A highly potent lymphatic system–targeting nanoparticle cyclosporine prevents glomerulonephritis in mouse model of lupus

Cyclosporine A (CsA) is a powerful immunosuppressant, but it is an ineffective stand-alone treatment for systemic lupus erythematosus (SLE) due to poor target tissue distribution and renal toxicity. We hypothesized that CD71 (transferrin receptor 1)–directed delivery of CsA to the lymphatic system would improve SLE outcomes in a murine model. We synthesized biodegradable, ligand-conjugated nanoparticles [P2Ns–gambogic acid (GA)] targeting CD71. GA conjugation substantially increased nanoparticle association with CD3(+) or CD20(+) lymphocytes and with intestinal lymphoid tissues. In orally dosed MRL-lpr mice, P2Ns-GA–encapsulated CsA increased lymphatic drug delivery 4- to 18-fold over the ligand-free formulation and a commercial CsA capsule, respectively. Improved lymphatic bioavailability of CsA was paralleled by normalization of anti–double-stranded DNA immunoglobulin G titer, plasma cytokines, and glomerulonephritis. Thus, this study demonstrates the translational potential of nanoparticles that enhance the targeting of lymphatic tissues, transforming CsA into a potent single therapeutic for SLE.