Abstract

Endometritis is a prevalent inflammatory disorder of the uterine lining that is primarily triggered by microbial infection and poses a significant threat to the reproductive health of women of childbearing age worldwide. Current clinical management relies heavily on empirical antibiotic administration, which is increasingly challenged by antibiotic resistance and disruption of the vaginal microbiota. Herein, we developed a thermosensitive poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) hydrogel as a targeted delivery system for natural phycocyanin (PC), a bioactive protein derived from microalgae with inherent anti-inflammatory and antioxidant properties to treat endometritis. This PC-loaded hydrogel (PCH) enables localized and sustained release of PC in the reproductive tract, comprehensively mitigating inflammation, scavenging reactive oxygen species (ROS), and restoring vaginal microbiota balance for effective endometritis therapy. Mechanistically, prolonged release of PC via the hydrogel activates the Nrf2/HO-1 signaling pathway, alleviates mitochondrial-mediated apoptosis, and inhibits the NF-κB pathway by suppressing the phosphorylation of IKKαβ and IκBα in the endometrium. Additionally, PLGA degradation products facilitate the enrichment of beneficial Lactobacillales, restoring vaginal microbiota homeostasis. This multifunctional PCH exhibits curative effects in endometritis and provides a promising therapeutic strategy for endometritis with high translational potential, addressing key limitations of current treatments. This PCH will establish a solid foundation for clinical applications and expand the exploration of applying natural compounds in the treatment of female reproductive diseases.