{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:30:50Z","timestamp":1786595450333,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"crossref","award":["I125102626741-1"],"award-info":[{"award-number":["I125102626741-1"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"crossref"}]},{"award":["I125102626741-1"],"award-info":[{"award-number":["I125102626741-1"]}],"id":[{"id":"https:\/\/ror.org\/01p8ehb87","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Despite extensive development of liposomal antibiotics, the structural determinants governing their stability, release, and biological activity remain poorly understood. This study investigated how the cholesterol content and drug-to-lipid ratio affect membrane organization and thereby determine the physicochemical and biological properties of linezolid-loaded liposomes. Methods: Nine liposomal formulations, varying in their cholesterol content (10\u201330 wt%) and drug-to-lipid ratios (1\u20135%), were prepared by thin-film hydration. Membrane organization was analyzed by ATR-FTIR spectroscopy and principal component analysis. Liposomes were further characterized by particle size, \u03b6-potential, encapsulation efficiency, storage stability, in vitro release in phosphate buffer with and without bovine serum albumin, antibacterial activity against B. subtilis, and antimycobacterial activity in an ex vivo PBMC-derived Mycobacterium tuberculosis granuloma model. Results: The cholesterol content and drug-to-lipid ratio markedly altered membrane interfacial organization, particularly the hydration of the carbonyl and phosphate regions. These structural changes correlated with differences in storage stability, protein-responsive release, and antibacterial activity. Functional behavior was non-monotonic, as 30-L showed the highest overall storage stability, while the apparent release depended jointly on the cholesterol content, drug loading, and medium. BSA altered the composition-dependent release pattern instead of producing a uniform effect. In the exploratory granuloma model, the formulations 10-S, 10-L, and 30-M reduced M. tuberculosis CFU by &gt;99%, whereas free linezolid produced approximately 60% inhibition. Conclusions: Membrane interfacial organization is a key determinant of the functional performance of liposomal linezolid, establishing a structure\u2013property\u2013function relationship that provides a mechanistic basis for the rational design of liposomal antibiotic delivery systems for tuberculosis therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080994","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:30:32Z","timestamp":1786465832000},"page":"994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Membrane Interfacial Organization Determines the Functional Performance of Liposomal Linezolid"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4769-5933","authenticated-orcid":false,"given":"Vadim","family":"Avdeev","sequence":"first","affiliation":[{"name":"Federal State Institution National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127473, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya","family":"Kolmogorov","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Tyulkova","sequence":"additional","affiliation":[{"name":"Federal State Institution National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127473, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Mozhokina","sequence":"additional","affiliation":[{"name":"Federal State Institution National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127473, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Samoilova","sequence":"additional","affiliation":[{"name":"Federal State Institution National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127473, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Gaida","sequence":"additional","affiliation":[{"name":"Federal State Institution National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127473, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0201-5495","authenticated-orcid":false,"given":"Anna","family":"Skuredina","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Belogurova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9357-8236","authenticated-orcid":false,"given":"Natalia","family":"Klyachko","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2264-4478","authenticated-orcid":false,"given":"Alexey","family":"Doroshenko","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-4491","authenticated-orcid":false,"given":"Irina","family":"Le-Deygen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vasilieva","sequence":"additional","affiliation":[{"name":"Federal State Institution National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127473, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","first-page":"100295","article-title":"Impacts of MDR\/XDR-TB on the global tuberculosis epidemic: Challenges and opportunities","volume":"7","author":"Chin","year":"2024","journal-title":"Curr. 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