Multifunctional Nanomedicine for Precision Theranostics in Hepatic Fibrosis: From Rational Design to Clinical Translation.

Hepatic fibrosis (HF) is a pathological wound-healing response to chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma. Although resmetirom and semaglutide have been approved for noncirrhotic metabolic dysfunction-associated steatohepatitis with fibrosis, they are restricted to a single etiology, and no nanomedicine has yet achieved clinical approval for HF. The translational bottleneck arises from the multicellular complexity of fibrogenesis, suboptimal pharmacokinetics and off-target toxicity of conventional therapeutics, and formidable biological barriers of the diseased hepatic microenvironment. This review provides an integrated, mechanism-to-translation analysis of multifunctional nanomedicines for precision HF theranostics. The pathophysiological mechanisms governing hepatic stellate cell activation and the fibrotic niche are dissected to delineate actionable targets and delivery barriers. Major nanocarrier classes (lipid-based, polymeric, inorganic, and biologically-derived) are critically evaluated with respect to physicochemical characteristics, targeting efficiency, and suitability for the fibrotic liver. Theranostic strategies spanning passive, active, and microenvironment-responsive targeting are synthesized, with emphasis on multifunctional platforms integrating anti-inflammatory, antifibrotic, gene-based, and immunomodulatory interventions. The clinical translation landscape is critically assessed, and technical, practical, and regulatory barriers are systematically analyzed. By distinguishing established evidence from emerging possibilities and prioritizing translation requirements, this review offers a rational framework for guiding next-generation precision nanomedicines toward clinical viability in HF.