{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:32:17Z","timestamp":1793212337119,"version":"4.5.0"},"reference-count":125,"publisher":"The Royal Society","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013405","name":"RVO","doi-asserted-by":"publisher","award":["61388963"],"award-info":[{"award-number":["61388963"]}],"id":[{"id":"10.13039\/100013405","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004240","name":"Czech Academy of Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Insulin is a central regulator of metabolic homoeostasis with diverse, tissue-specific actions across multiple organs. Despite major advances in insulin formulations, current therapies rely on systemic delivery and do not reproduce the physiological distribution of endogenous insulin, resulting in non-physiological tissue exposure and associated metabolic limitations. In this perspective, we discuss emerging strategies aimed at achieving tissue-selective insulin action, including molecular engineering of insulin analogues, modulation of insulin receptor isoform specificity and targeted delivery approaches. Attention is given to hepato-preferential, muscle-directed, brain-targeted and adipose-modulating strategies, highlighting their mechanistic basis, therapeutic potential and inherent limitations. While proof of principle has been established for several approaches, challenges remain in balancing tissue selectivity with whole-body metabolic control. Advances in protein design and delivery technologies may ultimately enable the development of next-generation insulin therapies that better mimic physiological insulin action and improve clinical outcomes in metabolic and neurodegenerative diseases.<\/jats:p>","DOI":"10.1098\/rsob.260175","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:07:13Z","timestamp":1791936433000},"source":"Crossref","is-referenced-by-count":0,"title":["Perspectives on tissue-selective insulin derivatives"],"prefix":"10.1098","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3043-0165","authenticated-orcid":false,"given":"Maxmili\u00e1n","family":"Hejl","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences 1 , Prague, Czech Republic"},{"name":"Department of Biochemistry, Faculty of Science, Charles University 2 , Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3848-2773","authenticated-orcid":false,"given":"Ji\u0159\u00ed","family":"Jir\u00e1\u010dek","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences 1 , Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"2026102813363436100_RSOB260175C1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.cell.2020.02.001","article-title":"Targeting strategies for tissue-specific drug delivery","volume":"181","author":"Zhao","year":"2020","journal-title":"Cell"},{"key":"2026102813363436100_RSOB260175C2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nrc2394","article-title":"Paul Ehrlich's magic bullet concept: 100 years of progress","volume":"8","author":"Strebhardt","year":"2008","journal-title":"Nat. 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