Nanoparticle-mediated SIRT1 inhibition suppresses M2 macrophage polarization and hepatocarcinogenesis in chronic hepatitis B

Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis B (CHB), with macrophage M2 polarization playing a critical role in shaping the tumor-promoting hepatic immune microenvironment. Sirtuin 1 (SIRT1) has been implicated in immune modulation and liver carcinogenesis. This study investigates the potential of Mimetic Nanoparticles (MNPs) for delivering SIRT1 inhibitors to regulate macrophage polarization and remodel the hepatic immune microenvironment, aiming to prevent HCC development post-CHB. A transgenic mouse model of CHB was established, and RNA sequencing (RNA-seq) and proteomics analyses revealed significant dysregulation of genes associated with M2 macrophage polarization, particularly SIRT1. Functional enrichment analysis highlighted key pathways, including PI3K-Akt and NF-κB, that contribute to CHB-driven immune alterations. Synthesized and characterized MNPs successfully delivered SIRT1 inhibitors, effectively inhibiting M2 macrophage polarization in vitro. In vivo administration of MNPs-SIRT1-FN significantly reduced M2 macrophage infiltration and suppressed tumor growth. These findings suggest that nanoparticle-mediated SIRT1 inhibition is a promising strategy for immunomodulation and HCC prevention in CHB patients. This study provides novel insights into nanoparticle-based immunotherapy for CHB-related HCC and highlights a potential therapeutic avenue for liver cancer prevention.