{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:49Z","timestamp":1786121389403,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Project of the Natural Science Foundation of Fujian Province","award":["2025J02032"],"award-info":[{"award-number":["2025J02032"]}]},{"DOI":"10.13039\/100007219","name":"Shanghai Municipal Natural Science Foundation","doi-asserted-by":"crossref","award":["23ZR1463300"],"award-info":[{"award-number":["23ZR1463300"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"crossref"}]},{"name":"open fund of the National Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers","award":["2024-KFA-008"],"award-info":[{"award-number":["2024-KFA-008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy and remains a major contributor to global cancer mortality. In situ vaccination (ISV) holds great potential for HCC therapy. Still, its efficacy is severely limited by intrinsic antigen scarcity and the tumor-associated macrophage (TAM)-mediated inhibition of dendritic cell (DC) maturation and T cell activation. In particular, the M2 TAM-HCC cell crosstalk may further aggravate ISV suppression. Moreover, as an internal organ tumor, HCC requires systemic administration of ISV agents, which often cause severe off-target toxicity. Methods: To address these challenges, we developed secretory phospholipase A2 (sPLA2)-responsive liposomes co-loaded with the TLR7\/8 agonist R848 and the ICD inducer doxorubicin (DOX) via a sequential remote loading method, termed sP-Lips@DR. Results: Incorporation of cholesterol (CHOL) significantly improved DOX encapsulation, and the sequential loading method enabled efficient co-encapsulation of both R848 and DOX. sP-Lips@DR responds to an sPLA2-overexpressed, mildly acidic microenvironment in HCC, enabling selective drug release. In addition, sP-Lips@DR exhibited sPLA2-responsive cytotoxicity toward H22 cells and macrophage phenotypic shift. Furthermore, sP-Lips@DR could disrupt the crosstalk between M2-like macrophages and H22 cells in an sPLA2-responsive manner. Conclusions: Overall, the preparation and in vitro evaluation of sP-Lips@DR demonstrate their potential to enhance ISV efficacy in HCC, providing a solid foundation for future in vivo investigations.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080964","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T16:48:08Z","timestamp":1785948488000},"page":"964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Drug-Loaded Enzyme-Responsive Liposomes Exert Specific Modulation on Liver Cancer Cells and Tumor-Associated Macrophages In Vitro"],"prefix":"10.3390","volume":"18","author":[{"given":"Shudong","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchen","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5614-1041","authenticated-orcid":false,"given":"Yan","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"MedEng-X Institutes, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","article-title":"Hepatocellular Carcinoma: Signaling Pathways and Therapeutic Advances","volume":"10","author":"Zheng","year":"2025","journal-title":"Signal Transduct. 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