Precision Delivery of Binary Cooperative Nanodrugs Self-Assembled by Berberine Glycyrrhetinic Acid Salts for Hepatocellular Carcinoma Treatment.

Berberine (BB) has demonstrated significant inhibitory effects on tumorigenesis and progression. However, its clinical application is hindered by challenges such as low bioavailability due to limited cell membrane permeability, nontargeted accumulation away from solid tumors, and increased toxicity associated with intravenous administration. To overcome these challenges, a lipophilic salt-forming strategy was employed to enhance lipophilicity, thereby promoting membrane permeability and targetability for tumor accumulation while simultaneously mitigating the toxicity associated with intravenous injection. In vitro findings revealed an almost 10-fold increase in fluorescence intensity with BB-GA NDs compared to BB alone. Furthermore, selective cytotoxicity against tumor cells exhibited a 4-fold elevation compared to normal cells. In vivo results underscored the remarkable tumor-selective accumulation of BB-GA NDs, effectively mitigating the intravenous injection toxicity associated with pure BB. The self-assembly of binary cooperative nanodrugs utilizing berberine glycyrrhetinic acid salts opens up innovative possibilities for drug delivery systems in traditional Chinese medicine.