Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways

Fang, Junyue; Xu, Rui; Cao, Yuan; Zhao, Zixuan; Li, Weifan; Lin, Li; Hou, Jingyi; Xu, Xiaoding; Saw, Phei Er

doi:10.7150/thno.112649

Nanotheranostics

International Journal of Biological Sciences

International Journal of Medical Sciences

Journal of Cancer

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Theranostics 2025; 15(16):7973-7989. doi:10.7150/thno.112649 This issue Cite

Research Paper

Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways

Junyue Fang^1,2,3,4, Rui Xu^1,2,3, Yuan Cao^1,2,3, Zixuan Zhao^1,2,3, Weifan Li^1,2,3, Li Lin^1,2,3,5, Jingyi Hou^1,2,3,6, Xiaoding Xu^1,2,3✉, Phei Er Saw^1,2,3,7✉

1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.
2. Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.
3. Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, P. R. China.
4. Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.
5. Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.
6. Department of Orthopedics and Department of Sports Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.
7. Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.

Citation:

Fang J, Xu R, Cao Y, Zhao Z, Li W, Lin L, Hou J, Xu X, Saw PE. Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways. Theranostics 2025; 15(16):7973-7989. doi:10.7150/thno.112649. https://www.thno.org/v15p7973.htm

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Abstract

Rationale: Sonodynamic therapy (SDT) has emerged as a promising non-invasive modality with deeper tissue penetration than photodynamic or chemodynamic therapies. However, its therapeutic efficacy remains limited due to inadequate reactive oxygen species (ROS) generation, largely attributed to tumor-intrinsic antioxidant systems and mitophagy. Existing combinations of SDT with immunotherapy are primarily additive and fail to address the mechanistic interplay between ROS suppression and immune evasion.

Methods: To overcome these limitations, we developed a redox-responsive RNA interference (RNAi) nanoplatform (NP) for the co-delivery of Nrf2 siRNA, the mitophagy inhibitor 3-Methyladenine (3-MA), and the sonosensitizer purpurin-18 (P-18). This NP enables tumor-specific release in high-glutathione environments and facilitates dual-pathway inhibition upon ultrasound activation.

Results: This synergistic platform simultaneously disrupted Nrf2-mediated antioxidant defenses and mitophagy-dependent mitochondrial clearance, resulting in enhanced intracellular ROS accumulation. Elevated ROS levels triggered immunogenic cell death (ICD), promoting dendritic cells maturation and antigen presentation. Concurrently, 3-MA inhibited NF-κB signaling, downregulating PD-L1 expression and mitigating T cell exhaustion. In murine breast cancer models, this dual-action approach elicited robust CD8⁺ T cell responses and significantly suppressed tumor growth and metastasis.

Conclusions: This study introduces a mechanistically integrated sonoimmunotherapeutic strategy that concurrently overcomes ROS suppression and immune checkpoint resistance. By orchestrating redox disruption and immune reprogramming, our nanoplatform provides a compelling framework for next-generation SDT-based immunotherapy.

Keywords: sonoimmunotherapy, mitophagy inhibition, immune checkpoint blockade, reactive oxygen species, redox-responsive nanoplatform

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APA

Fang, J., Xu, R., Cao, Y., Zhao, Z., Li, W., Lin, L., Hou, J., Xu, X., Saw, P.E. (2025). Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways. Theranostics, 15(16), 7973-7989. https://doi.org/10.7150/thno.112649.

ACS

Fang, J.; Xu, R.; Cao, Y.; Zhao, Z.; Li, W.; Lin, L.; Hou, J.; Xu, X.; Saw, P.E. Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways. Theranostics 2025, 15 (16), 7973-7989. DOI: 10.7150/thno.112649.

NLM

CSE

Fang J, Xu R, Cao Y, Zhao Z, Li W, Lin L, Hou J, Xu X, Saw PE. 2025. Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways. Theranostics. 15(16):7973-7989.

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