A modular approach toward producing nanotherapeutics targeting the innate immune system

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein Al -based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.

Automated summary

Immunotherapies focusing on the adaptive immune system have been extensively studied, while research on regulating the innate immune system is still limited. Nanoparticles show promise in engaging the innate immune system through interactions with phagocytic myeloid cells. A modular approach was used to efficiently incorporate various drugs into a nanobiologic platform, leading to prolonged allograft survival in a mouse model through the use of rapamycin-loaded nanobiologics. Additionally, biodistribution and safety of the nanobiologics were evaluated in nonhuman primates, supporting the potential clinical translation of this approach.