Tolerogenic nanotherapy for type 1 diabetes via targeted rapamycin delivery

Overview

This project validates a tolerogenic nanotherapy designed to treat type 1 diabetes by enabling long-term survival of transplanted pancreatic islets without continuous immunosuppression. The approach uses poly(ethylene glycol)-b-poly(propylene sulfide) nanocarriers to selectively deliver the mTOR inhibitor rapamycin to antigen-presenting cells (APCs) rather than T cells. This rerouting shifts rapamycin's mechanism from short-term immunosuppression to durable, antigen-specific immune tolerance, potentially allowing islet engraftment and maintenance of normoglycemia for over six months in a fully MHC-m mismatched allogeneic transplant setting.

Technical specifications

• Nanocarrier platform: PEG-b-PPS (poly(ethylene glycol)-b-poly(propylene sulfide)) nanoparticles for subcutaneous delivery
• Active agent: Rapamycin, repurposed via targeted delivery to induce a tolerogenic state in APCs
• Mechanism of action: Alters cellular biodistribution to avoid T cell suppression and instead promote antigen-specific tolerance
• Treatment regimen: Short-duration, approximately 14-day subcutaneous dosing
• Validated outcomes in mice: Over 100 days of normoglycemia in 83% of recipients in an intraportal, fully MHC-m mismatched islet transplant model; over 300 days of islet survival in a kidney capsule model
• Side effect profile: No observable adverse effects in published murine studies
• Future canine validation steps: Pharmacokinetic and immunomodulation profiling over one month, followed by intraportal allogeneic islet transplantation with six-month normoglycemia assessment, mixed lymphocyte reaction (MLR), graft and organ histology, and intraperitoneal glucose tolerance test (IPGTT)

Technology readiness level

The nanotherapy has demonstrated proof of concept in peer-reviewed murine studies, with published data in Nature Nanotechnology confirming mechanism, efficacy, and safety in clinically relevant islet transplant models. The current proposal advances the technology to a large-animal (canine) validation stage, which is a critical step toward clinical translation for type 1 diabetes and potentially other transplant and autoimmune applications.