Unlocking the potential of mRNA nanomedicines for comprehensive fibrosis therapy.

Fibrosis is a common pathological endpoint of numerous chronic diseases and a major driver of progressive organ dysfunction and failure. It is characterized by persistent fibroblast activation, excessive extracellular matrix deposition, and irreversible disruption of tissue architecture. Despite substantial clinical demand, current antifibrotic therapies largely rely on single-target interventions, often demonstrating limited efficacy. mRNA nanomedicine has emerged as a promising therapeutic paradigm due to its genomic safety, programmability, transient protein expression, and capacity for multipathway regulation. However, a unified framework integrating mRNA design, delivery technologies, and translational challenges in fibrosis remains lacking. This review systematically summarizes recent advances in mRNA-based nanotherapeutics for cardiac, renal, pulmonary, and hepatic fibrosis. We discuss the key principles of mRNA molecular engineering, including chemical modifications and sequence optimization, as well as innovations in lipid nanoparticles, polymeric carriers, and biomimetic nanoplatforms. These strategies enhance organ- and cell-specific targeting, improve pharmacokinetics, and mitigate immunogenicity. Importantly, mRNA nanomedicines enable coordinated modulation of profibrotic signaling networks, including the TGF-β/Smad, NF-κB, BMP, and PI3K/mTOR pathways, thereby promoting fibrosis resolution and functional recovery. Emerging delivery paradigms, such as inhalable formulations, hydrogel-based depots, and selective organ targeting (SORT) technologies, are also highlighted along with critical barriers, including endosomal escape, repeat-dosing immune responses, and manufacturing.