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In the present study, a series of liposomal formulations incorporating a novel lipidated TLR7\/8 agonist, INI-4001, were prepared to evaluate the effect of surface charge and lipid composition on the colloidal stability, cytotoxicity, innate immune activation, and adjuvant activity when combined with the recombinant Influenza A\/Shanghai\/1\/13 (H7N9) Virus Hemagglutinin antigen (H7). The tested formulations include neutral (DOPC\/Cholesterol), anionic (DOPG\/Cholesterol), and cationic (DOPC\/DC-Cholesterol, DOPC\/GL67, DOEPC\/Cholesterol, DOTAP\/Cholesterol, or DOTAP\u2009+\u2009DDAB\/Cholesterol) liposomes. These studies demonstrated that alongside the type and magnitude of particle surface charge, lipid composition was a determining factor in the regulation of immunogenicity and biocompatibility of INI-4001-loaded liposomes. Among the cationic liposomes evaluated, DOPC\/DC-Cholesterol liposomes exhibited the lowest in vitro cytotoxicity while enhancing TNF-\u03b1 induction from human peripheral blood mononuclear cells. Furthermore, murine immunization studies demonstrated that the same formulation enhanced H7-specific IgG titers and induced a Th1-polarized cell-mediated response compared to H7 antigen alone or the matched liposome lacking INI-4001. Of note, the anionic DOPG\/Cholesterol INI-4001 liposomes induced a rapid response with significantly higher IgG titers after a single immunization and promoted strong Th1-polarized cellular responses, which may be advantageous in an influenza pandemic setting. These findings highlight the key role of liposome characteristics in optimizing the safety and immunogenicity of TLR7\/8 agonist-adjuvanted subunit influenza vaccines.<\/jats:p>","DOI":"10.1007\/s13346-025-01917-6","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T19:57:27Z","timestamp":1752523047000},"page":"661-674","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Encapsulation of the lipidated TLR7\/8 agonist INI-4001 into ionic liposomes impacts H7 influenza antigen-specific immune responses"],"prefix":"10.1007","volume":"16","author":[{"given":"Fatemeh","family":"Mehradnia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardik","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Ferrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Partlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Borgogna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soma Shekar","family":"Dachavaram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendal","family":"T. 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Mice were housed in an AALAC accredited facility, and all procedures were performed in accordance with the UM IACUC approved animal use protocol (protocol code 015-19JEDBS, approved 9 April 2019). Human peripheral blood mononuclear cells were obtained from healthy adult donors through a University of Montana IRB-approved blood donor protocol (protocol code IRB# 43\u2009\u2212\u200916, approved 15 February 2023).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"David Burkhart, H\u00e9l\u00e8ne Bazin, Kendal T. Ryter, and Jay Evans are employees of and\/or shareholders of Inimmune Corp., which holds an exclusive license for INI-4001. David Burkhart, H\u00e9l\u00e8ne Bazin, Kendal T. Ryter, and Jay Evans are co-inventors of INI-4001.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}