ROS-responsive yeast microcapsule oral delivery system for targeted celastrol delivery and kidney stones treatment

Abstract Background Kidney stones are a common urological disease characterized by a cycle of calcium deposition and inflammation. Balancing macrophage polarization is a promising strategy for treatment. Celastrol (Cel) is an effective compound to treat kidney stones, but its oral use is limited by low bioavailability. Yeast microcapsule (YC) is a considerable candidate for oral drug delivery to improve bioavailability. Results An oral delivery system (HCeY) was developed using YC and hyperbranched poly(β-amino thioether ester) (HPBTEa). After oral dosing, the β-glucan on YC surface is recognized and transcytosed by intestinal M cells. The carriers are then internalized by macrophages and transported to renal inflammatory sites. At the site of the stones, high levels of reactive oxygen species (ROS) trigger the cleavage of thioether bonds in HPBTEa to release Cel. HCeY breaks the “renal injury-stone formation” cycle through three mechanisms: achieving renal targeting via macrophage “hitchhiking”; inhibiting STAT1 to reduce M1 macrophage polarization; and scavenging ROS to relieve endoplasmic reticulum stress and mitochondrial dysfunction. Conclusions This study developed a promising YC-assisted formulation that could enhance the bioavailability and renal accumulation of Cel, establishing a theoretical basis for the future clinical application of YC-based drug delivery systems in kidney stone therapy.