Rapamune® (oral rapamycin/sirolimus) administration is plagued by poor bioavailability, extensive fecal elimination, and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycin’s hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects (Fig. 1).

Subcutaneously administered rapamycin-loaded polymersomes (rPS) avoid fecal elimination and allow for sustained delivery of rapamycin to immune cell rich organs, especially the axillary lymph nodes. While oral rapamycin inhibits naïve T cell proliferation directly, 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 rapamycin’s cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model (Fig. 2a,b). Importantly, rPS treatment does not alter serum albumin:globulin ratios (Fig. 2c).

These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.