Bioactive glasses-mediated ion therapy ameliorates hepatic osteodystrophy by reprogramming the liver-bone axis.

Abstract

Hepatic osteodystrophy (HOD) is a debilitating metabolic bone disorder inextricably linked to chronic liver disease, with its prevalence surging alongside the global rise of metabolic dysfunction-associated steatohepatitis (MASH). Current clinical interventions remain fragmented, failing to concurrently address the upstream hepatic lipotoxicity and the downstream skeletal deterioration. Herein, we engineer copper-doped bioactive glasses (CuBGs) as a multifunctional ion-therapy nanoplatform that exploits natural hepatic tropism to synchronously rescue MASH-HOD pathology via targeted reprogramming of the liver-bone axis. By delivering localized therapeutic ions, CuBGs orchestrate robust hepatic metabolic recovery: they enhance glucose tolerance and restore mitochondrial oxidative phosphorylation (OXPHOS), thereby effectively halting intrahepatic triglyceride accumulation and quenching ROS-driven inflammation. Crucially, this hepatic rescue reactivates the liver-bone endocrine crosstalk by robustly upregulating the secretion of the hepatokine lecithin-cholesterol acyltransferase (LCAT). Systemic LCAT restoration directly stimulates profound osteoblastogenesis and new bone formation, decisively reversing MASH-induced trabecular bone loss without acting as a conventional anti-resorptive agent. This dual-organ modulation comprehensively ameliorates the interconnected multi-organ microenvironment in MASH-HOD without inducing systemic toxicity. Ultimately, this bioactive glass-mediated copper delivery system establishes a novel, highly scalable strategy for ion-based nanotherapeutics, offering a promising and integrated strategy for complex liver-bone comorbidities.