{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T15:26:00Z","timestamp":1787153160200,"version":"build-2736575974"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"32","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100031910","name":"Changping Laboratory","doi-asserted-by":"publisher","award":["(B2302)2026C-07-01"],"award-info":[{"award-number":["(B2302)2026C-07-01"]}],"id":[{"id":"10.13039\/100031910","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002338","name":"Ministry of Education of the People's Republic of China","doi-asserted-by":"publisher","award":["JYB2025XDXM501"],"award-info":[{"award-number":["JYB2025XDXM501"]}],"id":[{"id":"10.13039\/501100002338","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People's Republic of China","doi-asserted-by":"publisher","award":["2021YFA1601400"],"award-info":[{"award-number":["2021YFA1601400"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22225603"],"award-info":[{"award-number":["22225603"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22406007"],"award-info":[{"award-number":["22406007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22441051"],"award-info":[{"award-number":["22441051"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"New Cornerstone Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lipid nanoparticle (LNP)-mediated mRNA delivery has emerged as a powerful therapeutic modality, yet its clinical translation in oncology remains constrained by inherent hepatic tropism and inefficient endosomal escape. These limitations necessitate high-dose administration, which triggers lipid-associated toxicity and off-target protein expression in the liver. To overcome these barriers, we report a cleavable silyl-ether-based bioorthogonally activatable LNP platform, termed SiLNP, that enables tumor-specific activation and cytosolic mRNA release. We engineered ionizable lipids incorporating silyl ether structural fuses that respond to a phenylalanine trifluoroborate (Phe-BF3) trigger. This system leverages the upregulated transporter LAT-1 to actively import Phe-BF3 into tumor cells, where it triggers lipid desilylation and rapid cargo release. In vitro, SiLNPs demonstrated controllable external control over mRNA expression, achieving a 44-fold enhancement in mRNA expression compared to standard SM-102 LNPs with a 10-fold activation-to-silent ratio. In immunologically \u201ccold\u201d B16\u2013F10 melanoma models, SiLNPs encoding the N-terminal domain of gasdermin D (GDNT) induced tumor-specific pyroptosis, resulting in tumor growth inhibition without detectable systemic toxicity. Furthermore, this platform demonstrated versatility by delivering immunomodulatory mRNAs, including IL-2 and Cxcl9. Taken together, this work presents a metabolically targeted, bioorthogonal-activated delivery strategy to address the selectivity and efficiency limitations of current mRNA medicines, providing a promising platform for precision oncology.<\/jats:p>","DOI":"10.1021\/jacs.6c09548","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:02:26Z","timestamp":1785902546000},"page":"34639-34654","source":"Crossref","is-referenced-by-count":0,"title":["A Bioorthogonal Desilylation\nSystem Potentiates mRNA\nTherapeutics in Tumors"],"prefix":"10.1021","volume":"148","author":[{"given":"Mingzhe","family":"Zhang","sequence":"first","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Xu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexuan","family":"Ding","sequence":"additional","affiliation":[{"name":"Changping Laboratory , ,","place":["Beijing, China, 102206"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Guo","sequence":"additional","affiliation":[{"name":"Changping Laboratory , ,","place":["Beijing, China, 102206"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5587-4165","authenticated-orcid":true,"given":"Zhibo","family":"Liu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Changping Laboratory , ,","place":["Beijing, China, 102206"]},{"name":"Peking University Cancer Hospital and Institute , , ,","place":["Beijing, China, 100142"]},{"name":"Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies , ,","place":["Chengdu, China, 610213"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"11","key":"2026081910244435000_cit1","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1038\/s41587-022-01491-z","article-title":"Unlocking\nthe promise of mRNA therapeutics","volume":"40","author":"Rohner","year":"2022","journal-title":"Nat. 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Oncol."},{"issue":"52","key":"2026081910244435000_cit5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109256118","article-title":"On the mechanism of tissue-specific\nmRNA delivery by selective organ targeting nanoparticles","volume":"118","author":"Dilliard","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"21","key":"2026081910244435000_cit6","doi-asserted-by":"publisher","first-page":"9184","DOI":"10.1021\/jacs.2c02277","article-title":"Chemical and Biophysical\nSignatures of the Protein Corona in Nanomedicine","volume":"144","author":"Ren","year":"2022","journal-title":"J. Am. Chem. Soc."},{"issue":"7","key":"2026081910244435000_cit7","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/nbt.2612","article-title":"Image-based\nanalysis of lipid nanoparticle-mediated siRNA delivery, intracellular\ntrafficking and endosomal escape","volume":"31","author":"Gilleron","year":"2013","journal-title":"Nat. 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Chem."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c09548","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34639\/66395732\/jacs.6c09548.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34639\/66395732\/jacs.6c09548.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:41:37Z","timestamp":1787150497000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/32\/34639\/5243807\/A-Bioorthogonal-Desilylation-System-Potentiates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":43,"journal-issue":{"issue":"32","published-online":{"date-parts":[[2026,8,4]]},"published-print":{"date-parts":[[2026,8,19]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c09548","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}