ROS-responsive NIR-II-trackable tea polyphenol-based LYTAC nanotheranostics for precision protein degradation and endometrial receptivity improvement in PCOS

Endometrial dysfunction in polycystic ovary syndrome (PCOS) is associated with persistent activation of the androgen receptor (AR)-DPP4-reactive oxygen species (ROS)-mitochondrial stress axis in endometrial stromal cells. However, current therapeutic approaches are limited by insufficient cellular selectivity and an inability to coordinately disrupt the pathological axis. We developed ITP-LYTACs@Gel, an intrauterine nanotherapeutic platform. Its mesoporous tea polyphenol core incorporated an ICG-thioketal-spironolactone module, enabling ROS-responsive near-infrared-II fluorescence imaging and on-demand spironolactone release to suppress AR signaling. Aberrantly accumulated membrane DPP4 was captured by a DPP4 antibody and internalized through an SDC2-recognition peptide for lysosomal degradation. Meanwhile, the polyphenol core scavenged intracellular ROS, alleviated mitochondrial oxidative stress, and promoted mitochondrial recovery. Incorporation into gelatin hydrogel prolonged uterine retention and enhanced stromal distribution. In PCOS rats, intrauterine ITP-LYTACs@Gel reduced hormonal dysregulation and local inflammation, improved extracellular matrix remodeling, increased decidualization- and receptivity-related markers, and improved reproductive outcomes. Thus, the feedback-regulated system integrates AR inhibition, lysosomal DPP4 degradation, ROS scavenging, and mitochondrial repair, offering a promising strategy to improve endometrial receptivity and improve pregnancy outcomes in PCOS.