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A stable, injectable glucagon formulation in an aqueous solution could transform treatment, enabling mini-dosing for mild-to-moderate hypoglycemia or continuous infusion in closed-loop systems. Here, we introduce supramolecular poly(trehalose) diblock copolymer nanoparticles via polymerization-induced self-assembly (PISA) to generate distinct nanoparticle morphologies. A cysteine-modified glucagon analogue (Q24C) was conjugated to poly(trehalose methacrylate) coronas via pyridyl disulfide exchange. Glucagon stabilized by vesicles demonstrated enhanced resistance to degradation and fibrillation in aqueous media, maintaining stability for 30 days at 23\u221224 \u00b0C and upon solution heating. Glucagon\u2212vesicle conjugates effectively reversed insulin-induced hypoglycemia in male mice, maintaining glucose-counterregulatory activity after 30 days of storage at 23\u221224 \u00b0C. These findings highlight that polymer-stabilized glucagon nanoformulations overcome longstanding stability barriers while preserving biological activity, offering a robust platform for treating insulin-induced hypoglycemia in type-1 diabetes.<\/jats:p>","DOI":"10.1021\/acs.biomac.6c00988","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:02:13Z","timestamp":1790362933000},"page":"6484-6495","source":"Crossref","is-referenced-by-count":0,"title":["Stabilization of Glucagon by Trehalose Diblock Copolymer Vesicles for Hypoglycemic Counterregulation"],"prefix":"10.1021","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8968-1057","authenticated-orcid":true,"given":"Panagiotis G.","family":"Georgiou","sequence":"first","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]},{"name":"University of California , , 570 Westwood Plaza , , ,","place":["Los Angeles, California, United States, 90095-1569"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-055X","authenticated-orcid":true,"given":"Rajalakshmi P.","family":"Sivasankaran","sequence":"additional","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]},{"name":"University of California , , 570 Westwood Plaza , , ,","place":["Los Angeles, California, United States, 90095-1569"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]},{"name":"University of California , , 570 Westwood Plaza , , ,","place":["Los Angeles, California, United States, 90095-1569"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia-Rose","family":"Kayaian","sequence":"additional","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Cohen","sequence":"additional","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayden R.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Hevener","sequence":"additional","affiliation":[{"name":"David Geffen School of Medicine at UCLA , , 650 Charles E. Young Dr . , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"VA Greater Los Angeles Healthcare System GRECC , , ,","place":["Los Angeles, California, United States, 90073"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3692-6289","authenticated-orcid":true,"given":"Heather D.","family":"Maynard","sequence":"additional","affiliation":[{"name":"University of California , , 607 Charles E. Young Drive East , , ,","place":["Los Angeles, California, United States, 90095-1569"]},{"name":"University of California , , 570 Westwood Plaza , , ,","place":["Los Angeles, California, United States, 90095-1569"]},{"name":"University of California , , 420 Westwood Plaza , , ,","place":["Los Angeles, California, United States, 90095-1600"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"issue":"4","key":"2026101210520019200_cit1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2337\/ds19-0076","article-title":"Glucagon Therapy: A Comparison of Current and Novel Treatments","volume":"33","author":"Sherman","year":"2020","journal-title":"Diabetes Spectrum"},{"issue":"6","key":"2026101210520019200_cit2","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1080\/17446651.2021.1979391","article-title":"Nocturnal Hypoglycemia in Type 1 and Type 2 Diabetes: An Update on Prevalence, Prevention, Pathophysiology and Patient Awareness","volume":"16","author":"Maka Siamashvili","year":"2021","journal-title":"Expert Rev. Endocrinol. Metab."},{"issue":"2","key":"2026101210520019200_cit3","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1152\/physrev.00025.2016","article-title":"The New Biology and Pharmacology of Glucagon","volume":"97","author":"Mu\u0308ller","year":"2017","journal-title":"Physiol. Rev."},{"issue":"4","key":"2026101210520019200_cit4","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1210\/en.2016-1748","article-title":"Insulin and Glucagon: Partners for Life","volume":"158","author":"Holst","year":"2017","journal-title":"Endocrinology"},{"key":"2026101210520019200_cit5","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.peptides.2015.03.011","article-title":"Glucagon \u2212 Early Breakthroughs and Recent Discoveries","volume":"67","author":"Ahre\u0301n","year":"2015","journal-title":"Peptides"},{"key":"2026101210520019200_cit6","doi-asserted-by":"publisher","first-page":"171003","DOI":"10.1016\/j.peptides.2023.171003","article-title":"The Molecular Pharmacology of Glucagon Agonists in Diabetes and Obesity","volume":"165","author":"Novikoff","year":"2023","journal-title":"Peptides (N.Y.)."},{"issue":"9","key":"2026101210520019200_cit7","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.2337\/dbi22-0004","article-title":"The Liver\u2212\u03b1-Cell Axis in Health and in Disease","volume":"71","author":"Richter","year":"2022","journal-title":"Diabetes"},{"issue":"9","key":"2026101210520019200_cit8","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1111\/dom.15693","article-title":"Glucagon Agonism in the Treatment of Metabolic Diseases Including Type 2 Diabetes Mellitus and Obesity","volume":"26","author":"Winther","year":"2024","journal-title":"Diabetes, Obes. 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