Gold Nanorod-mesoporous silica core shell nanocomposites for NIR-II photothermal ablation and dual PD-L1/VEGF blockade therapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignancy often associated with high angiogenesis and immune suppression in the tumor microenvironment (TME). Targeting of the tumor immune microenvironment via the dual blockade of vascular endothelial growth factor (VEGF) and programmed death-ligand 1 (PD-L1) offers longer progression-free survival as a first-line treatment for patients with unresectable HCC. However, certain critical factors limit the clinical success of this therapy, including low stability of antibody, poor tumor pene-tration, weak immunogenicity, uncontrollable biological activity, short internal half-life, and failures in lasting antitumor immune response. Nanoparticle-based photothermal therapy (PTT) offers the possibility to amplify anti-tumor immune responses, although some issues still limit the expansion of this strategy, such as limited tumor penetration depth for the activation of immune cells and a weak immune response in a powerful immunosuppressive TME. Here, we designed a nanoplatform (GSBVVP) for combined use with PTT and dual blockade of VEGF and PD-L1 to achieve an enhanced PTT-mediated immune response for the treatment of HCC. This nanoplatform is composed of a gold nanorod/mesoporous silica core-shell nanoparticle, which demon-strated excellent photothermal conversion efficiency and could ablate tumor cells under 1208-nm laser irradi-ation (NIR-II). GSBVVP was loaded with a small-molecule inhibitor of PD-L1, released by NIR-II triggering. This increased the number of infiltrating CD8+ T cells via the inhibition of T cell PD-1 binding to PD-L1 on tumor cells. A peptide vaccine on the surface of GSBVVP induced anti-VEGF antibody production, thereby blocking the secretion of VEGF by tumor cells in the TME and suppressing the angiogenesis signaling pathway. Animal studies verified that GSBVVP-mediated photothermal immunotherapy significantly inhibited primary tumor growth, suppressed metastasis and prevented tumor recurrence. Our strategy of bridging photothermal ablation with dual blockade VEGF and PD-L1 by nanotechnology may have a great potential for clinical translation, and it is promising for cancer immunotherapy.