CD44-Targeted Delivery Platform of NAC-Laden Urine Stem Cell Exosomes Rescue Urothelial Injury by Interrupting PI3K-Akt Positive Feedback

ABSTRACT: Persistent urothelial injury driven by excessive oxidative stress and inflammation is a core hallmark of refractory bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Although N-acetylcysteine (NAC) exhibits potent anti-inflammatory and tissue-repair properties, its therapeutic efficacy via intravesical administration is severely hindered by rapid urinary washout and a lack of lesion targeting. Mesenchymal stem cells (MSCs) derived exosomes are promising carriers to address the defects of free NAC owing to its superior biocompatibility, intrinsic anti-inflammatory activity and favorable delivery performance. Here, we engineered a targeted cell-free nanoplatform (NAC@Exo) via electroporation-mediated loading of NAC into urine-derived stem cell (USC)-derived exosomes. Proteomic profiling confirmed that NAC@Exo retains abundant CD44-binding ligands, enabling specific lesion accumulation and prolonged retention in injured urothelium. In vitro, NAC@Exo was efficiently internalized by damaged human urothelial cells, promoting proliferation and suppressing cell death. In a cyclophosphamide-induced rat model, intravesically instilled NAC@Exo superiorly restored urothelial barrier integrity, attenuated local oxidative stress, and suppressed inflammatory cascades, significantly ameliorating voiding frequency and pain behaviors compared with exosomes or hyaluronic acid. Mechanistically, transcriptomic analysis and experimental validation revealed that NAC@Exo exerts tissue-protective effects by suppressing pathological hyperactivation of the PI3K-Akt signaling pathway, thereby interrupting the vicious ROS-inflammation feedback loop. Crucially, as a highly adaptable mucosal-adhesive nanoplatform, this CD44-targeted delivery system is not limited to NAC encapsulation and can be customized to carry diverse therapeutic payloads. Overall, this study provides a robust cell-free nanomedicine strategy to promote diverse urothelial injury repair, holding great translational potential for functional bladder regeneration.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE343833 | GEO | 2026/09/01

REPOSITORIES: GEO