A novel biomimetic nanoplatform (PZ@M-T) significantly inhibited hepatocellular carcinoma (HCC) progression by specifically activating the .
The nanoplatform triggers in HCC cells, leading to the release of mitochondrial DNA.
Endogenous mitochondrial DNA activates the cGAS-STING pathway in a specific manner.
Activation of the cGAS-STING pathway promotes dendritic cell maturation and repolarizes tumor-associated macrophages from M2 to M1 phenotype.
This process enhances cytotoxic T cell infiltration while suppressing regulatory T cells.
Collectively, these effects drive a robust anti-tumor immune response.
Simplified
Low immunogenicity remains a critical barrier to effective immunotherapy for hepatocellular carcinoma (HCC). Activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising strategy for HCC treatment; however, achieving specific activation of this pathway remains a major challenge. Herein, we report a novel biomimetic nanoplatform (PZ@M-T) that triggers to specifically activate the . This study utilized a hollow ZIF-8 metal-organic framework (MOF) coated with mesenchymal stem cell membrane (MSCm) as a biomimetic carrier of polyphyllin II (PPⅡ) functionalized with triphenylphosphine (TPP) via copper-free click chemistry for mitochondrial targeting. Acid-responsive PPⅡ release in the tumor microenvironment (TME) induced robust ferroptosis in HCC cells, eliciting mitochondrial stress to cause endogenous mitochondrial DNA (mtDNA) release, which specifically initiated the cGAS-STING pathway with the cooperation of Zn. This activation drove dendritic cell (DC) maturation, repolarized tumor-associated macrophages (TAMs) from the M2 to M1 phenotype, enhanced cytotoxic T cell infiltration, and suppressed regulatory T cells (Tregs), thereby collectively driving a robust anti-tumor immune response that significantly inhibited HCC progression. This innovative nanotherapeutic platform provides new promising strategy for tumor immunotherapy via specific activation of the cGAS-STING pathway and offers new insights into advanced chemo-immunotherapeutic approaches. 2+
Key numbers
76.7%
Tumor Inhibition Rate
Compared to 12.8% for TA-ZIF-8 and 30.2% for PPⅡ.
1.9×
Pro-inflammatory Cytokine Increase
Levels of IFN-β increased compared to control.
20.60%
Dendritic Cell Maturity
Compared to 2.86% in control group.
Full Text
We can’t show the full text here under this license.
Declarations. Ethics approval and consent to participate: All animal experiments in this study were approved by the Beijing University of Chinese Medicine Animal Welfare & Ethics Committee. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
