Magnetic chitosan nanoparticle-exosome hydrogel enhances bladder function in diabetic bladder dysfunction via activating the FAK-p38 MAPK-GATA4 axis in adipose-derived mesenchymal stromal cells

Abstract Previous attempts to combine adipose-derived mesenchymal stromal cells (ADSCs) with defocused low-energy shock wave (DLSW) have shown effectiveness in treating diabetic bladder dysfunction (DBD). However, the specific mechanisms underlying their therapeutic effects and strategies to enhance the colonization of ADSCs at the disease site remain challenging. Hereby, our investigation revealed that DLSW activated the FAK-p38 MAPK-GATA4 axis in ADSCs, resulting in enhanced secretion of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). Moreover, tube formation assay and major pelvic ganglia culture showed that the effects of VEGF and NGF on angiogenesis and nerve fiber growth were hindered by adding GATA4 inhibitors. We developed a thermosensitive hydrogel using chitosan nanoparticles (CSNP) incorporated with β-glycerophosphate and Fe3O4, and loaded it with exosomes (Exo) derived from DLSW-pretreated ADSCs to create a magnetic CSNP-Exo hydrogel. This hydrogel displayed favorable targeting ability, swelling properties, and sustained release profiles. In animal experiments, a DBD rat model was established by feeding a high-fat diet and injecting streptozotocin. Conscious cystometry results showed that the CSNP-Exo hydrogel ameliorated voiding function. Histological examinations revealed that CSNP-Exo hydrogel exhibited prolonged retention in the bladder and facilitated the expression of VEGF and NGF in damaged bladder tissues through Exo-mediated upregulation of GATA4. Correspondingly, staining results showed that vascular formation and neural repair in the bladder tissue were also significantly accelerated. Thus, magnetic CSNP-Exo hydrogel holds promising potential for the treatment of DBD.