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.