Hepatocellular carcinoma (HCC) exhibits profound glycolytic reprogramming, driving tumor growth, impairing apoptosis, and suppressing immune responses, leading to resistance to conventional therapies. To overcome this challenge, we developed a stimulus-responsive nanozyme composed of glucose oxidase (GOx) encapsulated in a pH-sensitive lipid-gelatin-peptone (LGP) nanogel. This tumor-selective nanozyme consumes glucose within tumors under acidic conditions, inducing oxidative and endoplasmic reticulum stress,Upregulates death receptors and sensitizes hepatocytes to TRAIL- and doxorubicin (DOX)-induced apoptosis. The co-delivery of GOx and DOX in nanoenzymes reprograms tumor immune metabolism, enhances immunogenic cell death, and promotes the release of damage-associated molecular patterns (DAMPs). These changes stimulate dendritic cell maturation and cytotoxic CD8 T cell activation. Transcriptome analysis confirmed that this nanoenzyme remodels the immunosuppressive microenvironment by inhibiting metabolic pathways and activating immune-related gene programs.When combined with anti-PD-1 checkpoint blockade, this nanozyme can induce potent tumor regression in an orthotopic HCC model, eliminate metastasis, and cause no systemic toxicity. Overall, this work introduces a multifunctional tumor-responsive nanozyme that integrates metabolic intervention, apoptosis initiation, and immune activation to overcome therapeutic resistance in HCC.

Original link

Stimuli-Responsive Nanozyme Reprograms Tumor Immunometabolism and Overcomes Therapeutic Resistance in Hepatocellular Carcinoma

Pub Date : 2026-01-06

DOI: 10.1021/acsnano.5c11352

Yen-Nhi Ngoc Ta,Van-Anh Thi Nguyen,Thu-Thuy Can,Meng-Cheng Hsieh,Bang Giang Thi Cao,Dehui Wan,Chian-Hui Lai,Chun-Chieh Wu,Fu-Fei Hsu,Yu-Ting Yen,Shen-Nien Wang,Yunching Chen