ArticleJournal of nanobiotechnology2026
Dual-targeted lipid nanoparticles for TET3 siRNA delivery: nanobiotechnology strategy to remodel tumor immune microenvironment in hepatocellular carcinoma.
Article in Journal of nanobiotechnology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundHepatocellular carcinoma (HCC) is characterized by a highly immunosuppressive tumor microenvironment (TME), where M2-polarized tumor-associated macrophages (TAMs) and exhausted CD8
resultsSingle-cell RNA sequencing identified ten-eleven translocation 3 (TET3) as highly expressed in M2 TAMs in HCC tissues. Mechanistically, TET3 promotes M2 polarization by enhancing interferon regulatory factor 4 (IRF4) transcriptional activity via hydroxymethylation, which in turn induces CD8⁺ T cell exhaustion through the CXCL12/CXCR4 axis. To target this pathway, we engineered dual-targeted lipid nanoparticles (TET3 siRNA@αmp-Lipo) modified with macrophage-specific peptides, enabling efficient and specific delivery of TET3 siRNA to M2 TAMs. In vitro experiments demonstrated the nanoparticles' excellent biocompatibility, stability, and ability to silence TET3, inhibiting M2 polarization and restoring CD8
conclusionsThis study identifies the TET3-IRF4 axis as a central epigenetic driver of immunosuppression in HCC and establishes TET3 siRNA@αmp-Lipo as a potent and translatable nanobiotechnology platform. By integrating targeted siRNA delivery with immune microenvironment remodeling, this strategy provides a promising approach to enhance immunotherapy for HCC and potentially other cancers with immunosuppressive TMEs.
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