Lipid nanoparticles with aptamers enable targeted mRNA delivery to CD4⁺ T cells

<i>In vivo</i> genetic engineering of T cells could overcome the logistical, biological, and safety challenges of <i>ex vivo</i> modification, but effective and safe delivery systems remain limited by a lack of cellular specificity. Here, we developed aptamer-functionalized lipid nanoparticles (LNPs) for targeted mRNA delivery to CD4 + T cells, employing both a validated CD4-binding aptamer (Apt62) and novel aptamers generated using our proprietary transformer-based AI language model, AptaBLE. LNPs formulated with ionizable lipid SM102 or MC3 and conjugated with aptamers at controlled densities were physiochemically characterized and assessed for binding, <i>in vitro</i> transfection, <i>in vivo</i> biodistribution, and safety evaluation. Aptamer-functionalized LNPs demonstrated selective nanomolar binding to recombinant CD4, achieved enhanced transfection of CD4⁺ versus CD4^- T cells <i>in vitro</i>, and significantly enriched mRNA delivery to immune-rich tissues <i>in vivo</i>, achieving up to 70-fold spleen signal enhancement with SM102 formulations Compared to non-targeted controls, while maintaining suitable safety profiles. Overall, these findings demonstrate aptamer-functionalized LNPs, augmented by AI-guided aptamer design, as a tunable, non-immunogenic platform for <i>in vivo</i> T-cell engineering.