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However, advances of oral protein formulation are usually hindered by protein susceptibility and suboptimal absorption in the gastrointestinal tract (GIT). Polymeric nano drug delivery systems are considered revolutionary candidates to solve these issues, which can be preferably tunable against specific delivery challenges. Herein, a tailored family of lysine\u2010based poly(ester amide)s (Lys\u2010aaPEAs) is designed as a general oral protein delivery platform for efficient protein loading and protection from degradation. Insulin, as a model protein, can achieve effective internalization by epithelial cells and efficient transport across the intestinal epithelium layer into the systemic circulation, followed by controlled release in physiological environments. After the oral administration of insulin carried by Lys\u2010aaPEAs with ornamental hyaluronic acid (HA), mice with type 1 diabetes mellitus showed an acceptable hypoglycemic effect with alleviated complications. A successful oral insulin delivery is associated with patient comfort and convenience and simultaneously avoids the risk of hypoglycemia compared with injections, which is of great feasibility for daily diabetes therapy. More importantly, this versatile Lys\u2010aaPEAs polymeric library can be recognized as a universal vehicle for oral biomacromolecule delivery, providing more possibilities for treating various diseases.<\/jats:p>","DOI":"10.1002\/adhm.202300311","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T02:23:15Z","timestamp":1680142995000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Oral Delivery of Protein Drugs via Lysine Polymer\u2010Based Nanoparticle Platforms"],"prefix":"10.1002","volume":"12","author":[{"given":"Shuyan","family":"Han","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering State Key Laboratory of Oncology in South China Sun Yat\u2010sen University  518107 Shenzhen P. R. 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