Epsilon-caprolactone-modified polyethylenimine as a genetic vehicle for stem cell-based bispecific antibody and exosome synergistic therapy.

Bispecific antibodies (BsAb) have gained significant momentum in clinical application. However, the rapid enzymolysis and metabolism of protein drugs usually induce short circulation in vivo, and developing an efficient protein delivery system still is a bottleneck. Mesenchymal stem cells (MSCs) have become an attractive therapeutic carrier for cancers. Genetic modification enables MSCs to express and secrete specific proteins, which is essential for therapeutic efficacy. However, efficient gene transfer into MSCs is still a challenge. In this study, we applied epsilon-caprolactone-modified polyethylenimine (PEI-CL) as an efficacy carrier for plasmid transfection into MSC that served as in situ 'cell factory' for anti-CD3/CD20 BsAb preparation. Herein, the PEI-CL encapsulates the minicircle plasmid and mediates cell transfection efficiently. Thus, the anti-CD3/CD20 BsAb is secreted from MSC and recruited T cell, resulting in highly sensitive cytotoxicity in the human B-cell lymphoma. Furthermore, these stem cells produce exosomes bearing MiR-15a/MiR-16, which could negatively regulate cancer's oncogenes BCL-2 for adjuvant therapy. Meanwhile, high immunologic factors like tumor necrosis factor-α and interferon-γ are generated and enhance immunotherapy efficacy. The engineered MSCs are demonstrated as an efficient route for BsAb production, and these bioactive components contribute to synergistic therapy, which would be an innovative treatment.