Arginine-Loaded Nano-Calcium-Phosphate-Stabilized Lipiodol Pickering Emulsions Potentiates Transarterial Embolization-Immunotherapy

Abstract

Transarterial chemoembolization (TACE) continues to stand as a primary option for treating unresectable hepatocellular carcinoma (HCC). However, the increased tumor hypoxia and acidification will lead to the immunosuppressive tumor microenvironment (TME) featuring exhausted T cells, limiting the effectiveness of subsequent therapies following TACE. Herein, a stable water-in-oil lipiodol Pickering emulsion by employing calcium phosphate nanoparticles (CaP NPs) as stabilizers is developed and used to encapsulate L-arginine (L-Arg), which is known for its ability to modulate T-cell metabolism. The obtained L-Arg-loaded CaP-stabilized lipiodol Pickering emulsion (L-Arg@CaPL) with great emulsion stability can not only neutralize the tumor acidity via reaction of CaP NPs with protons but also enable the release of L-Arg, thereby synergistically promoting the reinvigoration of exhausted CD8+ T cells and effectively reversing tumor immunosuppression. As a result, TACE therapy with L-Arg@CaPL shows greatly improved therapeutic responses as demonstrated in an orthotopic liver tumor model in rats. This study highlights an effective yet simple nanoparticle-stabilized Pickering emulsion strategy to promote TACE therapy via modulation of the immunosuppressive TME, presenting great potential for clinical translation.