Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease that is characterized by alterations in the balance between effector and regulatory CD4 T cells. We observed the upregulation of the immune checkpoints (ICs) PD-1 and TIGIT in pathogenic CD4 T cells during disease progression, and downregulation of their ligands PD-L1 and CD155. Inspired by biomimetic nanotechnology, we fabricated dexamethasone (DXM)-loaded IFN-γ-treated MHC class I deficient cancer membrane-coated nanoparticles (IM-MNPs/DXM) to safely harness the immunosuppressive power of tumor cells for the treatment of SLE. The IM-MNPs inherited the membrane functions, which allowed these particles to evade immune clearance and accumulate in inflammatory organs. The IM-MNPs specifically targeted SLE CD4 T cells and agonist PD-1/TIGIT signaling to inhibit effector T cell function while enhancing the immunosuppressive function of regulatory T cells (Tregs). The sustained release of DXM inhibited the production of proinflammatory cytokines in the inflammatory microenvironment to further promote Treg-mediated immune homeostasis. The IM-MNPs/DXM showed significant therapeutic efficacy in ameliorating lupus nephritis (LN) and decreasing side effects in vivo. Therefore, the particle represents a promising platform to improve current SLE treatment efficacy while minimizing systemic side effects of DXM and ICs agonist therapy.