Citation: Yuhua Ma, Jiayuan Zhang, Yonghui Duan, Ziyu Zhang, Runtong Zhang, Zuhai Lei, Ben Shi, Yi Lu, Wei Wu, Haisheng He. Bergenin lipid prodrug nanoparticles: Synthesis, enhanced oral bioavailability, and mechanistic studies[J]. Chinese Chemical Letters, ;2026, 37(7): 112134. doi: 10.1016/j.cclet.2025.112134 shu

Bergenin lipid prodrug nanoparticles: Synthesis, enhanced oral bioavailability, and mechanistic studies

Yuhua Ma ^{a, 1} ,
Jiayuan Zhang ^{a, 1} ,
Yonghui Duan ^a ,
Ziyu Zhang ^b ,
Runtong Zhang ^b ,
Zuhai Lei ^f ,
Ben Shi ^{g, *,} ,
Yi Lu ^{b, c, d} ,
Wei Wu ^{b, c, d, e} ,
Haisheng He ^{b, *,}

a.
Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, Qinghai Engineering Research Center of Modern Tibetan Medicine Development, School of Pharmacy, Qinghai Minzu University, Xining 810007, China
b.
Key Laboratory of Smart Drug Delivery of Ministry of Education, National Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, School of Pharmacy, Fudan University, Shanghai 201203, China
c.
Shanghai Skin Disease Hospital Tongji University School of Medicine, Shanghai 200443, China
d.
Fudan Zhangjiang Institute, Shanghai 201203, China
e.
Center for Medical Research and Innovation Shanghai Pudong Hospital Fudan University Pudong Medical Center, Shanghai 201399, China
f.
School of Pharmacy, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, China
g.
Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers and Chem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200438, China

shi_ben@fudan.edu.cn

he_haisheng@fudan.edu.cn

Received Date: 6 September 2025
Revised Date: 17 November 2025
Accepted Date: 18 November 2025
Available Online: 19 November 2025

Figures(4)

Bergenin (BG), a bioactive coumarin derivative, suffers from poor solubility and low oral bioavailability, restricting its clinical potential. To overcome these limitations, we developed a lipid prodrug strategy by conjugating BG with bioactive fatty acids of different chain lengths (6C, 12C, 18C) via ester bonds, formulating the conjugates into solid lipid nanoparticles (SLNs), and systematically investigating the structure–activity relationship. Fatty acid conjugation not only enhanced lipophilicity, lipid matrix compatibility, and enzymatic stability but also imparted distinct biological effects that shaped oral absorption. Stearic acids (18C) conferred strong resistance to enzymatic hydrolysis, whereas lauric acid (12C) offered the most favorable balance in improving drug loading, stability, and membrane permeability. Pharmacokinetic studies in rats demonstrated that 12C-BG SLNs achieved the greatest enhancement in oral bioavailability, with an 8.6-fold increase over BG-SLNs and more than 40-fold improvement relative to reported suspensions and phospholipid solid dispersions. Mechanistic studies indicated that absorption was primarily driven by prodrug monomers released during intestinal lipolysis, with a minor contribution from undigested nanoparticles, and moreover the fatty acid chain length strongly influenced cellular permeability and systemic exposure. Collectively, these results underscore the critical role of bioactive fatty acids as conjugating groups in modulating prodrug fate and highlight a promising platform for enhancing the oral delivery of poorly soluble phytochemicals.
- Bergenin,
- Lipid prodrugs,
- Solid lipid nanoparticles,
- Oral bioavailability,
- Particle trafficking
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