Hierarchically structured microcapsules for oral delivery of emodin and tanshinone IIA to treat renal fibrosis

Renal fibrosis is the expected outcome of many chronic kidney diseases, and effective treatments are needed. Emodin (EMO) and tanshinone IIA (Tan IIA) are active ingredients in traditional Chinese herbs and have been effective in treating renal fibrosis. However, their application is greatly limited by inferior oral absorption, unexpected drug-drug interactions, and their ability to influence their respective pharmacokinetic profiles when used in combination. To mitigate these limitations, a new co-delivery approach based on a nano-in-micro system was designed by embedding Tan IIA-loaded nanoparticles (Tan IIA-NPs) in EMO-containing microcapsules. Microcapsules were prepared using the sharp flow technique that resulted in uniform spherical morphology and high encapsulation efficiency and drug loading. Furthermore, the encapsulated Tan IIA-NPs within the microcapsules exhibited superior cellular internalization and transmembrane transport due to the modification with cell-penetrating peptides and polyethylene glycol that facilitated the oral absorption of Tan IIA. Additionally, this nano-in-micro system exhibited evident sequential drug release. The oral bioavailability of EMO and Tan IIA was significantly improved when they were loaded into the hierarchically structured microcapsules, ultimately contributing to superior therapeutic outcomes in rats with unilateral ureteral obstruction. Therefore, the nano-in-micro carrier designed in this study could provide an efficient strategy for the effective oral delivery of combined therapies to treat renal fibrosis.