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

Therapeutic responses in hepatocellular carcinoma (HCC) are often limited by resistance-associated survival signaling and immune escape. 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. This antitumor effect was accompanied by transcriptional remodeling of the tumor microenvironment, with reduced proliferation-associated programs and increased immune-activation pathways. In addition, NanoNOSOR-mediated AKT–mTOR axis suppression downregulated PD-L1 immune checkpoint expression and enhanced intratumoral CD8⁺ T-cell infiltration and activation, linking tumor-intrinsic pathway inhibition to reduced immune escape. Biosafety analysis showed no overt hepatotoxicity, nephrotoxicity, or major organ damage. Together, these findings establish NanoNOSOR as a tumor-targeted NO–TKI co-delivery strategy that enhances therapeutic response and reprograms the HCC tumor microenvironment, providing a potential nanotherapeutic platform for overcoming therapeutic resistance in HCC.