Organ fibrosis is a hallmark of chronic inflammatory disease and accounts for 45 % of deaths in the industrialized world [1]. Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and fatty liver disease associated with obesity. Liver fibrosis, a wound-healing response, involves extracellular matrix (ECM) accumulation due to persistent liver damage and inflammatory reactions [2]. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source of excessive production of extracellular matrix proteins [3]. Hepatic stellate cell activation represents a critical event in fibrosis because these cells become the primary source of extracellular matrix in the liver upon injury. As pathways of fibrogenesis are increasingly clarified, the key challenge will be translating new advances into the development of antifibrotic therapies for patients with chronic liver disease.

The diagnosis of cirrhosis portends an increased risk of morbidity and mortality. Liver biopsy is considered the gold standard for the diagnosis of cirrhosis and the staging of fibrosis. However, as an invasive procedure, liver biopsy has several inherent risks and notable costs, including post-procedural pain in up to 50 % of cases and rare but potentially life-threatening complications such as haemorrhage in 0.6–1 % of cases [4]. Logistically, a liver biopsy procedure requires a facility with peri-procedural and post-procedural monitoring and an operator with specific medical expertise, both of which are expensive. In addition, there are several limitations such as sampling error and intra- and inter-rater variability of liver biopsy that diminish its accuracy and reproducibility [5]. In order to overcome the limitations of liver biopsy, a number of non-invasive techniques have been investigated for the assessment of cirrhosis. Non-invasive markers of cirrhosis can be radiologic or serum-based [6], [7], [8]. Radiologic techniques based on ultrasound, magnetic resonance imaging and elastography have been used to assess liver fibrosis. Serum-based biomarkers of cirrhosis have also been developed. These are broadly classified into indirect and direct markers. Indirect biomarkers reflect liver function, which may decline with the onset of cirrhosis. Direct biomarkersreflect extracellular matrix turnoverand include molecules involved in hepatic fibrogenesis.

The liver’s normal function relies on several plasma proteins and endocrine factors, with insulin-like growth factor 1 (IGF-1) and its receptor playing pivotal roles. IGF-1 deficiency can result in altered gene expression and disruption of liver architecture, cytoskeleton, cell junctions, and ECM [9], [10], [11]. Studies in mouse models of non-alcoholic steatohepatitis and cirrhosis demonstrated that IGF-1 can improve steatosis, inflammation, and fibrosis [12]. Mechanistically, IGF-1 induces HSC senescence, inactivating these cells and inhibiting fibrosis in a p53-dependent manner [12].

AMD3100, a CXCR4 antagonist, blocks the CXCL12/CXCR4 axis and its signaling pathway [13]. The interaction between CXCR4 and CXCL12 enhances the chemotactic function of inflammatory cells, such as monocytes and lymphocytes [14]. By inhibiting this pathway, AMD3100 reduces immune cell infiltration, thereby mitigating inflammation. Additionally, CXCL12/CXCR4 axis promotes HSC activation and proliferation, contributing to liver fibrosis [15]. Therefore, AMD3100 can directly inhibit fibrosis by blocking the CXCR4 signaling pathway in HSCs.

Nanotechnology-based formulations, such as Fe3O4 and MnO2 nanoparticles (NPs), have shown a significant role as delivery tools for a variety of payloads in cirrhosis therapy. Although iron overload and cellular senescence have been shown to be implicated in liver fibrosis, their possible mechanistic connection remains unclear [16]. Recent studies have showed that Fe3O4-Au NPs can serve as dual-modality contrast agents for CT and MRI in accurate detection of progressive liver disease [17], while Fe3O4 and ferulic acid coencapsulated poly (lactic-co-glycolic acid) NPs can effectively alleviate liver fibrosis by acting on macrophages and HSCs [18]. In addition, MnO2 NPs can generate Mn2 + ions that can be utilized in enhanced T1-weighted MRI [19], and offer a safe nano-drug delivery system without long-term toxicity in vivo [20], [21], [22]. These NPs can also alleviate tumor hypoxia by triggering the decomposition of H2O2 in the tumor microenvironment [23], [24]. Hollow mesoporous silica nanostructures with large cavities are excellent drug delivery systems capable of loading high quantities of therapeutic agents, therelease of these agents can be precisely controlled by tuning the shell structure or coating [25]. However, the combined use of Fe-Mn NPs in cirrhosis therapy has not been reported.

Therefore, in this study, we developed a novel nanoparticle system by loading IGF-1 and AMD3100 onto Fe-Mn-based drug carriers, forming Fe-Mn-IGF-AMD NPs. Fe-Mn-IGF-AMD NP group exhibited the most remarkable safety profiles while simultaneously exerting multiple therapeutic effects against liver cirrhosis.