Targeting CD155 in lung adenocarcinoma: A5 nanobody-based therapeutics for precision treatment and enhanced drug delivery

This study presents a novel approach targeting CD155, an overexpressed protein in lung adenocarcinoma (LUAD), using nanobodies with exceptional precision and efficacy. The significant upregulation of CD155 in LUAD, associated with poor patient outcomes, highlights its potential as a therapeutic target. An anti-CD155 nanobody (A5 Nb) is developed that binds to CD155-positive lung cancer cells with high affinity (A5 Nb Kd = 0.23 nM). The complementarity-determining region of A5 Nb forms hydrophobic interactions and hydrogen bonds with CD155, promoting selective binding and stabilization of A5 Nb-CD155 complex. This interaction inhibits focal adhesion signaling by downregulating paxillin (PXN), leading to a >50% reduction in cell migration. Additionally, A5 Nb conjugated to liposomes loaded with doxorubicin (A5-LNP-DOX) demonstrates a 2- to 3-fold increase in uptake and cytotoxicity in CD155-positive A549 cells, suggesting its potential as a targeted drug delivery system. Therapeutic efficacy was further validated in both lung orthotopic mouse models and lung cancer organoid xenografts, where A5-LNP-DOX exhibited robust antitumor effects and selective targeting. The CD155-PXN axis emerges as a clinically relevant target, correlating with poor outcomes in patients with lung cancer. This study highlights the therapeutic potential of A5 nanobodies in targeting CD155-overexpressing lung cancer cells and offers insights for future developments in lung cancer therapeutics.