Neutrophil‐Targeting Framework Nucleic Acid Based NETosis‐Inhibiting Nanoplatform Orchestrates Intra‐ and Extra‐tumoral Attack to Suppress Primary Tumor and Liver Metastasis

Abstract Advanced cancers frequently develop liver metastases with limited therapeutic options due to poor drug efficacy and hepatotoxicity. Neutrophil extracellular traps (NETs) drive liver metastasis by activating tumor cells and inducing immunosuppression. Targeted inhibition of peptidylarginine deiminase type 4 (PAD4), a key enzyme for NET formation, can disrupt this pro‐metastatic cascade. To address inefficient delivery of the PAD4 inhibitor GSK484, a neutrophil‐targeting nanoplatform (TPG: tFNA‐Ac‐PGP@GSK484) loaded with GSK484 is engineered by conjugating tetrahedral framework nucleic acids (tFNAs) with the neutrophil‐targeting peptide Ac‐PGP. Molecular docking and dynamics simulations confirm stable binding of GSK484 to tFNAs. In vitro, TPG suppresses reactive oxygen species and NETosis markers prominently, attenuating NET‐driven tumor proliferation, migration, invasion, and immune evasion. In vivo, TPG reduces primary tumor volume and liver metastasis markedly, extending the median survival days of the treated mice. These findings establish TPG as a dual‐action nanotherapy that blocks NETosis at its source and remodels the tumor microenvironment, providing a targeted strategy against primary tumors and liver metastatic dissemination.