Intestinal Probiotic Lysate Modified Bifunctional Nanoparticle for Efficient Colon Cancer Immunotherapy

Background: In cancer immunotherapy, gene therapy has become a promising strategy through the introduction of immunostimulatory components into its formulation. However, ideal non-viral gene delivery platforms capable of simultaneously maintaining a high delivery efficiency and immune activation are still in demand. As an intestinal probiotic, Lactobacillus reuteri has potential correlation with cancer progression. Its unique antigenicity also confers its immunomodulatory activity. Method: We engineered a new non-viral siRNA delivery system, DMPLAC. By wrapping the lysate of Lactobacillus reuteri, it is expected to enhance the anti-cancer immunostimulatory properties. Result: Supported by certain internalization pathways, the prepared DMPLAC nanoparticles showed high siRNA delivery efficiency in vitro (up to 97.62%). They also strongly promoted the maturation and activation of immune cells, including dendritic and T cells, both in vitro and in vivo. By loading siRNA targeting the immune checkpoint CD47 gene, the DMPLAC/siCD47 complex strongly suppressed the growth of multiple colon cancer models through local administration with high safety. Conclusions: Our study developed a novel intestinal probiotic lysate-based gene delivery system with dual immunomodulatory abilities, suggesting a potential strategy for cancer immunotherapy.