Journal
BIOMATERIALS
Volume 284, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2022.121492
Keywords
Liver fibrosis; Hepatic stellate cells; Extracellular matrix; Kupffer cells; CXCR4
Funding
- National Natural Science Foundation of China [81872817]
- China Postdoctoral Science Foundation [2021T140317, 2021M700070]
- Jiangsu Postdoctoral Science Foundation [2021K231B]
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A versatile nanocomplex was developed that improved liver fibrosis therapy by overcoming biological barriers and co-regulating Kupffer cells, extracellular matrix, and hepatic stellate cells.
Hepatic stellate cell (HSC)-targeted delivery is an attractive strategy for liver fibrosis therapy, but the efficacy is hampered by poor delivery of nanomaterials and complicated microenvironments of the fibrotic liver. Here, we report a versatile CXCR4-inhibiting nanocomplex composed of polymeric CXCR4 antagonism (PAMD, PA), CLD (clodronate) and siPAI-1 (siRNA of plasminogen activator inhibitor-1) that surmounts multiple barriers to improve the outcome by co-regulating Kupffer cells (KCs), extracellular matrix (ECM) and HSCs. Upon encountering biological barriers, the nanocomplex exerted penetrating and targeting functions, efficiently overcoming KCs capture, ECM trapping and nonspecific recognition of HSCs, finally contributing to the enhanced HSCs uptake. Moreover, an enlarged antifibrotic activity is realized through synergetic regulation of KCs apoptosis, ECM degradation and HSCs inactivation. Overall, such a versatile nanocomplex provides a framework for designing HSC-targeted delivery system and has valuable potential as a novel antifibrotic strategy.
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