Project Summary Endometriosis affects 10-15% of women of reproductive age, and the incidence increases to 50-60% in women with chronic pelvic pain and infertility. The current treatments include surgical removal of lesions or hormonal suppression; however, these may have many side effects and high risks of relapse. Precision-targeted therapy with a non-hormonal drug can successfully eradicate endometriosis lesions and alleviate pain symptoms while reducing its off-target toxicity. pSTAT3 signaling plays a crucial role in immunosuppression and inflammation in endometriosis. A potential therapeutic approach then is to downregulate the endometriosis-specific inflammation using antioxidant drugs. Cerium oxide nanoparticles (nanoceria) are potent STAT3 inhibitors due to their anti-inflammatory and immunomodulatory effects. The small-sized nanoceria can accumulate in endometriotic lesions by extravasation through permeable, angiogenic endometrial vasculature. Our preliminary results demonstrated pSTAT3 overexpression leads to estrogen-dependent inflammation in endometriosis, and our ROS scavenging nanoceria remarkably reduces the number of endometriotic lesions in a mouse model. The nanodrug (nanoceria), coated with albumin protein and conjugated with NIR fluorescent dye (indocyanine green), shows successful systemic endometrial tissue targeting under photoacoustic image guidance. We hypothesize the novel nanodrug (albumin-nanoceria-ICG) will significantly suppress endometriotic lesion growth and result in reduced pain and infertility. Multimodal imaging simultaneously offers real-time monitoring of endometriosis progression and pregnancy and fetal development in living animals. Aim 1 will investigate how pSTAT3 in endometriosis contributes to inflammatory and immunosuppressive conditions using our endometriosis mouse model and in vivo imaging. Aim 2 will evaluate the theranostic potential of nanoceria on endometriosis progression and pain alleviation. Aim 3 examines whether the nanodrug will improve fertility, endometrial receptivity, and implantation. The proposed studies will support uncovering the molecular mechanism of inflammation in endometriosis and lead to non-surgical and non-hormonal treatment.