4.8 Article

Sequential Nano-Penetrators of Capillarized Liver Sinusoids and Extracellular Matrix Barriers for Liver Fibrosis Therapy

Journal

ACS NANO
Volume 16, Issue 9, Pages 14029-14042

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsnano.2c03858

Keywords

liver fibrosis; liver sinusoidal endothelial cell; hepatic stellate cell; pathological barrier normalization; targeted delivery

Funding

  1. National Key R&D Program of China [2022YFE0198400]
  2. National Natural Science Foundation of China [82020108029, 82073398]
  3. Ministry of Science and ICT, Republic of Korea [18 K 2 A 9 A 2 A 0 6 0 19 172, FY 2 0 18, NRF-2021R1A2B5B03002123]

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An efficient nanodrug delivery system was developed to sequentially overcome the dual pathological barriers of liver sinusoidal capillarization and extracellular matrix deposition, achieving higher drug accumulation in activated hepatic stellate cells.
During liver fibrogenesis, liver sinusoidal capillarization and extracellular matrix (ECM) deposition construct dual pathological barriers to drug delivery. Upon capillarization, the vanished fenestrae in liver sinusoidal endothelial cells (LSECs) significantly hinder substance exchange between blood and liver cells, while excessive ECM further hinders the delivery of nanocarriers to activated hepatic stellate cells (HSCs). Herein, an efficient nanodrug delivery system was constructed to sequentially break through the capillarized LSEC barrier and the deposited ECM barrier. For the first barrier, LSEC-targeting and fenestrae-repairing nanoparticles (named HA-NPs/SMV) were designed on the basis of the modification with hyaluronic acid and the loading of simvastatin (SMV). For the second barrier, collagenase I and vitamin A codecorated nanoparticles with collagen-ablating and HSC-targeting functions (named CV-NPs/siCol1 alpha 1) were prepared to deliver siCol1 alpha 1 with the goal of inhibiting collagen generation and HSC activation. Our in vivo results showed that upon encountering the capillarized LSEC barrier, HA-NPs/SMV rapidly released SMV and exerted a fenestrae-repairing function, which allowed more CV-NPs/siCol1 alpha 1 to enter the space of Disse to degrade deposited collagen and finally to achieve higher accumulation in activated HSCs. Scanning electronic microscopy images showed the recovery of liver sinusoids, and analysis of liver tissue sections demonstrated that HA-NPs/SMV and CV-NPs/siCol1 alpha 1 had a synergetic effect. Our pathological barrier-normalization strategy provides an antifibrotic therapeutic regimen.

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