Dual-targeted lipid nanoparticles for TET3 siRNA delivery: nanobiotechnology strategy to remodel tumor immune microenvironment in hepatocellular carcinoma - PubMed
21 hours ago
- #lipid nanoparticles
- #nanobiotechnology
- #immunotherapy
- The study focuses on hepatocellular carcinoma (HCC) and its immunosuppressive tumor microenvironment (TME), characterized by M2-polarized tumor-associated macrophages (TAMs) and exhausted CD8+ T cells.
- Single-cell RNA sequencing identified TET3 as highly expressed in M2 TAMs in HCC. TET3 promotes M2 polarization via hydroxymethylation of IRF4, which leads to CD8+ T cell exhaustion through the CXCL12/CXCR4 axis.
- Researchers developed dual-targeted lipid nanoparticles (TET3 siRNA@αmp-Lipo) modified with macrophage-specific peptides to deliver TET3 siRNA specifically to M2 TAMs.
- In vitro tests showed the nanoparticles had good biocompatibility, stability, and effectively silenced TET3, inhibiting M2 polarization and restoring CD8+ T cell function.
- In vivo studies demonstrated that TET3 siRNA@αmp-Lipo significantly suppressed tumor growth, reduced M2 TAM infiltration, and reversed CD8+ T cell exhaustion in HCC models.
- The study identifies the TET3-IRF4 axis as a key epigenetic driver of immunosuppression in HCC and presents the nanoparticle platform as a promising strategy to enhance immunotherapy.