A Glycyrrhiza Glabra-derived pH/ROS Dual-Responsive Phytomedicine Nanoplatform for Combatting Triple-Negative Breast Cancer via Amplified Mitochondrial Damage.

In this work, we engineered a novel core-shell nanoplatform (TG@GPH) based on glycyrrhizic acid (GL) for enhanced mitochondrial-targeted therapy against triple-negative breast cancer (TNBC). Specifically, the amphiphilic structure of GL enabled encapsulation of triphenylphosphine-glycyrrhetinic acid (TPP-GA or TG) with a high loading capacity (> 24%); whereas its ortho-hydroxy groups facilitated the anchoring of a polyethylenimine-phenylboronic acid (PEI-PBA) inner shell via borate ester bonds, followed by electrostatic coating of a hyaluronic acid outer shell. The TG@GPH micelles exhibited good physiological stability and efficient uptake by MDA-MB-231 cells; however, they dissociated under acidic and elevated ROS conditions due to acid-labile cleavage of boronate ester bonds and ROS-triggered oxidative breakage of carbon-boron bonds, thereby rapidly releasing the TG payload. Thereafter, TG selectively targeted mitochondria and stimulated the opening of the mitochondrial permeability transition pores, resulting in mitochondrial impairment characterized by ROS overproduction, membrane potential depletion, and energy supply blockade, culminating in tumor cell apoptosis. Accordingly, TG@GPH suppressed tumor growth in MDA-MB-231 xenograft mouse models with an inhibition rate of 79.70%. Overall, the developed TG@GPH micelles displayed considerable potential for TNBC treatment and provided a compelling paradigm for transforming natural compounds into intelligent building blocks for sophisticated drug delivery systems.