A translational systems medicine approach to devising nanotherapeutics for targeted intervention of MASLD

Zhenyu Luo; Jingyi Wu; Banghao Xu; Dongyang Wu; Yi Zhong; Mengxuan Hao; Yiran Xu; Junhan Yang; Yi Wang; Volker M Lauschke; Songmin Ying; Ningtao Cheng

doi:10.1016/j.biomaterials.2026.124089

A translational systems medicine approach to devising nanotherapeutics for targeted intervention of MASLD

Biomaterials. 2026 Feb 18:331:124089. doi: 10.1016/j.biomaterials.2026.124089. Online ahead of print.

Authors

Zhenyu Luo¹, Jingyi Wu¹, Banghao Xu¹, Dongyang Wu², Yi Zhong³, Mengxuan Hao⁴, Yiran Xu¹, Junhan Yang¹, Yi Wang¹, Volker M Lauschke⁵, Songmin Ying⁶, Ningtao Cheng⁷

Affiliations

¹ Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
² Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
³ Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of Physiology and Pharmacology and Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
⁴ Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
⁵ Department of Physiology and Pharmacology and Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China. Electronic address: volker.lauschke@ki.se.
⁶ Department of Pharmacy, Center for Regeneration and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China; Zhejiang-Denmark Joint Laboratory of Regeneration and Aging Medicine, Yiwu, Zhejiang 322000, China; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China. Electronic address: yings@zju.edu.cn.
⁷ School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, Zhejiang 310058, China. Electronic address: ncheng@zju.edu.cn.

PMID: 41762518
DOI: 10.1016/j.biomaterials.2026.124089

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent substantial clinical burdens due to their multifactorial etiology and the paucity of available treatments. Despite the identification of numerous potential therapeutic targets and extensive clinical trials, so far, only a single drug has been approved for the treatment of MASH. This study proposes a conceptually new therapeutic design strategy grounded in an integrative, multidisciplinary approach. Utilizing bioinformatic analyses of clinical transcriptomic datasets, we identified ERN1 (IRE1α), a central component of the unfolded protein response, as a key regulatory node in MASLD progression. Leveraging this finding, we engineered a hepatoselective reactive oxygen species (ROS)-scavenging lipid nanoparticle (LNP) encapsulating KIRA6, a selective ERN1 kinase inhibitor. Preclinical evaluation in murine models of MASLD induced by the methionine-choline-deficient (MCD) diet or high-fat diet (HFD) revealed significant reductions in hepatic lipid accumulation and inflammation, along with marked attenuation of liver fibrosis. Our findings present a viable therapeutic candidate for MASLD/MASH and offer a conceptual framework for developing pathophysiology-informed treatment strategies against complex, multifactorial diseases.

Keywords: ERN1; Hepato-tropism; LNP; MASLD; Systems medicine.