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While cancer cell\u2010intrinsic CD28 facilitates immune escape by functioning as a non\u2010classical RNA\u2010binding protein to stabilize\n                    <jats:italic>CD274<\/jats:italic>\n                    (PD\u2010L1) mRNA, inhibiting this pathway in cancer cells without impairing essential T cell CD28 costimulation remains a major structural challenge. Here, we report the development of a 16:0 LPC\u2010modified SM102\u2010based lipid nanoparticle (LPC\u2010LNP) that exploits altered tumor lipid metabolism for highly selective cancer cell transfection. By leveraging elevated lysophosphatidylcholine acyltransferase (LPCAT) uptake mechanisms inherent to malignant cells, LPC\u2010LNPs efficiently deliver\n                    <jats:italic>Cd28<\/jats:italic>\n                    small interfering RNA directly to tumor cells while strictly avoiding T cell sequestration. In vivo administration of LPC\u2010LNP\u2010Cd28 successfully knocked down 80% of cancer cell CD28, substantially reduced PD\u2010L1 expression, and circumvented the off\u2010target immunosuppression observed with commercial lipid formulations. Consequently, targeted\n                    <jats:italic>Cd28<\/jats:italic>\n                    silencing reshapes the immunosuppressive tumor microenvironment, augmenting twofold CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and dendritic cell activation to extend survival in murine breast and lung cancer models to 1.3\u20131.5 folds. Furthermore, the combined use of LPC\u2010LNP\u2010Cd28 effectively eradicates resistance to anti\u2010PD\u20101 therapy. This study provides a highly translatable, cancer\u2010specific nanomedicine platform, confirming that selectively antagonizing tumor\u2010intrinsic CD28 holds profound promise for advanced cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.76003","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T10:17:00Z","timestamp":1781000220000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Specific Delivery of CD28 siRNA via Lyso\u2010PC C\u201016 Modified Lipid Nanoparticles Overcomes Anti\u2010PD\u20101 Resistance by Remodeling Tumor Microenvironment"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8075-3106","authenticated-orcid":false,"given":"Yangyang","family":"Chai","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology Institute of Immunology College of Life Sciences Nankai University  Tianjin P. 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