PMID- 35039683 OWN - NLM STAT- MEDLINE DCOM- 20220427 LR - 20221106 IS - 1748-3395 (Electronic) IS - 1748-3387 (Print) IS - 1748-3387 (Linking) VI - 17 IP - 3 DP - 2022 Mar TI - Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability. PG - 319-330 LID - 10.1038/s41565-021-01048-2 [doi] AB - Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution. CI - (c) 2022. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Burke, Jacqueline A AU - Burke JA AUID- ORCID: 0000-0001-8697-2123 AD - Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. AD - Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. FAU - Zhang, Xiaomin AU - Zhang X AD - Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. FAU - Bobbala, Sharan AU - Bobbala S AD - Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA. FAU - Frey, Molly A AU - Frey MA AD - Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA. FAU - Bohorquez Fuentes, Carolina AU - Bohorquez Fuentes C AD - Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. AD - Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. FAU - Freire Haddad, Helena AU - Freire Haddad H AD - Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. AD - Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. FAU - Allen, Sean D AU - Allen SD AD - Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA. FAU - Richardson, Reese A K AU - Richardson RAK AUID- ORCID: 0000-0002-6058-5886 AD - Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA. FAU - Ameer, Guillermo A AU - Ameer GA AUID- ORCID: 0000-0001-6023-048X AD - Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu. AD - Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu. AD - Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu. AD - Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu. AD - Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. g-ameer@northwestern.edu. AD - Simpson Querrey Institute, Northwestern University, Chicago, IL, USA. g-ameer@northwestern.edu. AD - International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu. FAU - Scott, Evan A AU - Scott EA AUID- ORCID: 0000-0002-8945-2892 AD - Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. evan.scott@northwestern.edu. AD - Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. evan.scott@northwestern.edu. AD - Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. evan.scott@northwestern.edu. AD - Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA. evan.scott@northwestern.edu. AD - Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA. evan.scott@northwestern.edu. AD - Simpson Querrey Institute, Northwestern University, Chicago, IL, USA. evan.scott@northwestern.edu. AD - International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. evan.scott@northwestern.edu. AD - Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. evan.scott@northwestern.edu. LA - eng GR - DP2 HL132390/HL/NHLBI NIH HHS/United States GR - P30 CA060553/CA/NCI NIH HHS/United States GR - R21 AI159795/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220117 PL - England TA - Nat Nanotechnol JT - Nature nanotechnology JID - 101283273 RN - 0 (Immunosuppressive Agents) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - *Hematopoietic Stem Cell Transplantation MH - Immunosuppressive Agents/pharmacology MH - *Islets of Langerhans Transplantation MH - Sirolimus/pharmacology MH - Tissue Distribution PMC - PMC8934301 MID - NIHMS1756305 COIS- Competing Interests J.A.B., S.D.A., E.A.S., and G.A.A. are coinventors on a patient application related to the work presented in this manuscript. The remaining authors declare no competing interests. EDAT- 2022/01/19 06:00 MHDA- 2022/04/28 06:00 PMCR- 2022/07/17 CRDT- 2022/01/18 05:59 PHST- 2020/10/13 00:00 [received] PHST- 2021/11/09 00:00 [accepted] PHST- 2022/01/19 06:00 [pubmed] PHST- 2022/04/28 06:00 [medline] PHST- 2022/01/18 05:59 [entrez] PHST- 2022/07/17 00:00 [pmc-release] AID - 10.1038/s41565-021-01048-2 [pii] AID - 10.1038/s41565-021-01048-2 [doi] PST - ppublish SO - Nat Nanotechnol. 2022 Mar;17(3):319-330. doi: 10.1038/s41565-021-01048-2. Epub 2022 Jan 17.