A novel biomimetic nanoplatform amplifies ferroptosis for specific cGAS-STING pathway activation to enhance hepatocellular carcinoma chemo-immunotherapy

作者：Hulinyue Peng, Aqian Chang, Huizhong Zhang, Xiaohan Xu, Wenqi Wang, Ke Zhang, Jingwen Yang, Sha Xie, Xiaoyu Peng, Xingbin Yin, Changhai Qu, Jing Fu, Jian Ni, Xiaoxv Dong · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03870-5 · 被引用次数：5 · 研究领域：interferon and immune responses、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

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 ferroptosis to specifically activate the cGAS-STING pathway. 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 2+ . 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 i...