Microenvironment-induced programmable nanotherapeutics restore mitochondrial dysfunction for the amelioration of non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disorder with severe complications. Mitochondrial dysfunction due to over-opening of the mitochondrial permeability transition pore (mPTP) in liver cells plays a central role in the development and progression of NAFLD. Restoring mitochondrial function is a promising strategy for NAFLD therapy. Herein, we designed and developed a microenvironment-induced programmable nanotherapeutic to restore mitochondrial function and ameliorate NAFLD. cyclosporine (Cyclosporine capsules) A (CsA), as a highly effective inhibitors of the opening of mPTP, was chosen in the present work. Nanotherapeutics were prepared by assembling two structurally simple multifunctional glucosamine derivatives: dextran-grafted galactose (Dex-Gal) and Dex-triphenylphosphine (Dex-TPP). Galactose units in the nanotherapeutics guide the hepatocyte-specific uptake. Detachment of galactose from acidic lysosomes via Schiff base cleavage exposes the TPP moieties, which subsequently steers the nanotherapeutics to escape from lysosomes and target mitochondria through an enhanced positive charge, enabling precise in situ drug delivery. Simultaneously, the nanotherapeutics improved mitochondrial dysfunction by inhibiting palmitic acid-induced opening of the mitochondrial permeability transition pore in HepG2 cells, maintaining mitochondrial membrane potential, and decreasing reactive oxygen species production. Furthermore, CsA@Dex-Gal/TPP accumulated in the livers of NAFLD mice, restored mitochondrial autophagy, regulated abnormalities in glucose and lipid metabolism, and improved hepatic lipid deposition. This study offers a new cascading strategy for targeting liver cell mitochondria to treat NAFLD and other mitochondria-associated diseases. STATEMENT OF SIGNIFICANCE: We design microenvironment-induced programmable nanotherapeutics for NAFLD Nanotherapeutics has the capabilities of lysosomal escape and mitochondrial targeting Nanotherapeutics improves mitochondrial dysfunction and ameliorates NAFLD This study offers a new cascading strategy for other mitochondria-associated diseases.