From Therapeutic Dilemma to Precision Modulation: Harnessing Biomaterials to Target the Dual Face of TGF-β in...

Osteoarthritis (OA) is a debilitating degenerative joint disease marked by the progressive breakdown of cartilage, synovium, and subchondral bone. This comprehensive narrative review synthesizes findings from recent foundational and preclinical studies to elucidate the complex, concentration and context-dependent functional dichotomy of the transforming growth factor-beta (TGF-β) signaling pathway in OA pathophysiology. At physiological levels, TGF-β signaling via the canonical SMAD2/3 pathway promotes chondrocyte anabolism, whereas aberrant overactivation, often through the SMAD1/5/8 axis, drives pathological processes including chondrocyte hypertrophy, synovial fibrosis, and aberrant bone remodeling. However, these signaling outputs are not fixed; they are highly dependent on the specific tissue compartment, disease stage, receptor profile, and the local inflammatory microenvironment, which collectively dictate the ultimate functional outcome. While conventional systemic interventions lack the precision to differentially modulate these opposing functions, engineered biomaterials have emerged as versatile platforms for achieving spatiotemporally precise regulation. We detail key strategies employing hydrogels, nanocarriers, and functionalized scaffolds that enable targeted therapeutic outcomes through controlled delivery, receptor blockade, or downstream pathway intervention. Although these biomaterial-based strategies remain predominantly at the experimental and preclinical stage, they represent a conceptually advanced approach to addressing this therapeutic dilemma. Future directions must focus on overcoming major translational barriers-including joint retention, targeting specificity, long-term biosafety, manufacturing reproducibility, and precise patient and disease-stage stratification-to advance these strategies toward clinical utility.