Targeted delivery of Lupeol via hyaluronic acid-modified ZIF-8 for anti-hepatic fibrosis therapy

Hepatic fibrosis (HF), a common pathological consequence of chronic liver injury, is driven by the excessive proliferation and activation of hepatic stellate cells (aHSCs). Non-alcoholic steatohepatitis, the inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease, NAFLD), serves as a key driver of the HF process. Although previous studies have found that lupeol can act as an FXR-agonist to ameliorate MASLD through the FXR-SHP pathway, its therapeutic potential is severely limited by drawbacks such as poor solubility, low stability, rapid degradation, insufficient targeting specificity, collectively constrain its therapeutic potential. To overcome these limitations, we developed the HA/Lupeol@ZIF-8—a dual-functional nano-delivery system combining CD44-targeting and pH-responsive drug release. It encapsulates the FXR-agonist lupeol in ZIF-8 framework and is surface-modified with hyaluronic acid to allow for active targeting of CD44-highly-expressing aHSCs. In the acidic-fibrotic microenvironment, ZIF-8 undergoes pH-responsive degradation, enabling precise release of both the lupeol and Zn 2+ . The released Zn 2+ further disrupt glycolysis and facilitate the reversion of aHSCs to quiescent state, thereby synergistically enhancing the anti-fibrotic efficacy. The nanoparticles exhibited a uniform size (125.7 ± 0.16 nm), high stability, pH-dependent drug release and strong CD44-binding affinity, collectively improving lupeol's solubility and targeted delivery. Both in vitro and vivo experiments confirmed that HA/Lupeol@ZIF-8 suppresses fibrotic markers through FXR-SHP activation. This study not only elucidates the anti-fibrotic mechanism of Lupeol but also presents an integrated targeted and microenvironment responsive strategy with considerable potential for clinical translation in the treatment of HF. • The first to propose a novel research approach focusing on the mechanism by which lupeol prevents and treats hepatic fibrosis through the "FXR-SHP" signaling pathway. This holds significant original innovation for elucidating the "same treatment for different diseases" potential of lupeol. • A hyaluronic acid-modified ZIF-8 carrier was employed in this design to directly address the core limitations of lupeol, namely its poor solubility, inadequate targeting, and low stability, thereby achieving efficient and precise delivery to activated hepatic stellate cells. • For the first time, a "trinity" nano therapeutic strategy based on lupeol was constructed, integrating CD44-active targeting and pH-responsive drug release functions. This system demonstrates excellent in vivo stability and controllable release properties, successfully overcoming key issues associated with traditional ZIF-8 materials, such as poor targeting in physiological environments, susceptibility to dissociation in gastric acid, and drug leakage leading to toxic side effects. It provides a novel functionalized carrier solution for highly efficient and low-toxicity targeted drug delivery.