{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:21:07Z","timestamp":1787242867485,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:00:00Z","timestamp":1760832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-74-30011"],"award-info":[{"award-number":["19-74-30011"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ICBFM SB RAS","award":["125012300659-6"],"award-info":[{"award-number":["125012300659-6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Therapeutics involving small interfering RNA (siRNA) have enormous potential for treating a number of diseases, but their effective delivery to target cells remains a major challenge. We studied the influence of the structure and combination of targeted (folate conjugated, F13) and shield lipoconjugates (P1500, diP1500) on the ability of cationic liposomal formulations based on the 2X3-DOPE system to deliver siRNA into cells in vitro and in vivo. The loop-structured PEG lipoconjugate equipped with two hydrophobic anchor groups (diP1500) demonstrated superior performance across multiple evaluation criteria. The F13\/diP1500 composition maintained a compact particle size (126.0 \u00b1 23.0 nm), while F13\/P1500 with the same PEG chain equipped with one anchor group maintained an increased particle size of 241.8 \u00b1 65.7 nm. Most critically, F13\/diP1500 preserved substantial positive surface charges (21.6\u201330.5 mV) across all N\/P ratios, demonstrating superior ability in avoid the \u201cPEG dilemma\u201d, whereas F13\/P1500 suffered substantial charge neutralization (3.9\u20139.1 mV). Competitive inhibition with free folate confirmed receptor-mediated cellular accumulation of siRNA mediated by F13 containing liposomal compositions. In vivo biodistribution revealed statistically significant circulation advantages: DSPE-PEG2000\/diP1500 achieved the highest plasma concentration at 15 min (1.84 \u00b1 0.01 pmol\/mL), representing the first direct in vivo comparison of compositions with PEG lipoconjugates of the same length, but formed different structures in the liposomes due to the presence of one or two anchor groups. Our findings provide critical insights for the rational design of targeted liposomal delivery systems, highlighting the importance of balanced optimization between folate targeting functionality and PEG shielding for effective siRNA delivery both in vitro and in vivo.<\/jats:p>","DOI":"10.3390\/molecules30204127","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:44:10Z","timestamp":1760957050000},"page":"4127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Loop-Structured PEG-Lipoconjugate Enhances siRNA Delivery Mediated by Liner-PEG Containing Liposomes"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3736-0803","authenticated-orcid":false,"given":"Daniil V.","family":"Gladkikh","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3727-4905","authenticated-orcid":false,"given":"Elena V.","family":"Shmendel","sequence":"additional","affiliation":[{"name":"Lomonosov Institute of Fine Chemical Technologies, MIREA\u2014Russian Technological University, Vernadsky Ave. 86, 119571 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darya M.","family":"Makarova","sequence":"additional","affiliation":[{"name":"Lomonosov Institute of Fine Chemical Technologies, MIREA\u2014Russian Technological University, Vernadsky Ave. 86, 119571 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5372-1325","authenticated-orcid":false,"given":"Mikhail A.","family":"Maslov","sequence":"additional","affiliation":[{"name":"Lomonosov Institute of Fine Chemical Technologies, MIREA\u2014Russian Technological University, Vernadsky Ave. 86, 119571 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4044-1049","authenticated-orcid":false,"given":"Marina A.","family":"Zenkova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-005X","authenticated-orcid":false,"given":"Elena L.","family":"Chernolovskaya","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1124\/jpet.122.001234","article-title":"RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies","volume":"384","author":"Traber","year":"2023","journal-title":"J. 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