Harnessing a triphenylphosphine-based AIE nano-platform for triggering incomplete mitophagy to continuously augment anti-tumor immune response in hepatocellular carcinoma

• Published in: Nano today Vol. 54; p. 102090
• Main Authors: Song, Yang, Yang, Zhenyu, Wang, Xiaoli, Ye, Yayi, Yan, Xianwu, Huang, Yubing, Huang, Xiaowan, Zhang, Hao, Qian, Jieying, Zhang, Yunjiao
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-02-2024
• Subjects: cGAS-STING; Hepatocellular carcinoma; Immunotherapy; Incomplete mitophagy; Innate immune; Triphenylphosphine; Innate immune; Hepatocellular carcinoma; Incomplete mitophagy; cGAS-STING; Triphenylphosphine; Immunotherapy
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2023.102090

Hepatocellular carcinoma (HCC) ranks as the second leading cause of cancer-related mortality globally, with an escalating incidence. However, HCC exhibits a robust immune tolerance microenvironment, rendering patients with low immune responsiveness and resistance to tumor immunotherapy. In this study, we successfully identified a highly effective mitochondria-targeting compound, AIE-Mito-TPP, through screening in Hepa1–6 cells. Notably, AIE-Mito-TPP induced substantial mitochondrial damage, leading to the release of mitochondrial DNA (mtDNA) and subsequent activation of the cGAS-STING pathway. Moreover, AIE-Mito-TPP facilitated the release of antigens in Hepa1–6 cells to promote dendritic cells maturation and repolarized tumor-associated macrophages. Mechanistically, we demonstrated that AIE-Mito-TPP triggered incomplete mitophagy which constantly released mtDNA and contributed to the activation of the cGAS-STING pathway. Leveraging the advantages of PEG-PLGA nanoparticles, known for their reduced toxicity, enhanced liver enrichment, and prolonged circulation, we developed a PEG-PLGA nano-platform that encapsulated AIE-Mito-TPP. The nanoparticles were coated with inhibitory peptides against PD-L1 (DPPA-1) and matrix metalloproteinase 2/9 (MMP-2/9) responsive peptides. This innovative design aimed to maximize the benefits of innate immunity stimulated by AIE-Mito-TPP while simultaneously blocking the PD-1/PD-L1 checkpoint. Notably, this combination approach significantly reprograms tumor immune microenvironment, facilitated in situ regression of HCC, and prolonged the survival of mice bearing Hepa1–6 tumors. Our study presents a novel mitochondria-targeting strategy to stimulate innate immunity in HCC through the induction of incomplete mitophagy and sheds light on the potential of AIE-Mito-TPP for therapeutic applications. Moreover, developing a nano-delivery system enhances the efficacy and safety profile of AIE-Mito-TPP, warranting further exploration of its clinical utility.
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•AIE-Mito-TPP induces sustained mtDNA-liberation into the cytosol, boosting the activation of innate immune responses.•Incomplete mitophagy induced by AIE-Mito-TPP exacerbates mitochondrial damage and further augments cGAS-STING activation.•Utilizing the AIE-Mito-TPP nanoplatform assisted by PD-L1 blockade yields a potent immunotherapeutic response against HCC.