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While lipid nanoparticles (LNPs) excel with large nucleic acids, they are unsuitable for delivering small, zwitterionic and highly hydrophilic CDNs. Here, we find that the tertiary amine oxide lipid (AOL) promotes stable encapsulation of CDNs into LNP through enhanced hydrogen bonding and electrostatic interactions, resulting in ultra-high encapsulation efficiency of 86.8%. Compared to cationic liposomes, AOL-incorporating LNP exhibits superior tumor penetration and cytosolic cargo delivery, eliciting broad and potent intratumoral STING activation. In line with growing emphasis on combination therapy in oncology, we further incorporate lipidated mitoxantrone in the LNP as an inducer of immunogenic cell death to enhance tumor antigen presentation and STING-driven immunotherapy. The obtained LNP provokes potent immunostimulatory and antitumor effects in multiple challenging animal models, including triple-negative breast cancer, pancreatic cancer and melanoma.<\/jats:p>","DOI":"10.1093\/nsr\/nwag340","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:46:13Z","timestamp":1780659973000},"source":"Crossref","is-referenced-by-count":0,"title":["Amine oxide lipid nanoparticles for delivery of cyclic dinucleotides"],"prefix":"10.1093","volume":"13","author":[{"given":"Yao","family":"Chen","sequence":"first","affiliation":[{"name":"Southern University of Science and Technology Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]},{"name":"Bioscience and Biomedical Engineering Thrust, Hong Kong University of Science and Technology (Guangzhou) , Guangzhou 511458 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Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengbo","family":"Chen","sequence":"additional","affiliation":[{"name":"Southern University of Science and Technology Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2019an","family":"Li","sequence":"additional","affiliation":[{"name":"Southern University of Science and Technology Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saijie","family":"Wang","sequence":"additional","affiliation":[{"name":"Southern University of Science and Technology Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Southern University of Science and Technology Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-3435","authenticated-orcid":false,"given":"Jun","family":"Wu","sequence":"additional","affiliation":[{"name":"Bioscience and Biomedical Engineering Thrust, Hong Kong University of Science and Technology (Guangzhou) , Guangzhou 511458 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5008-4703","authenticated-orcid":false,"given":"Xingyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Southern University of Science and Technology Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, , Shenzhen 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"2026090111421197000_bib1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa1716153","article-title":"Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis","volume":"379","author":"Adams","year":"2018","journal-title":"N Engl J 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