Fibrosis: Bridging fundamental mechanisms to precision medicine via advanced therapeutics

Fibrosis is a progressive, pan-organ pathology characterized by excessive deposition of extracellular matrix (ECM), tissue stiffening, and ultimately organ failure. Despite a deepened understanding of its molecular mechanisms, effective therapies remain scarce, largely because the dense scar ECM, elevated interstitial fluid pressure (IFP), and metabolic heterogeneity severely limit drug penetration and lead to off-target toxicity. This review integrates converging mechanisms of fibrosis with advances in precision delivery, laying out a roadmap for the development of next-generation antifibrotic therapeutics. We first summarize the multicellular core mechanisms of fibrosis-myofibroblasts, immune cells, and barrier cells-as well as the interconnected TGF-β, PDGF, WNT/β-catenin and metabolic circuits, which together generate a hostile, stiff microenvironment. Subsequently, we highlight how single-cell and spatial multi-omics, complex humanized models, and AI-driven network analysis are redefining target identification, patient stratification and the "design inputs" for advanced drug and gene delivery systems. Building on these insights, we critically evaluate stimuli-responsive nanocarriers leveraging ROS, pH, enzymatic activity or exogenous triggers, as well as local depots, microneedles and inhalation formulations capable of overcoming systemic delivery limitations and fibrotic microenvironmental barriers. Key carrier platforms-including lipid, polymeric and inorganic nanoparticles, extracellular vesicles (EVs) and protein/peptide vectors-are compared in terms of organ tropism, penetration capacity, payload types, and translational application limitations. By explicitly mapping clinical and emerging antifibrotic agents to their primary delivery barriers, we propose a pan-fibrotic framework that integrates shared core pathways with organ-specific "zip codes" and synergistically develops intelligent payloads and vehicles to achieve precise, clinically translatable antifibrotic therapy.