Programmable Modular Peptide Nanocarriers for Targeted siRNA Delivery to Immune Cells

Genetically engineered immune cell therapies have achieved significant progress in treating various diseases. However, efficiently and selectively delivering genetic material to specific immune cells remains a major challenge. In this study, we developed a modular peptide-based system for the targeted delivery of siRNA to immune cells, including macrophages, dendritic cells, and T cells. The system consists of three functional modules: a hydrophilic cell-penetrating peptide module for efficient membrane penetration, an RNA-binding sequence for siRNA encapsulation, and immune cell-targeting motifs for specific recognition. The results show that the rationally designed peptide system achieves 80–90% siRNA delivery efficiency in macrophages and dendritic cells in vitro compared to 15% in T cells when using the unmodified peptide. By modifying the peptide with cell-specific targeting motifs, we enhanced siRNA delivery efficiency in T cells to ∼60%. Furthermore, in a tumor model, our system selectively delivers siRNA to target immune cells, with CRM achieving 41% siRNA delivery to macrophages, significantly higher than that of the baseline peptide. This modular peptide-based approach provides a robust and scalable platform for efficient gene delivery to immune cells, offering the potential for advancing therapeutic applications in immune modulation and related diseases.