In vivo CAR-T for the treatment of autoimmune diseases: Current progress and future directions.

Autoimmune diseases are a clinical challenge because current immunosuppressive therapies fail to eliminate pathogenic immunocytes, such as autoreactive B cells, plasma cells, and antigen-presenting cells, which induce chronic inflammation. Chimeric antigen receptor T (CAR-T) cell therapy offers a targeted strategy to eliminate these disease-driving populations. Early ex vivo CAR-T cell studies on severe autoimmunity have shown effective B-cell depletion and sustained remission. However, its toxicity, cost, and lengthy manufacturing process limit its widespread clinical use. In vivo CAR-T technologies-using viral vectors or mRNA lipid nanoparticles to generate CAR-T cells directly within the patient-aim to overcome these barriers. Preclinical and emerging clinical data indicate that these platforms can rapidly reprogram circulating T cells, induce potent B-cell clearance, and achieve clinical improvement in refractory diseases. Viral vectors provide durable expression but raise integration and immunogenicity concerns, whereas mRNA-LNP systems enable transient, controllable CAR expression with greater manufacturing scalability. These advances have positioned in vivo CAR-T cells as a promising therapeutic strategy for autoimmune diseases. Continuing progress in delivery specificity, safety engineering, trial design, and cost-effective production is essential for translating this approach into widely accessible treatments. In this review, we synthesized preclinical and emerging clinical evidence, compared delivery platforms, and proposed practical recommendations for safety engineering, trial design, and manufacturing, which will help guide future translational efforts and accelerate clinical adoption.