Systemic lupus erythematosus (SLE) is a complex autoimmune disease marked by dysregulated B-cell activation, autoantibody production, and systemic inflammation. Therapy development is limited by species-specific immune differences, poor modeling of human pathology in conventional mice, and low clinical predictive value. Similarly, immune-related adverse events (IRAEs), such as cytokine release syndrome (CRS), remain a major challenge in cell-based cancer immunotherapies like CAR-T. To address these issues, we developed a humanized preclinical SLE mouse model that mirrors human immune responses and serves as a platform to evaluate B-cell-targeted CAR-T therapies and immune toxicity.The SLE phenotype was induced by imiquimod (IMQ), a Toll-like receptor 7 agonist that activates plasmacytoid dendritic cells and B cells. In CD34⁺ humanized mice, IMQ induced a humanized SLE-like phenotype, allowing human immune cells to respond to TLR7 stimulation and closely modeling human disease.CAR-T cells were delivered in vivo using lipid nanoparticles (LNPs) conjugated with anti-CD5 antibodies to target CD5⁺ T cells. LNP internalization delivers DNA encoding a CD19-specific CAR, and transfected T cells were characterized by flow cytometry and digital droplet PCR. LNP pharmacokinetics were analyzed via LC-MS/MS, and tissue distribution was assessed by CAR gene detection.T-cell activation and CRS were monitored via multiplex assays for cytokines (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-6, IL-10) and chemokines (MCP-1, CCL5). Anti-drug antibody responses were evaluated by anti-PEG ELISA and anti-CAR MSD assays. CAR-T efficacy was assessed using serum anti-dsDNA antibodies and urinary lipocalin-2, key biomarkers of SLE activity.In summary, this humanized SLE model with integrated analytical panels provides a physiologically relevant platform for evaluating therapeutic efficacy and immune toxicity, accelerating preclinical development of human-targeted therapies for autoimmune disease and cancer immunotherapy.