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Bile acids metabolism-mediated immunoregulatory nanoparticles for the treatment of cholestatic liver injury
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DOI：10.1186/s12951-026-04911-3.png)
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Abstract
En 中文
Cholestatic liver disease (CLD) is an autoimmune liver disease characterized by progressive bile stasis, with limited treatment options. To address the issue of precise multi-target interventions, a tissue-targeted nanodelivery system (TF/MSN-OCA) was designed to mimic physiological bile acids (BAs) transport pathways in the intestine, achieving hepatic dual regulation of the immune-inflammatory response and BAs metabolism in cholestasis. In patients with obstructive cholestasis (OC), JAK1 mRNA expression was upregulated approximately four fold and showed a strong correlation with hepatic biochemical parameters (p < 0.01) and BAs levels (p < 0.001). This aberrant JAK1 activation was consistently recapitulated in two complementary cholestatic mouse models. Accordingly, mesoporous silica nanoparticles (MSN) were functionalized with obeticholic acid (OCA) to encapsulate the JAK1 inhibitor tofacitinib (TF), forming an oral nanotherapeutic platform termed TF/MSN-OCA for cholestatic liver injury. The results demonstrated OCA-modified MSN enhanced intestinal uptake and hepatic accumulation. Upon treatment with taurocholic acid (TCA, a natural ASBT substrate) and thioridazine (T939264, an ASBT inhibitor), OCA-modified MSN were confirmed to be internalized by enterocytes through an ASBT-dependent mechanism, achieving transmembrane transported across Caco2 cells monolayers. The therapeutic efficacy of TF/MSN-OCA was evaluated in multiple in vitro and in vivo models, revealing dual synergistic mechanisms: 1) activation of ileal and hepatic farnesoid X receptor (FXR) suppressed CYP7A1-mediated BAs synthesis while promoted BSEP-dependent BAs efflux. 2) Concurrent inhibition of p-JAK1/p-STAT3 signaling attenuated inflammatory responses and restored hepatic macrophage homeostasis. This study demonstrates a synergistic nanotherapeutic strategy integrates biomimetic ASBT-mediated BAs transport mechanisms and regulates hepatic metabolic-immune axis. TF/MSN-OCA provides a promising therapeutic platform for cholestatic and related hepatobiliary pathologies.
Keywords:
Cholestasis
Bile acids
Farnesoid X receptor
JAK1/STAT3 pathway
Oral hepatic-targeted drug delivery
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