Meningeal Lymphatic System-Driven Nanodelivery Unlocks Ursolic Acid's Pleiotropic Benefits To Optimize Multiple Sclerosis Treatment.

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS), characterized by peripheral immune cells infiltration, neuroinflammation, and demyelination. Addressing complex pathological mechanisms and spatially multifocal lesions, including deep cervical lymph nodes (dCLNs), meningeal lymphatic vessels (MLVs), and the brain parenchyma, remains a major challenge in MS treatment. Here, we present a streamlined nanotherapeutic strategy using self-assembled ursolic acid nanoparticles (UA-NPs) administered via near-neck subcutaneous injection (n.s.c.). This route strategically exploits the dCLNs-MLVs pathway, anatomically aligned with the multifocal nature of MS lesions, while it is capable of bypassing the blood-brain barrier. Multiple lines of experimental evidence collectively demonstrates that n.s.c. UA-NPs achieve (1) enhanced accumulation in key immune interfaces related to MS, specifically the dCLNs and MLVs, as well as in the brain parenchyma, remarkably outperforming intravenous injection; (2) prolonged cerebral residence time (n.s.c. 48 h vs i.v. 8 h) while minimizing systemic exposure; (3) unlocked the multipharmacological potential of ursolic acid, achieving immunomodulation, inflammation suppression, and myelin repair that correspond to MS pathology. Consequently, n.s.c. UA-NPs reverse various MS-related behavioral disorders, offering a minimalist, yet multifunctional therapeutic paradigm with spatial precision that surpasses conventional approaches.