Breaking the endometriosis-stroke axis: lesion-focused hydrogel reprogramming of thromboinflammatory networks

Abstract

Endometriosis is a chronic, systemic inflammatory disorder characterized by the ectopic implantation of endometrial-like tissue and accompanied by persistent pain and infertility. Beyond the pelvis, accumulating epidemiological evidence indicates that endometriosis confers a significantly elevated risk of cardiovascular and cerebrovascular disease, including ischemic stroke. This association points to a shared pathogenic continuum in which chronic inflammation, aberrant neuroimmune signaling, dysregulated coagulation, and endothelial dysfunction jointly drive both local lesion persistence and distant vascular vulnerability. In this review, we integrate emerging clinical and mechanistic data to define endometriosis as a disease capable of exporting thromboinflammatory signals from the pelvic microenvironment into the systemic circulation. We delineate how endometriotic lesions function as hubs of immune activation, neurovascular remodeling, and procoagulant signaling, generating mediators such as tissue factor-bearing extracellular vesicles, activated platelets, and inflammatory cytokines that mirror key drivers of ischemic stroke pathogenesis. Building on this framework, we examine injectable, in situ-forming hydrogel platforms as precision biomaterials designed to locally reprogram the endometriotic niche. We highlight photothermal and magnetothermal hydrogels capable of on-demand ablation of ectopic lesions while simultaneously attenuating inflammation, disrupting pathological innervation, and suppressing coagulation-linked signaling cascades. By targeting the lesion as a source of systemic thromboinflammation, these approaches introduce a strategy to mitigate not only pelvic pathology and chronic pain but also downstream cerebrovascular risk. Finally, we address critical translational considerations, including material biodegradability, safety, spatial confinement, and regulatory pathways, that will determine clinical feasibility. Collectively, this synthesis positions endometriosis within a broader thrombo-neuroinflammatory disease spectrum and proposes biomaterial-based microenvironmental modulation as a route toward precision interventions that link local disease control to prevention of distant vascular sequelae.