AI Article Synopsis
- Metabolic dysfunction-associated steatohepatitis (MASH) complicates the delivery of therapeutic proteins due to excess extracellular matrix (ECM), leading to the development of a new treatment strategy called "Fibrosis overexpression and retention (FORT)."
- FORT utilizes specially designed retinoid-derivative lipid nanoparticles (LNPs) that enhance mRNA expression in fibrotic areas and include modifications to promote protein anchoring in the ECM.
- The approach has shown a tenfold increase in protein expression and improved retention of engineered therapeutic proteins in fibrotic lesions, proving effective in various animal models of MASH while reducing toxicity.
Article Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) poses challenges for targeted delivery and retention of therapeutic proteins due to excess extracellular matrix (ECM). Here we present a new approach to treat MASH, termed "Fibrosis overexpression and retention (FORT)". In this strategy, we design (1) retinoid-derivative lipid nanoparticle (LNP) to enable enhanced mRNA overexpression in fibrotic regions, and (2) mRNA modifications which facilitate anchoring of therapeutic proteins in ECM. LNPs containing carboxyl-retinoids, rather than alcohol- or ester-retinoids, effectively deliver mRNA with over 10-fold enhancement of protein expression in fibrotic livers. The carboxyl-retinoid rearrangement on the LNP surface improves protein binding and membrane fusion. Therapeutic proteins are then engineered with an endogenous collagen-binding domain. These fusion proteins exhibit increased retention in fibrotic lesions and reduced systemic toxicity. In vivo, fibrosis-targeting LNPs encoding fusion proteins demonstrate superior therapeutic efficacy in three clinically relevant male-animal MASH models. This approach holds promise in fibrotic diseases unsuited for protein injection.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11350072 | PMC |
| http://dx.doi.org/10.1038/s41467-024-51571-8 | DOI Listing |
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