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

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.