Therapeutic Modulation of Meningeal Lymphatics: A Systematic Review of Preclinical Evidence Across Neurological Disorders

Meningeal lymphatic vessels (MLVs) have emerged as critical modulators of cerebral homeostasis, immune surveillance, and metabolic clearance. Their dysfunction is increasingly implicated in the pathogenesis of neurodegenerative and neuroinflammatory conditions. This systematic review aimed to synthesize current preclinical evidence on the therapeutic modulation of MLVs across animal models of neurological disease, focusing on pathological, behavioral, and immunological outcomes. We conducted the literature search in the PubMed, Embase, Web of Science, and Scopus databases in accordance with PRISMA guidelines and included peer-reviewed, controlled preclinical studies investigating interventions aimed at enhancing meningeal lymphatic drainage in neurological disease models. Risk of bias was assessed using Covidence’s quality assessment template, supported by the SYRCLE Risk of Bias tool. Given the heterogeneity of models and interventions, a qualitative synthesis was performed. Therapeutic strategies - such as VEGF-C delivery, photo-biomodulation, pharmacological agents, and genetic modulation - were consistently associated with improved MLV structure and function, enhanced clearance of neurotoxic proteins (e.g., Aβ), reduced neuroinflammation, and improved cognitive and motor performance across the disease models. Thus, enhancing meningeal lymphatic drainage represents a promising preclinical therapeutic approach for a wide spectrum of neurological conditions. Future research should aim to standardize methodologies, explore sex- and age-specific effects, and accelerate translation into human trials.