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Breviscapine (BRE) possesses excellent cardioprotective efficacy against myocardial infarction (MI). However, its oral application is severely hindered by BCS Class IV properties, including poor solubility and permeability, accompanied by P-glycoprotein (P-gp)-mediated drug efflux and gastrointestinal absorption barriers. Arginine-rich CPPs such as R8 can promote cellular uptake, whereas cationic surface characteristics may restrict particle mobility in gastrointestinal mucus. Conversely, hydrophilic and electro-neutral surfaces favor mucus penetration but may reduce epithelial uptake. This imposes challenges for balancing these two absorption barriers. To solve these problems, we developed surface-engineered nanocrystals with sequential barrier-crossing capability (R8-F127-VES@BRE-NCs).

We engineered multifunctional nanocrystals (R8-F127-VES@BRE-NCs) featuring a sequential barrier-crossing design: nanocrystal technology increases saturation solubility, Pluronic F127 imparts mucus-penetrating capability, R8 peptide facilitates epithelial internalization, and Vitamin E Succinate (VES) may contribute to efflux modulation.

Comprehensive characterization and in vitro studies suggested that this integrated design helped address the trade-off between mucus diffusion and epithelial uptake. Pharmacokinetic studies revealed a marked enhancement in oral BRE absorption, with C_max and AUC_0-∞ increased to 185.76 ng/mL and 1418.34 ng·mL^-1·h (4.27- and 7.37-fold over BRE-raw). Following establishment of the isoprenaline-induced myocardial injury model, 14-day oral treatment with R8-F127-VES@BRE-NCs showed enhanced cardioprotective effects, as evidenced by reduced infarct size and improved oxidative stress-related biochemical indicators.

R8-F127-VES-modified nanocrystals provide a promising strategy for overcoming oral delivery barriers and enhancing the cardioprotective effects of orally administered BRE.