Extracellular matrix-targeted biomaterials and nanocarriers for pelvic-floor repair/regeneration in stress urinary incontinence: local modulation of the MMP/TIMP axis and NF-κB/MAPK-linked remodeling programs

Stress urinary incontinence (SUI) is associated with pelvic-floor extracellular-matrix (ECM) remodeling, including an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) that can weaken periurethral load-bearing connective tissue. This Review frames SUI as a clinically relevant ECM-failure niche and synthesizes ECM-targeted biomaterials and nanocarriers designed to rebalance the MMP/TIMP axis while enabling pragmatic pharmacodynamic readouts for early translation. We organise recent preclinical and early translational work across three modality classes: (i) protease-responsive injectable hydrogels that provide temporary mechanical support while tuning degradation and local protease inhibition; (ii) matrices functionalized with extracellular vesicles (EVs) carrying microRNAs and proteins that influence matrix turnover; and (iii) lipid nanoparticles delivering small interfering RNA to transiently suppress upstream drivers of ECM catabolism, including NF-κB/MAPK signalling. For each class, we map controllable design variables to expected on-target effects and highlight concrete failure modes that often limit reproducibility and translation, such as potency and batch variability, placement sensitivity, viscoelastic fatigue, immune activation, and penetration-retention trade-offs. We conclude with an assessment package linking tissue mechanics to molecular remodeling by combining transperineal shear-wave elastography (SWE) with urinary EV microRNA panels to support context-of-use definition and cross-platform comparison under defined conditions.