Injectable therapeutic system incorporating neurogenesis-programmed stem cells concomitantly promoting muscle regeneration treats stress urinary incontinence.

Abstract

Stress urinary incontinence (SUI) remains a significant clinical challenge due to the lack of strategies that simultaneously address muscle degeneration, neurogenic atrophy, and vascular deficits. Here, we report an innovative injectable system that combines a thermo-responsive poly(N-isopropylacrylamide)-COOH/leucine/decellularized extracellular matrix hydrogel with adipose-derived stem cells (ADSCs) pre-programmed by zeolitic imidazolate framework-8/polyethylene glycol 200@magnesium (ZIF-8/PEG200@Mg) nanoparticles. In vitro, programmed ADSCs exhibit enhanced neurogenic differentiation, while the hydrogels support robust myogenic activity and cell viability. In a female rat model of SUI-chosen to reflect the higher prevalence of SUI in women-the composite system leads to a marked improvement in leak point pressure (LPP) and restores urethral sphincter function. Mechanistic analyses reveals upregulation of muscle regeneration (e.g., Myoz1, Smyd1) and neurogenesis/neuromuscular junction stabilization (NMJ) stabilization genes (e.g., Dok7, Musk), highlighting a coordinated multi-lineage regenerative process. This work establishes an integrated regeneration-plus-support injectable strategy, offering a regenerative medicine-based approach that surpasses conventional bulking or sling therapies for SUI.