Nanomedicine targeting the PD-1/PD-L1 axis in autoimmune diseases: breaking conventional barriers to restore immune tolerance

Autoimmune diseases (ADs) arise from the breakdown of self-tolerance, leading to pathogenic immune responses against healthy tissues. The PD-1/PD-L1 immune checkpoint is pivotal for maintaining peripheral tolerance by suppressing autoreactive T cells, and its dysfunction drives the pathogenesis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and other ADs. Conventional approaches-including monoclonal antibodies, soluble PD-L1 fusion proteins, small-molecule or RNA regulators, and cell- or gene-based therapies-have shown promise. However, their broader application is constrained by systemic immunosuppression, off-target effects, infection and malignancy risks, and manufacturing complexities. Nanomedicine offers transformative solutions by leveraging polymeric nanoparticles, liposomes or lipid nanoparticles, extracellular vesicles (EVs), and biomimetic cell-membrane coatings to deliver PD-1/PD-L1 agonists with high spatial and temporal precision. These nanocarrier platforms enable localized checkpoint activation, co-delivery of tolerogenic agents, and improved biodistribution with reduced systemic toxicity. Here, we systematically review the structural and signaling features of the PD-1/PD-L1 axis, outlines the limitations of conventional therapeutic modalities, and highlights how nanocarrier-based approaches overcome these barriers to restore immune homeostasis in ADs. By integrating mechanistic insights with advanced delivery technologies, this review outlines a roadmap for next-generation, precision-engineered interventions aimed at reestablishing immune tolerance and improving clinical outcomes in ADs.