{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T20:55:07Z","timestamp":1781816107832,"version":"3.54.5"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Peptide Science"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Extrahepatic delivery of small interfering RNA (siRNA) remains a major translational challenge because most nanocarriers preferentially accumulate in the liver, while endosomal sequestration limits productive cytosolic release. Inflammatory macrophages in the spleen are attractive therapeutic targets in systemic inflammation, yet spleen\u2010selective delivery systems with efficient endosomal escape remain underdeveloped. Here, a structure\u2010guided peptide engineering workflow was used to generate histidine\u2010rich, pH\u2010switchable endosomolytic peptides for spleen\u2010selective siRNA delivery. Sequence design integrated pH\u2010dependent charge transition modeling, amphipathic helix prediction, membrane interaction scoring, and safety filtering. Six candidate peptides were synthesized and evaluated for pH\u2010responsive structure, membrane disruption, hemocompatibility, siRNA complexation, serum stability, macrophage uptake, endosomal escape, biodistribution, and anti\u2010inflammatory efficacy. The lead peptide, HSEP\u20106, showed a predicted net charge increase from +3.1 at pH\u20097.4 to +7.4 at pH\u20095.5, helix content increasing from 17% to 56%, and acidic calcein release increasing from 9% to 62%. In inflammatory macrophages and LPS\u2010challenged mice, HSEP\u20106 enabled efficient siRNA delivery, spleen\u2010selective accumulation, marked Irf5 silencing, reduced TNF\u2010\u03b1 and IL\u20106, and no measurable systemic toxicity, supporting histidine\u2010rich pH\u2010switchable peptides as a rational platform for extrahepatic RNA delivery.<\/jats:p>","DOI":"10.1002\/psc.70105","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T04:46:42Z","timestamp":1780116402000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2010Guided Engineering of Histidine\u2010Rich pH\u2010Switchable Endosomolytic Peptides for Spleen\u2010Selective siRNA Delivery to Inflammatory Macrophages"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2176-9420","authenticated-orcid":false,"given":"Dilpreet","family":"Singh","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences CT University  Sidhwan Khurd Punjab India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202304692"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2008.01.031"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109\u2010006\u20100119\u20104"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201010148\u20101"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2021.121308"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/c4nr06556e"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306318120"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.02.005"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psc.2955"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.12.004"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010010\u20100138\u20102"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0169\u2010409x(01)00221\u20106"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevE.106.034408"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2021.645297"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn392"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1385\/1-59259-890-0:571"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/c8nr07701c"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1039\/d4bm01433b"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.3c01198"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.202300366"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2020.110804"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202504363"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2025.102803"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c13982"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202500878"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/d4bm00038b"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13346\u2010016\u20100304\u20100"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2024.122859"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2409569122"},{"key":"e_1_2_11_31_1","unstructured":"Thermo Fisher Scientific \u201cInvivofectamine 3.0 Reagent User Guide and Product Information for In\u00a0Vivo siRNA\/miRNA Delivery; Catalog Numbers IVF3001 and IVF3005 \u201d Waltham MA: Thermo Fisher Scientific; accessed 2026."},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010025\u201003681\u20108"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00713a027"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.202"}],"container-title":["Journal of Peptide Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psc.70105","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psc.70105","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psc.70105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T20:10:40Z","timestamp":1781813440000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/psc.70105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/psc.70105"],"URL":"https:\/\/doi.org\/10.1002\/psc.70105","archive":["Portico"],"relation":{},"ISSN":["1075-2617","1099-1387"],"issn-type":[{"value":"1075-2617","type":"print"},{"value":"1099-1387","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"assertion":[{"value":"2026-03-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70105"}}