Percutaneous implantation of ethanol fueled catalytic hydrogel suppresses tumor growth by triggering ferroptosis

Percutaneous ethanol injection therapy (PEIT) is a nonthermal locoregional treatment modality widely used in the treatment of solid tumors such as small hepatocellular carcinoma (HCC). Restricted by the inhomogeneous diffusion and unwanted leakage of injected ethanol, PEIT that usually requires multiple injections is often associated with a high local recurrence rate and potential severe complications. Herein, we propose an alternative locoregional treatment strategy to effectively ablate tumors by utilizing the reactive oxygen species generated from the percutaneously implanted catalytic couple fueled by orally administrated ethanol. It is shown that the catalytic couple of alcohol oxidase and iron catalyst hemin conjugated chitosan can sequentially convert ethanol to cytotoxic hydrogen peroxides and then hydroxyl radials, thereby result in efficient cancer cell killing by triggering ferroptosis. Upon being fixed inside tumors with in-situ formed alginate hydrogels, such catalytic couple together with multiple ethanol gavages shows great inhibitory effect on murine H22 liver and 4T1 breast tumors, comparable to those treated by PEIT. The efficient therapeutic potency of the combination treatment is further confirmed in a rat orthotopic N1S1 HCC model. This work highlights that our 'alcohol drinking' anti-tumor strategy is of great effectiveness, operation convenience, and high safety.