Boosting oral bioavailability of taraxasterol via a nanocrystal-mucoadhesive micropatch platform for potent multi-mechanistic protection against drug-induced liver injury

Drug-induced liver injury (DILI) is a serious adverse reaction with limited therapeutic options. Taraxasterol (TAS), a natural triterpenoid with hepatoprotective potential, suffers from poor aqueous solubility and low oral bioavailability, hindering its clinical application. Here, we develop an integrated oral delivery platform comprising TAS nanocrystals (TAS NCs) stabilized by D-α-tocopherol polyethylene glycol succinate (TPGS), embedded within chitosan-carbopol polyelectrolyte complex (EPC) micropatches, and encapsulated in enteric-coated capsules (TAS NCs@EPC/CAP). This design sequentially overcomes multiple absorption barriers through a multi-stage process: nanocrystallization enhances dissolution and permits TPGS-mediated P-glycoprotein inhibition and hepatocyte uptake; the mucoadhesive EPC micropatches prolong intestinal residence and transiently open tight junctions; and enteric coating ensures site-specific release in the small intestine. In mice, TAS NCs@EPC/CAP dramatically improved oral bioavailability (AUC increased 3.1-fold vs. free TAS) and achieved sustained liver enrichment. In both acetaminophen-induced intrinsic and isoniazid/rifampicin-induced idiosyncratic DILI models, TAS NCs@EPC/CAP exerted superior hepatoprotection, as evidenced by normalized liver function markers (ALT, AST, LDH), attenuated oxidative stress (ROS, MDA, GSH, SOD), suppressed inflammation (IL-1β, IL-6, TNF-α), and reduced hepatocyte apoptosis. Integrated network pharmacology and experimental validation revealed that TAS NCs@EPC/CAP potentiates the effects of TAS, leading to enhanced activation of the Nrf2/HO-1 antioxidant signaling, more pronounced inhibition of JNK-mediated stress pathways, and greater modulation of the Bax/Bcl-2/caspase-3 apoptotic cascade. This study establishes a clinically translatable oral delivery strategy for TAS and provides a versatile platform for enhancing the bioavailability of poorly soluble natural products, with potent efficacy against diverse forms of DILI.