Exosomal immune decoy integrates cfDNA scavenging and mTOR inhibition for synergistic lupus nephritis therapy.

Objective: Lupus nephritis (LN) treatment faces the challenge of balancing effective immunosuppression with systemic safety. To address this, we aimed to develop a biomimetic nanoplatform capable of simultaneously targeting multiple pathogenic pathways in LN, thereby achieving potent immunomodulation without broad toxicity. Methods: A "smart immune decoy" (RAPA@MEX-PL) was engineered by encapsulating rapamycin (RAPA) in mesenchymal stromal cell-derived exosomes (MEX) and coating the surface with a cationic polylysine (PLL) corona. The platform was designed to concurrently: (1) the polylysine corona potently scavenges cell-free DNA (cfDNA) to quench TLR9-mediated inflammation, (2) the MEX core mediates the repolarization of macrophages from an M1 to an M2 phenotype, and (3) localized RAPA release provides durable mTOR inhibition, synergistically rebalancing autoimmune responses. Renal targeting, immunomodulatory activity, and systemic safety were evaluated in lupus-prone mouse models. Results: In lupus-prone mice, RAPA@MEX-PL demonstrated precise accumulation in renal tissue, leading to a significant reduction in auto-antibody levels and resolution of glomerular inflammation. The platform concurrently addressed three key pathogenic pathways-cfDNA scavenging, macrophage repolarization and mTOR inhibition-resulting in synergistic rebalancing of autoimmune responses. Notably, it circumvented the metabolic side effects typically associated with systemic RAPA administration. Conclusions: The RAPA@MEX-PL nanoplatform represents a targeted and effective immunotherapeutic strategy for LN, capable of achieving sufficient immunosuppression without systemic toxicity. These findings emphasize its potential as a favorable candidate for the therapy for autoimmune diseases.