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Here, we establish a sequential pretargeting strategy exploiting the high\u2010affinity host\u2013guest recognition between adamantane (ADA) and cucurbit[7]uril (CB[7]) to enhance tumor enrichment. Preadministered ADA\u2010conjugated anti\u2010PD\u2010L1 antibody (ADA\u2010\u03b1PD\u2010L1) primes tumors for efficient capture of subsequently infused CB[7]\u2010functionalized LNPs (CN\u2010LNPs), improving intratumoral retention and cellular uptake. To concurrently address the immunosuppressive tumor microenvironment, NLG919 is covalently incorporated into the ionizable lipid of CN\u2010LNPs to inhibit IDO\u2010mediated tryptophan catabolism, effectively attenuating regulatory T cell activity while preserving the pretargeting functionality of the nanocarrier. CN\u2010LNPs are employed as a delivery platform to encapsulate a circular RNA encoding IL\u20102\u2010Fc fusion protein (CN\u2010LNPs@cRNA\n                    <jats:sup>IL\u20102F<\/jats:sup>\n                    ), enabling intratumoral cytokine production to potentiate antitumor immunity. CN\u2010LNPs@cRNA\n                    <jats:sup>IL\u20102F<\/jats:sup>\n                    elicit robust antitumor immunity to suppress tumor growth and extend survival, establishing a versatile platform that overcomes the intratumoral delivery limitations commonly associated with conventional LNPs system.\n                  <\/jats:p>","DOI":"10.1002\/anie.9573178","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:00:08Z","timestamp":1791356408000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Supramolecular Pretargeting Lipid Nanoparticles Based on Host\u2013Guest Recognition Potentiate Cancer Immunotherapy by Reprogramming Tumor Microenvironment"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8597-3855","authenticated-orcid":false,"given":"Jinqun","family":"Gan","sequence":"first","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Department of Chemistry Tsinghua University  Beijing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Department of Chemistry Tsinghua University  Beijing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Department of Chemistry Tsinghua University  Beijing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6858-0142","authenticated-orcid":false,"given":"Shizhen","family":"Cui","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Standardization and Measurement for Nanotechnology National Center for Nanoscience and Technology  Beijing P.R. 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