Metabolism-modulating nanoparticles for remodeling adipose-liver crosstalk to reverse liver fibrosis

  • J Control Release. 2026 Jul 10:395:115026. doi: 10.1016/j.jconrel.2026.115026.
Ling-Feng Zhang  1 ,  Su-Qing Liang  1 ,  Qing-Wen Huang  1 ,  Jia-Wen Ru  1 ,  Ze-Quan Ding  2 ,  Chun-Yu Zhang  1 ,  Yi Wang  1 ,  Tian-Jiao Zhou  1 ,  Lei Xing  3 ,  Xian Wu Cheng  4 ,  Yu-Kyoung Oh  5 ,  Hu-Lin Jiang  6
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210000, China.
  • 3. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 4. Provincial Key Laboratory of Stress and Cardiovascular Disease, Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji 133000, China. Electronic address: [email protected].
  • 5. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 6. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; Provincial Key Laboratory of Stress and Cardiovascular Disease, Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji 133000, China; College of Pharmacy, Yanbian University, Yanji 133002, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China; Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea; Joint International Research Laboratory of Target Discovery and New Drug Innovation, MOE, Nanjing 210009, China. Electronic address: [email protected].
PMID: 42142745 DOI: 10.1016/j.jconrel.2026.115026
Abstract

The interplay between adipose tissue and liver becomes dysregulated during liver fibrogenesis. Despite its importance, the adipose-liver axis remains overlooked, limiting the efficacy of current liver-centric therapies. In this study, we developed a dual-tissue metabolic modulation strategy to reprogram interorgan communication between adipose tissue and liver. To reduce adipose lipid overload, adipocyte-targeting peptide-modified nanoparticles loaded with rosiglitazone (P-Lip/RGL) were designed to induce white adipocyte browning and enhance lipid oxidation, thus reducing the metabolic burden exert on the liver. To alleviate fibrosis, galactose-modified nanoparticles loaded with resmetirom (G-Lip/RMT) were formulated to stimulate mitochondrial biogenesis and promote fatty acid β-oxidation. Combined administration of P-Lip/RGL and G-Lip/RMT restored lipid homeostasis within adipose-liver axis, disrupted pathological signaling, and established a beneficial metabolic feedback loop. This dual-tissue modulation markedly resolved fibrosis and rebalanced systemic metabolism. Overall, this work not only highlights the significance of modulating adipose-liver crosstalk but also provides a promising avenue for developing anti-fibrotic regimens.

Keywords
Hepatocyte; Liver fibrosis; Remodel adipose-liver crosstalk.
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