Tumor‐Specific Delivery of CD28 siRNA via Lyso‐PC C‐16 Modified Lipid Nanoparticles Overcomes Anti‐PD‐1 Resistance by Remodeling Tumor Microenvironment

ABSTRACT Uncovering novel targets that synergize with immune checkpoint blockade (ICB) is an urgent clinical priority. While cancer cell‐intrinsic CD28 facilitates immune escape by functioning as a non‐classical RNA‐binding protein to stabilize CD274 (PD‐L1) 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‐modified SM102‐based lipid nanoparticle (LPC‐LNP) 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‐LNPs efficiently deliver Cd28 small interfering RNA directly to tumor cells while strictly avoiding T cell sequestration. In vivo administration of LPC‐LNP‐Cd28 successfully knocked down 80% of cancer cell CD28, substantially reduced PD‐L1 expression, and circumvented the off‐target immunosuppression observed with commercial lipid formulations. Consequently, targeted Cd28 silencing reshapes the immunosuppressive tumor microenvironment, augmenting twofold CD8 + T cell infiltration and dendritic cell activation to extend survival in murine breast and lung cancer models to 1.3–1.5 folds. Furthermore, the combined use of LPC‐LNP‐Cd28 effectively eradicates resistance to anti‐PD‐1 therapy. This study provides a highly translatable, cancer‐specific nanomedicine platform, confirming that selectively antagonizing tumor‐intrinsic CD28 holds profound promise for advanced cancer immunotherapy.