pH-degradable, bisphosphonate-loaded nanogels attenuate liver fibrosis by repolarization of M2-type macrophages

Immune-suppressive (M2-type) macrophages can contribute to the progression of cancer and fibrosis. In chronic liver diseases, M2-type macrophages promote the replacement of functional parenchyma by collagen-rich scar tissue. Here, we aim to prevent liver fibrosis progression by repolarizing liver M2-type macrophages toward a non fibrotic phenotype by applying a pH-degradable, squaric ester-based nanogel carrier system. This nanotechnology platform enables a selective conjugation of the highly water-soluble bisphosphonate alendronate, a macrophage-repolarizing agent that intrinsically targets bone tissue. The covalent delivery system, however, promotes the drug's safe and efficient delivery to nonparenchymal cells of fibrotic livers after intravenous administration. The bisphosphonate payload does not eliminate but instead reprograms profibrotic M2-toward antifibrotic M1-type macrophages in vitro and potently prevents liver fibrosis progression in vivo, mainly via induction of a fibrolytic phenotype, as demonstrated by transcriptomic and proteomic analyses. Therefore, the alendronateloaded squaric ester-based nanogels represent an attractive approach for nano therapeutic interventions in fibrosis and other diseases driven by M2-type macrophages, including cancer. Significance Fibrosis is a consequence of most chronic liver diseases, but currently no approved antifibrotic treatment is available. M2-type macrophages drive fibrosis progression and prevent regression, even when effective causal therapies have been employed. M2-type macrophages activate a cascade of fibrogenic effector cells and can prevent removal of excess scar tissue. To switch these profibrogenic M2 to fibrolytic (regenerative) macrophages, we developed a pH-degradable, nanogel-based delivery system which can be covalently functionalized with the macrophage-repolarizing bisphosphonate alendronate. The nanogels efficiently deliver the clinically approved drug into hepatic nonparenchymal cells after intravenous administration. They do not eliminate macrophages but repolarize their phenotype and subsequently block fibrosis progression. This approach establishes a nanotherapeutic delivery platform to treat further M2-type macrophage-driven diseases, including cancer.

Automated summary

In this study, liver fibrosis progression was prevented by repolarizing M2-type macrophages towards a non-fibrotic phenotype using a pH-degradable nanogel carrier system. The nanogels efficiently delivered the drug alendronate to nonparenchymal cells of fibrotic livers, reprogramming profibrotic M2 into antifibrotic M1 macrophages and preventing liver fibrosis progression. This approach has potential implications for the treatment of diseases driven by M2-type macrophages, including cancer.