# Zhimu-Huangbai codecoction for the treatment of type II diabetes mellitus through its self-assembling nanoparticles

## TL;DR

This study shows that natural nanoparticles in a traditional Chinese medicine decoction help treat type 2 diabetes and improve drug absorption.

## Contribution

The study identifies natural nanoparticles in Zhimu-Huangbai decoction as key to its anti-diabetic effects and enhanced bioavailability.

## Key findings

- N-ZBD nanoparticles significantly reduced blood glucose and lipid levels in T2DM rats.
- N-ZBD enhanced intestinal absorption and bioavailability of active compounds compared to free drugs.
- N-ZBD showed pharmacokinetic profiles comparable to the full decoction but with improved metrics.

## Abstract

Traditional Chinese medicine (TCM) decoctions represent a complex system comprising multiple phases, and their therapeutic effects cannot be fully elucidated solely at the molecular level. The nanophase within TCM decoctions plays a significant role in mediating their pharmacological activities. Zhimu and Huangbai herbal decoction (ZBD), traditionally used to treat type 2 diabetes mellitus (T2DM), is a formulation combining Rhizoma Anemarrhenae and Cortex phellodendri chinensis. Our prior research identified natural nanoparticles (N-ZBD) within ZBD. However, the role of these nanoparticles in ZBD’s anti-T2DM effects and their potential impact on the oral bioavailability of its active components remain unclear. Therefore, this study aimed to examine the anti-T2DM effects of N-ZBD and to assess whether N-ZBD could enhance the bioavailability of its primary active compounds. Initially, we employed a dialysis centrifugation method to isolate the N-ZBD (nanoparticles derived from Zhimu-Baihu Decoction) from ZBD. The separated N-ZBD exhibited an average particle size of 234.4 ± 1.04 nm, a polydispersity index (PDI) of 0.56 ± 0.06, and a zeta potential of − 12 .97 ± 1.46 mV. Then, a type 2 diabetes mellitus (T2DM) rat model was created by administering a low dose of streptozotocin (35 mg/kg) intraperitoneally following 4 weeks on a high-fat diet. After a 7-week treatment period, compared with the model group, the levels of FBG, TC, TG and LDL in MET group, N-ZBD group and ZBD group were significantly reduced, and the morphology of islets was significantly improved. In all phases state of ZBD, N-ZBD had a significant therapeutic effect on T2DM rats, which was comparable to that of ZBD. In order to explore whether N-ZBD has the effect of promoting absorption, we assessed the intestinal absorption properties of N-ZBD, ZBD, and free drugs (mangiferin, timosaponin BII, berberine, phellodendrine, neomangiferin and jatrorrhizine) utilizing a single-pass intestinal perfusion (SPIP) model. Compared to free drugs, N-ZBD enhanced the absorption of active ingredients in the jejunum and ileum. In order to explore whether N-ZBD can improve the bioavailability of active ingredients, a method using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was also established to compare the pharmacokinetic profiles of six primary active compounds in plasma after the oral administration of ZBD, N-ZBD and free drugs. The pharmacokinetic profiles of N-ZBD and ZBD in rats were comparable. Notably, N-ZBD exhibited higher Cmax, AUC0-t, and T1/2 values for the index compounds compared to free drugs and a reduced plasma clearance rate. In conclusion, N-ZBD is primarily responsible for ZBD’s anti-T2DM effects and significantly enhances the bioavailability of active ingredients, highlighting the essential role of natural nanoparticles in the therapeutic effectiveness of decoctions.

The online version contains supplementary material available at 10.1186/s13020-025-01290-z.