Harnessing a Triphenylphosphine-Based AIE Nano-Platform for Triggering Incomplete Mitophagy to Continuously Augment Anti-Tumor Immune Response in Hepatocellular Carcinoma

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.