hao Ren^4✉, Hongqian Guo^1✉

1. Department of Urology, Drum Tower Hospital, Medical school of Nanjing University, Institute of Urology, Nanjing University, Nanjing 210008, Jiangsu, China.
2. Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
3. Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
4. School of Pharmaceutical Science, Nanjing Tech University, Nanjing 211816, Jiangsu, China.
#These authors contributed equally to the article

✉ Corresponding authors: Dr. Xiaozhou Mou, PhD: mouxzedu.cn. Prof. Hao Ren, PhD: hrenedu.cn. Dr. Hongqian Guo, Ph.D; dr.ghqedu.cn.

Abstract

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 (O₂) 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 O₂ 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, O₂ 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 O₂ 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 O₂ and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.

Keywords: Mitochondria-targeted, Oxygen and nitric oxide codelivery, Reverse immunosuppression, Sonodynamic therapy, Immune response

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