Thermoresponsive Ozone-Enriched Spray Gel for Postsurgical Treatment of Hepatocellular Carcinoma

Surgical resection of hepatocellular carcinoma suffers from a high recurrence rate. Ozone directly kills tumor cells by generating reactive oxygen species in vitro, but its high reactivity and short half-life severely limit its tumor accumulation and penetration for the treatment of tumors in vivo. Herein, a thermoresponsive ozone-enriched spray gel is developed to suppress the tumor recurrence of hepatocellular carcinoma (Huh-7 tumors). Briefly, a perfluorocarbon nanoemulsion (PFTBA@LIP) consisting of a perfluorotributylamine core and a lipid monolayer is fabricated, which is encapsulated in the thermoresponsive hydrogel. Ozone is then dissolved in the nanoemulsion owing to its high affinity to PFTBA (O₃/PFTBA@LIP@Gel), which effectively improves its stability. Of note is that O₃/PFTBA@LIP@Gel induces both ferroptosis and apoptosis by regulating the expression of relevant genes (GPX4, ACSL4, CDKN1A, etc.) and inducing considerable lipid peroxidation, which significantly reduces the tumor recurrence of the Huh-7 tumor by spraying the gel in the surgical cavity and prolongs the survival of tumor-bearing mice.