Lesion-centric reprogramming: hydrogel-enabled photothermal reset of endometriosis pain

Endometriosis-associated pelvic pain represents a prototypical failure of systemic therapy for a locally organized, neuroinflammatory disease. Persistent pain arises from the convergence of estrogen-driven lesion survival, chronic inflammation, fibrosis, and aberrant neuroangiogenesis, leading to sustained peripheral nociceptor sensitization and maladaptive neuroimmune remodeling that is poorly reflected by lesion burden alone. This disconnect underscores a fundamental need for therapies that directly interrogate and remodel the lesion microenvironment rather than suppress endocrine signaling globally. Recent advances in biomaterials engineering and energy-based therapies have enabled a new class of localized interventions based on hydrogel-enabled photothermal ablation. Injectable and in situ-forming hydrogels provide conformal, lesion-confined platforms capable of sustained drug delivery and dynamic responsiveness to external stimuli. When integrated with photothermal agents such as polydopamine or gold nanostructures, these systems convert near-infrared irradiation into spatially restricted thermal energy, permitting on-demand ablation of ectopic endometrial tissue with high precision. Critically, photothermal activation extends beyond cytotoxicity, enabling spatiotemporal modulation of matrix mechanics, enhancement of intralesional drug diffusion, and targeted disruption of inflammatory signaling and lesion-nerve crosstalk that sustain chronic pain states. Preclinical studies demonstrate that hydrogel-based photothermal platforms achieve robust lesion regression, attenuate local inflammatory and neurogenic signaling, and exhibit favorable biosafety profiles, outperforming monotherapies based on pharmacologic suppression or thermal ablation alone. In this Review, we integrate mechanistic insights from endometriosis pain biology with emerging hydrogel and photothermal technologies, critically evaluating material design principles, ablation dynamics, and multifunctional therapeutic architectures. We further address key translational challenges, including tissue penetration, thermal dose control, targeting specificity, and clinical implementation. Collectively, hydrogel-enabled photothermal strategies redefine localized, non-hormonal intervention for endometriosis-associated pelvic pain, establishing a precision framework for remodeling pathological pain microenvironments rather than merely suppressing symptoms.