This review outlines the rationale and early preclinical efforts to use chimeric antigen receptor–engineered regulatory T cells (CAR Tregs) to target misfolded/aggregated proteins and suppress neuroinflammation in neurodegenerative diseases, including Parkinson's disease.

While conceptual and preclinical, CAR Treg strategies offer a novel immunomodulatory approach to reduce inflammation driven by protein aggregates and could be translated into targeted therapies for Parkinson's disease if specificity, safety, and delivery challenges are resolved.

Regulatory T cells (Tregs) promote immune tolerance by recognizing non-foreign self-antigens. Consequently, Tregs suppress chronic immune responses and prevent autoimmunity. Chimeric antigen receptor Tregs (CAR Tregs) enhance Treg responses by genetic modification for cell-specific targeting. This can lead to effective treatments for autoimmune diseases, transplant rejection, and graft-versus-host disease. An extension of CAR Tregs involves their potential ability to regulate immune responses to misfolded and aggregated proteins, which drive neurodegenerative diseases. These protein aggregates can trigger immune responses that lead to neural injury. Early preclinical and translational strategies suggest CAR Treg therapies can treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In each case, a Treg-based approach transforms a neurotoxic, inflammatory environment through neurotrophic responses. By doing so, CAR Tregs may restore brain balance and slow disease progression. This review highlights ongoing efforts to develop CAR Treg strategies as potential therapies for neurodegenerative disorders.