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Nonetheless, they are predominantly administered parenterally due to poor absorption through the gastrointestinal tract. Additionally, repeated injections of biologics such as insulin cause injection pain, leading to dose\u2010skipping and poor medication adherence. Recently, our group and others have shown that nanoparticle\u2010based drug delivery systems enhance intestinal permeation and oral delivery of biologics such as insulin and exenatide. However, their effectiveness is not on par with chemical permeation enhancers (PEs) including \u00a0fatty acids, lipids, and 1\u2010phenylpiperazine (PPZ), which are toxic at their effective doses. In this work, we report successful PPZ grafting onto silica nanoparticles with no apparent toxicity and significantly increased permeation of macromolecules such as insulin in an in vitro Caco\u20102 monolayer model and a co\u2010culture model. In vivo experiments, with silica\u2010PPZ\u2010based novel PE improves the permeation of FITC\u2010dextran\u20104\u00a0kDa in healthy mice compared to bare silica nanoparticles and macromolecule alone. In a high\u2010fat diet mouse model, the use of silica\u2010PPZ significantly enhances insulin absorption in the intestine. This led to markedly lower and more sustained blood glucose levels compared to controls without any associated toxicity to mice. Overall, we have shown, for the first time, that PPZ\u2010grafted silica nanoparticles can serve as a safe and effective permeation enhancer for the oral administration of insulin and potentially other biologics.<\/jats:p>","DOI":"10.1002\/advs.202520918","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T21:01:08Z","timestamp":1773003668000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Piperazine\u2010Functionalized Nanoparticles Enable Oral Insulin Delivery in Obese Mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuxue","family":"Cao","sequence":"first","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences The University of Queensland  Brisbane QLD Australia"},{"name":"Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences Monash University  Parkville VIC 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