Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are efficiently transported across the intestinal epithelium using both in vitro and in vivo models. In mice, orally administered FcRn-targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13.7%*hour compared with only 1.2%*hour for nontargeted nanoparticles. In addition, targeted nanoparticles containing insulin as a model nanoparticle-based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating that the enhanced nanoparticle transport was specifically due to FcRn. FcRn-targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration.Prostate Cancer Foundation (Award in Nanotherapeutics)National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence U54-CA151884)National Heart, Lung, and Blood Institute (Program of Excellence in Nanotechnology Award Contract HHSN268201000045C)National Institutes of Health (U.S.) (Grant EB000244)National Institutes of Health (U.S.) (R01 Grant EB015419-01)American Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipNational Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Graduate Research Fellowship 5 U54 CA151884-02
