Protease‐Activated Theranostic Nanomedicine for Endometriosis Treatment

ABSTRACT Endometriosis is a chronic gynecological disorder characterized by ectopic growth of endometrial tissue and is associated with pelvic pain and infertility. Here, we identify aberrant matrix metalloproteinase‐9 (MMP‐9) overexpression in endometriotic lesions and develop a novel nanomedicine that integrates MMP‐9‐targeted therapy, ratiometric photoacoustic (PA) imaging, and controlled drug delivery to improve endometriosis diagnosis and treatment. We design MMP‐9‐cleavable peptide‐functionalized nanoparticles that produce turn‐on imaging signals upon enzymatic activation by MMP‐9, enabling sensitive and specific visualization of endometriotic lesions. Comprehensive in vitro and in vivo studies validate the responsiveness of the nanoparticles to MMP‐9 activity, with inhibitor assays confirming MMP‐9‐dependent specificity. In vivo PA imaging demonstrates precise localization and real‐time monitoring of endometriotic lesions, findings further corroborated by ex vivo tissue analyses using near‐infrared fluorescence imaging. Importantly, these peptide‐based nanoparticles serve as carriers for the targeted delivery of letrozole (LTZ), a potent therapeutic agent, allowing selective drug release via MMP‐9‐mediated enzymatic activity within endometriotic lesions. This targeted delivery enhanced the therapeutic efficacy of LTZ while minimizing its systemic side effects and toxicity. Collectively, our integrated theranostic nanoplatform enables simultaneous diagnosis and targeted therapy of endometriosis, highlighting the potential of MMP‐9‐responsive nanotherapeutics combined with advanced imaging for precision medicine in gynecological disorders.