Hepatic fibrosis progresses concomitantly with a variety of biomechanical alternations, especially increased liver stiffness. These biomechanical alterations have long been considered as pathological consequences. Recently, growing evidence proposes that these alternations result in the fibrotic biomechanical microenvironment, which drives the activation of hepatic stellate cells (HSCs). Here, an inorganic ascorbic acid-oxidase (AAO) mimicking nanozyme loaded with liquiritigenin (LQ) is developed to trigger remodeling of the fibrotic biomechanical microenvironment. The AAO mimicking nanozyme is able to consume intracellular ascorbic acid, thereby impeding collagen I deposition by reducing its availability. Simultaneously, LQ inhibits the transcription of lysyl oxidase like 2 (LOXL2), thus impeding collagen I crosslinking. Through its synergistic activities, the prepared nanosystem efficiently restores the fibrotic biomechanical microenvironment to a near-normal physiological condition, promoting the quiescence of HSCs and regression of fibrosis. This strategy of remodeling the fibrotic biomechanical microenvironment, akin to "pulling the rug out from under", effectively treats hepatic fibrosis in mice, thereby highlighting the importance of tissue biomechanics and providing a potential approach to improve hepatic fibrosis treatment.

Center of Advanced Innovation Technologies Faculty of Materials Science and Technology VSB Technical University of Ostrava Ostrava CZ 708 00 Czech Republic

Clinical Imaging Research Centre Centre for Translational Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore 117599 Singapore

Department of Chemistry and Biochemistry Mendel University in Brno Brno CZ 61300 Czech Republic

Departments of Diagnostic Radiology Surgery Chemical and Biomolecular Engineering and Biomedical Engineering Yong Loo Lin School of Medicine and College of Design and Engineering National University of Singapore Singapore 119074 Singapore

Institute of Molecular and Cell Biology Agency for Science Technology and Research 61 Biopolis Drive Proteos Singapore 138673 Singapore

Nanomedicine Translational Research Program Yong Loo Lin School of Medicine National University of Singapore Singapore 117597 Singapore

Tianjin Key Laboratory of Drug Delivery and High Efficiency School of Pharmaceutical Science and Technology Faculty of Medicine Tianjin University Tianjin 300072 China

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