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Here, we engineer a dynamic, injectable hydrogel depot technology for months-long delivery of lipidated peptides. Using semaglutide as a model, we establish a modular formulation framework integrating: (i) formulation-driven tuning of depot mechanics to control release kinetics, (ii) cargo complexation strategies leveraging hydrophobic and multivalent ion-mediated interactions, and (iii) oxidative stabilization through sacrificial antioxidant excipients. We evaluated depot performance by rheology, in vitro cargo release, and in vivo pharmacokinetic and pharmacodynamic studies in rodents. Optimized formulations sustained semaglutide exposure for over six weeks from a single administration with two-fold reduction in peak-to-trough exposure and comparable total bioavailability relative to daily dosing, resulting in improved glucose control, weight regulation, and preservation of pancreatic islet content. These results suggest potential for quarterly dosing in humans. Together, this work establishes integrated and generalizable structure-property-performance relationships that account for cargo\u2013matrix and cargo\u2013excipient interactions across burst, diffusion, and erosion regimes to inform a practical formulation framework for engineering long-acting depots for sustained peptide delivery.<\/jats:p>","DOI":"10.64898\/2026.05.17.725768","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T03:55:24Z","timestamp":1779162924000},"source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Property\u2013Performance Engineering of Hydrogel Depots for Long-Acting Peptide Delivery"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9214-747X","authenticated-orcid":false,"given":"Changxin","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Materials Science & Engineering, Stanford University, Stanford, CA 94305, 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