Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Rapamycin is an orally administered immunosuppressant that is plagued by poor bioavailability and a wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, a wide range of side effects and provides inadequate transplantation protection. Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)) (PEG-b-PPS) polymersome (PS) nanocarriers modulates the cellular biodistribution of rapamycin to change its immunosuppressive mechanism of action for enhanced efficacy while minimizing side effects. While oral rapamycin inhibits naive T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to the cellular biodistribution of rapamycin. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.