Tumour-targeted nitric oxide nanotherapy overcomes sorafenib resistance and reprograms antitumour immunity in hepatocellular carcinoma

Resistance to sorafenib, a first-line tyrosine kinase inhibitor (TKI) for advanced HCC, has been associated with activation of the AKT–mTOR pathway, suggesting that suppression of this axis may improve therapeutic efficacy. Here, we developed NanoNOSOR, an HCC-targeted SP94 peptide-functionalized lipid–PLGA nanoplatform for tumor-targeted, pH-responsive co-delivery of the nitric oxide donor DNIC and sorafenib.

DNIC sensitized murine and human HCC cells to sorafenib by suppressing AKT–mTOR signaling. Co-loading DNIC and sorafenib into SP94-functionalized nanoparticles enhanced HCC cell uptake, promoted pH-responsive payload release, and achieved synergistic AKT–mTOR pathway suppression and cytotoxicity in vitro. In orthotopic HCC-bearing mice, NanoNOSOR preferentially accumulated in tumors and showed superior antitumor activity over single-agent nanoparticle formulations, as indicated by suppression of primary tumor growth and lung metastasis, together with increased tumor cell apoptosis.