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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by infiltration of peripheral immune cells, neuroinflammation, and demyelination. Addressing the complex pathological mechanisms and spatially multifocal lesions, including deep cervical lymph nodes (dCLNs), meningeal lymphatic vessels (MLVs), and brain parenchyma, remains a major challenge in MS treatment. This article introduces a simplified neurotherapeutic strategy using self-assembled ursolic acid nanoparticles (UA-NPs) administered via near-subcutaneous cervical injection (n.s.c.). This route strategically leverages the dCLNs–MLVs pathway, which anatomically corresponds to the multifocal nature of MS lesions while bypassing the blood-brain barrier. Multiple lines of experimental evidence collectively show that n.s.c. UA-NPs: (1) enhance accumulation at key MS-relevant immune interfaces, particularly in dCLNs and MLVs, as well as in brain parenchyma, significantly outperforming intravenous injection; (2) prolong brain residence time (n.s.c. 48 hours versus intravenous 8 hours) while minimizing systemic exposure; and (3) release the multi-pharmacological potential of ursolic acid, achieving immunomodulation, inflammation suppression, and myelin repair, all consistent with MS pathology. Consequently, n.s.c. UA-NPs reverse multiple MS-related behavioral deficits, providing a minimalist yet multifunctional therapeutic paradigm with spatial precision that surpasses conventional approaches.
