Effective intracellular delivery of biologic drugs, such as peptide- and protein-based therapeutics, remains a major challenge because the plasma membrane restricts their cellular uptake. Consequently, most biologics in clinical use act on extracellular targets, despite the growing number of peptides and proteins developed against intracellular molecules with high therapeutic potential. Many key pathways in cancer biology are intracellular, and enabling biologic access to these sites could substantially expand treatment options.
Pathogenic bacteria face the same barrier when delivering toxins into host cells and have evolved specialized mechanisms to overcome it. Our research focuses on bacterial virulence factors, particularly the autotransporter (AT) family of proteins, some of which display intrinsic cell-penetrating activity [1]. In response to the increasing demand for efficient intracellular delivery systems, we are repurposing these naturally evolved bacterial nanomachines for the transport of biologic drugs. Using this approach, we have demonstrated that ATs can deliver both large proteins and small peptides into human cells. Using a cancer model, we also demonstrate that the delivered peptides retain therapeutic activity comparable to an analogous chemotherapy agent.
1. Clarke KR, et al. Phylogenetic Classification and Functional Review of Autotransporters. Front. Immunol., doi:10.3389/fimmu.2022.921272 (2022).