Biomimetic HDL nanoparticles functionalized with bromelain and chondroitin sulfate for enhanced penetration and targeted therapy of liver fibrosis.

Activated hepatic stellate cells (aHSCs) play a central role in liver fibrosis by promoting excessive extracellular matrix (ECM) deposition, while oxidative products in fibrotic livers perpetuate their activation. The treatment of liver fibrosis remains challenging because the ECM barrier limits drug uptake by aHSCs. To overcome this challenge, we developed high-density lipoprotein (HDL) nanoparticles loaded with silybin (SIL), and modified them with chondroitin sulfate (CS) and bromelain (BRO). The resulting formulation, denoted as BRO/CS-SIL@HDL nanoparticles (BCSH), was designed to enhance hepatic enrichment, facilitate penetration through the collagen-rich ECM, and enable CD44 receptor-mediated targeting. BCSH showed efficient internalization even in the presence of a collagen barrier. BCSH treatment markedly reduced inflammation, oxidative stress, collagen deposition, and HSC activation. Then RNA seq was further performed to explore the potential molecular mechanisms underlying the therapeutic effects of the nanoparticles, revealing alterations in multiple signaling pathways and biological processes related to liver fibrosis. In conclusion, these results suggest that BCSH represents a promising therapeutic strategy for liver fibrosis.