OBJECTIVE: Systemic lupus erythematosus (SLE) is a severe autoimmune disease with significant health impacts, yet effective therapies remain elusive. Recent advances underscore the promise of chimeric antigen receptor (CAR) T-cell therapy for SLE. However, conventional CAR T cells manufacturing is complex, limiting its clinical application. METHODS: To overcome the limitations, we developed an in vivo engineered CAR-T system using CD5-targeted lipid nanoparticles (aCD5-CD19/LNP) delivering CD19-directed CAR mRNA. RESULTS: aCD5-CD19/LNP efficiently generates functional CAR T cells capable of targeting CD19+ B cells in vitro. In the MRL/lpr murine SLE model, aCD5-CD19/LNP-generated CAR T cells achieved robust B cell depletion, particularly eliminating pathogenic splenic plasmablasts (CD19+CD20-CD27+) and switched memory B cells (CD19+CD20+CD27+IgD-). This targeted depletion reduced autoreactive antibodies, reduced proinflammatory cytokines, and attenuated histopathological damage in renal and dermal tissues. Critically, this in vivo strategy induced sustained remission without requiring lymphodepletion preconditioning or ex vivo cell manipulation. CONCLUSION: Our findings support in vivo-generated CAR T cells as a potentially clinically viable, effective modality for SLE, offering a scalable pathway toward curative immunotherapy.