{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:57:13Z","timestamp":1764831433886,"version":"3.46.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270096","82470080"],"award-info":[{"award-number":["82270096","82470080"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Program of Natural Science Foundation of Tianjin Municipal Science and Technology Commission","award":["24JCZDJC00650"],"award-info":[{"award-number":["24JCZDJC00650"]}]},{"name":"Tianjin Municipal Education Commission Key Natural Science Project","award":["2023ZD012"],"award-info":[{"award-number":["2023ZD012"]}]},{"DOI":"10.13039\/501100011342","name":"State Key laboratory of Experimental Hematology","doi-asserted-by":"crossref","award":["24ZXZSSS00030","8QZ001010017"],"award-info":[{"award-number":["24ZXZSSS00030","8QZ001010017"]}],"id":[{"id":"10.13039\/501100011342","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>The overactivation of endosomal Toll-like receptor (TLR) in macrophages plays an important role in the pathogenesis of acute lung injury (ALI). There is currently still a lack of nano-formulated and macrophage-targeted endosomal TLR inhibitors that have been approved for clinical uses. We previously discovered that the elevation of endosomal pH using nanodevices provides a promising strategy to specifically inhibit endosomal TLRs in macrophages. The weakly basic drug hydroxychloroquine (HCQ) has been reported for its capability to accumulate in endolysosomes and modulate the acidity in these compartments. To enhance its macrophage-targeting ability and the therapeutic efficacy in vivo, herein we formulated HCQ into a nanoform using liposomes, named HCQ-L. We found that HCQ-L was less cytotoxic and more effective in inhibiting endosomal TLRs (including TLR3, TLR4, TLR 7\/8) than the molecular HCQ. Subsequently, a hexapeptide, Pep12, was inserted onto the surface of HCQ-L to form HCQ-L-P12. Interestingly, Pep12 modification significantly improved the stability of liposomes in aqueous solution for at least 2 years; while having enhanced inhibitory effects on TLR7\/8 signaling, HCQ-L-P12 displayed similar effects on inhibiting the TLR4 pathway and down-stream pro-inflammatory cytokine production when compared with HCQ-L. Furthermore, both HCQ nanoformulations potently elevated the endosomal pH. In vivo evaluation showed that HCQ-L-P12 and HCQ-L (but not molecular HCQ) were able to alleviate lung inflammation and injuries by decreasing inflammatory cell infiltration upon intratracheal instillation in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. This research provides a new strategy to fabricate lipid-based nanocarriers for targeted delivery of endosomal pH modulators to treat ALI and other acute and chronic inflammatory disorders.<\/jats:p>","DOI":"10.3390\/jfb16120450","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:47:37Z","timestamp":1764780457000},"page":"450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hexapeptide-Liposome Nanosystem for the Delivery of Endosomal pH Modulator to Treat Acute Lung Injury"],"prefix":"10.3390","volume":"16","author":[{"given":"Yuting","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rujing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mimi","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liya","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiameng","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiqiang","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4547-8740","authenticated-orcid":false,"given":"Shan-Yu","family":"Fung","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6707-8481","authenticated-orcid":false,"given":"Hong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1056\/NEJMra1608077","article-title":"Acute respiratory distress syndrome","volume":"377","author":"Thompson","year":"2017","journal-title":"N. 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