Exploiting Bacterial Shuttles: Enhancing Deep Tissue Delivery of Nanoparticles for Targeted Cancer Therapy

Cancer, a leading cause of death, poses challenges for chemotherapy due to limited selective accumulation. Targeted approaches and nanoparticles exploit enhanced permeability but face obstacles in effective delivery. Bacteria, historically effective for cancer targeting, show promise as carriers for nanoparticles, overcoming deep tissue hindrances. Yet, conjugated forms often compromise selective accumulation and tissue penetration due to increased immunogenicity, limiting bacterial motility and proliferation. This study engineered bacteria with cancer-targeting abilities expressing strep tags for streptavidin binding. We evaluated their binding to Chlorin-e6 (Ce6) nanoparticles, a potential photosensitizer for photodynamic therapy, selecting strains with optimal performance. Validating enhanced delivery, we assessed bacterial tumor-selective colocalization and nanoparticle delivery in a fibrous tumor microenvironment in vitro. To address reduced delivery efficiency in vivo, bacteria were intravenously injected and induced to conjugate with peritumorally introduced nanoparticles, confirming effective delivery to hypoxic cancer tissue regions. This underscores bacteria's role as cancer-targeting agents and shuttles enhancing deep tissue delivery.