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Here, multicarboxyl dendritic lipopeptides were developed to enhance cisplatin loading via platinum coordination and improve tumor targeting. Structure\u2013activity relationship studies identified DG3 as the optimal lipopeptide, enabling high drug-loading LNPs (hDDLN) with good stability and delivery efficiency. Pt\/hDDLN showed a superior therapeutic index over conventional liposomes in vitro and in vivo. Combining Pt\/hDDLN with the stimulator of interferon genes (STING) agonists synergistically enhanced immunotherapy by promoting cytotoxic T lymphocyte (CTL) infiltration, dendritic cell (DC) maturation, and reducing Regulatory T cell (Treg). Mechanistically, hDDLN activated DCs via the inducible nitric oxide synthase-cyclic guanosine monophosphate-phosphorylated myosin light chain (iNOS-cGMP-pMLC) pathway, boosting pro-inflammatory responses. This coordination-driven strategy advances LNP-based cisplatin delivery for chemo-immunotherapy of malignancies.<\/jats:p>","DOI":"10.1021\/acsami.6c09272","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:51:29Z","timestamp":1784011889000},"page":"39771-39784","source":"Crossref","is-referenced-by-count":0,"title":["Immunoregulatory\nDendritic Lipopeptide Nanoparticles\nfor High-Capacity Cisplatin Delivery and Pancreatic Cancer Chemo-Immunotherapy"],"prefix":"10.1021","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7671-2395","authenticated-orcid":true,"given":"Xiuli","family":"Zheng","sequence":"first","affiliation":[{"name":"Sichuan University , , ,","place":["Chengdu, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulei","family":"Wang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 24 Tong Jia Xiang , ,","place":["Nanjing, China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyi","family":"Feng","sequence":"additional","affiliation":[{"name":"Sichuan University , , ,","place":["Chengdu, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3831-9044","authenticated-orcid":true,"given":"Lei","family":"Jiang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , 24 Tong Jia Xiang , ,","place":["Nanjing, China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"2026072908062885500_cit1","doi-asserted-by":"publisher","first-page":"115323","DOI":"10.1016\/j.bcp.2022.115323","article-title":"Cisplatin\nin cancer treatment","volume":"206","author":"Romani","year":"2022","journal-title":"Biochem. 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