Metabolism-modulating nanoparticles for remodeling adipose-liver crosstalk to reverse liver fibrosis.

The interplay between adipose tissue and liver becomes dysregulated during liver fibrogenesis. Despite its importance, the adipose-liver axis remains overlooked, limiting the efficacy of current liver-centric therapies. In this study, we developed a dual-tissue metabolic modulation strategy to reprogram interorgan communication between adipose tissue and liver. To reduce adipose lipid overload, adipocyte-targeting peptide-modified nanoparticles loaded with rosiglitazone (P-Lip/RGL) were designed to induce white adipocyte browning and enhance lipid oxidation, thus reducing the metabolic burden exert on the liver. To alleviate fibrosis, galactose-modified nanoparticles loaded with resmetirom (G-Lip/RMT) were formulated to stimulate mitochondrial biogenesis and promote fatty acid β-oxidation. Combined administration of P-Lip/RGL and G-Lip/RMT restored lipid homeostasis within adipose-liver axis, disrupted pathological signaling, and established a beneficial metabolic feedback loop. This dual-tissue modulation markedly resolved fibrosis and rebalanced systemic metabolism. Overall, this work not only highlights the significance of modulating adipose-liver crosstalk but also provides a promising avenue for developing anti-fibrotic regimens.