Engineered Immunological Niches and Antigen-Specific Nanoparticles: A Targeted Approach to Treating Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a debilitating autoimmune disease that affects nearly three million people worldwide, leading to progressive neurological dysfunction and disability. Among its various forms, primary progressive multiple sclerosis (PPMS) is the most severe and least treatable, characterized by relentless neurodegeneration without the periods of remission seen in relapsing-remitting MS. Unlike its more common counterpart, PPMS progresses steadily, often leaving patients with irreversible disability within a decade of diagnosis. The existing treatment landscape for PPMS is bleak—ocrelizumab, the only FDA-approved drug, provides only modest benefits, slowing disease progression without reversing damage. Furthermore, its mechanism, which depletes B cells, suppresses the immune system broadly, making patients more susceptible to infections and reducing vaccine efficacy. These limitations highlight an urgent need for new therapeutic strategies that can specifically target the underlying disease mechanisms without causing widespread immunosuppression. One of the primary obstacles in developing better treatments for PPMS is the difficulty in studying the disease at the tissue level. The central nervous system (CNS) is highly inaccessible, making direct biopsies of affected brain and spinal cord tissue nearly impossible. Without a reliable way to examine immune activity and disease progression in real-time, researchers are left with indirect methods, such as analyzing blood samples, which fail to capture the complex immune interactions occurring within diseased tissue. This gap in knowledge hinders the identification of precise therapeutic targets and the development of more effective, less immunosuppressive treatments.

New research paper published in Proceedings of the National Academy of Sciences and conducted by researchers from the University of Michigan led by Professors Lonnie Shea and Aaron Morris developed a novel approach to studying PPMS and designing targeted therapies. Their strategy involved engineering a subcutaneously implanted biomaterial scaffold—termed an immunological niche (IN)—that mimics diseased tissue by recruiting immune cells from the body. This niche provides a minimally invasive, accessible window into the cellular and molecular dynamics of the disease, allowing for repeated sampling without the need for risky CNS biopsies. By using this innovative system, the researchers aimed to identify immune dysfunction specific to PPMS and leverage those insights to develop a therapeutic intervention. The research team designed a nanoparticle-based treatment that simultaneously modulates immune signaling and delivers disease-specific antigens to promote immune tolerance. Unlike conventional therapies that broadly suppress immune function, this approach selectively targets dysregulated pathways while encouraging regulatory immune responses.

The researchers developed and implanted a porous biomaterial scaffold under the skin of mice. This scaffold, known as an immunological niche (IN), was designed to recruit immune cells and mimic diseased tissue, effectively serving as a surrogate for inaccessible CNS lesions. After implanting these scaffolds, they induced a progressive form of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model that mimics human PPMS. By analyzing the immune cells accumulating within the INs, the team sought to identify key molecular signatures associated with disease progression. Their initial findings were striking—immune cells within the niche displayed distinct, disease-specific alterations, particularly in chemokine signaling. Among these changes, CC chemokines were found to be significantly upregulated, particularly CCL2, CCL4, and CCL5, which are known to drive inflammation and immune cell infiltration in MS. These findings confirmed that the IN could effectively capture immune dysregulation occurring in PPMS, providing a powerful tool for real-time monitoring of disease-related immune activity. Once the researchers identified the dysregulated immune pathways, they sought to test whether targeting them could lead to therapeutic benefits. They designed nanoparticles made from poly(lactide-co-glycolide) (PLG), a biodegradable polymer commonly used in drug delivery. These nanoparticles were engineered to both suppress inflammatory chemokine signaling and deliver disease-relevant antigens to the immune system, a dual approach intended to counteract autoimmunity while promoting immune tolerance. To test their effectiveness, the researchers administered these nanoparticles intravenously to mice with progressive EAE at different stages of the disease. The results were compelling—mice that received the treatment early, before the onset of symptoms, exhibited little to no disease progression. Even when administered after symptoms had already begun, the nanoparticles significantly reduced disease severity, demonstrating their potential for both prevention and treatment. To understand how the nanoparticles achieved these effects, the authors examined immune responses in treated and untreated mice. They found that the nanoparticles not only suppressed inflammatory chemokine signaling but also increased populations of regulatory T cells (Tregs), a subset of immune cells known to suppress autoimmunity. This shift in immune balance suggested that the treatment was not merely dampening inflammation but actively promoting a more regulated and controlled immune response. Further supporting this, when the researchers analyzed cytokine production in the spleens of treated mice, they found reduced levels of key pro-inflammatory cytokines such as IFN-γ, IL-2, and IL-17—molecules that drive MS pathology. These molecular changes were reflected in the clinical outcomes, as mice that received the nanoparticle treatment had lower neurological disability scores compared to untreated controls. Moreover, the authors  performed live imaging of immune activity in the CNS using a bioluminescent reporter system. They injected mice with a luminol-based probe that detects myeloperoxidase (MPO) activity, a marker of inflammatory immune cell infiltration in the brain and spinal cord. Imaging revealed that untreated mice displayed widespread MPO activity in the CNS, indicating severe neuroinflammation. In contrast, mice treated with antigen-loaded nanoparticles showed dramatically reduced MPO signals, confirming that the therapy successfully suppressed neuroinflammation at the source.

In conclusion, Professors Lonnie Shea and Aaron Morris developed a biomaterial-based immunological niche that acts as a surrogate for diseased CNS tissue, they created a powerful platform for studying immune dysfunction in chronic diseases. This approach offers a novel way to capture the real-time immune activity of a disease that has traditionally been difficult to study due to the inaccessibility of affected tissues. The ability to repeatedly analyze immune responses without invasive procedures provides a new avenue for understanding disease progression and refining treatment strategies. In the case of progressive multiple sclerosis, where existing therapies offer only partial symptom relief, this breakthrough could guide the development of more precise and effective treatments that go beyond simply suppressing the immune system. Beyond its immediate application in MS, this method has the potential to be adapted for other autoimmune and inflammatory diseases. Conditions such as rheumatoid arthritis, lupus, and type 1 diabetes involve complex immune interactions that are difficult to study in living patients. The immunological niche technology could allow for non-invasive monitoring of these diseases, leading to earlier detection of disease-related immune changes and more personalized treatment approaches. By providing a way to analyze the immune system in a setting that closely mimics the body’s natural response, this strategy could accelerate the discovery of novel therapeutic targets across a range of conditions. We believe the use of antigen-loaded nanoparticles as a targeted therapy represents another significant advancement. Unlike conventional MS treatments, which rely on broad immune suppression, this approach directly addresses the underlying immune dysregulation by retraining the immune system. The findings demonstrate that delivering disease-relevant antigens in a controlled manner can reduce inflammation and promote regulatory immune responses, an approach that could be extended to other autoimmune diseases where antigen-specific tolerance is a therapeutic goal. This strategy also aligns with emerging trends in precision medicine, where treatments are designed based on an individual’s unique immune profile rather than using a one-size-fits-all approach. According to the authors, the implications for patient care are profound. If this approach proves successful in human trials, it could lead to safer and more effective treatments for progressive multiple sclerosis, a condition that currently has limited therapeutic options. The ability to deliver a single injection that modifies immune function without causing widespread immunosuppression could dramatically improve quality of life for patients, reducing both disease burden and the side effects associated with long-term immunosuppressive therapy. Furthermore, the real-time monitoring of immune responses through the immunological niche could enable clinicians to tailor treatments based on how an individual’s immune system is behaving, rather than relying on generalized treatment regimens that may not be optimal for every patient.