Triterpenoids and ultrasound dual-catalytic nanoreactor ignites long-lived hypertoxic reactive species storm for deep tumor treatment

Inducing redox imbalance in cancer cells aided by external stimuli is a promising strategy to treat cancer. However, maximizing efficacious reactive species content with durable effects in deep tumors remains to be challenging. Here, we report an herbal medicine-based nanoreactor (OH7) self-assembled by oleanolic acid (OA) and two sonosensitizers. OH7 couples two cascade reactions under sonication, including dual-sonosensitizer-participated consecutive reactions for generating long-living peroxyl radical (ROO•) and OA-participated serial reactions for forming highly cytotoxic peroxynitrite (ONOO−). The site-directed reactive species burst exerts excellent cytotoxicity on two-dimensional cancer cell cultures and multicellular tumor spheroids. The high elasticity of OH7 for deep tumor transportation, the enhanced intratumoral convection by ultrasound, and the formation of ONOO− to destroy extracellular matrix jointly facilitate satisfactory penetration depth of sonosensitizers. Of note, the deep penetration and the long-lived hypertoxic reactive species generating ability can realize effective tumor inhibition by systemic administration. This study opens up new insights into the reactive species-related bioactive mechanisms to support green development of biocompatible high-performance sonocatalytic nanoreactor for potential clinical applications.