Elucidating a Tumor‐Selective Nanoparticle Delivery Mechanism at the Colorectal Lumen–Tumor Interface for Precise Local Cancer Therapy

Abstract Although various colorectal cancer (CRC)‐targeted nanoparticles have been developed to selectively deliver anticancer agents to tumor tissues, severe off‐target side effects still persist due to unwanted systemic nanoparticle distribution, limiting the therapeutic outcome. Here, by elucidating a tumor‐selective nanoparticle delivery mechanism occurring at the colorectal lumen–tumor interface, an alternative CRC‐targeted delivery route is proposed, which enables highly tumor‐selective delivery without systemic distribution, through direct drug delivery from the outside of the body (colorectal lumen) to tumors in the colorectum. Owing to the presence of accessible tumor‐specific receptors such as CD44 at the colorectal lumen–tumor interface, but not at the colorectal lumen–normal tissue interface, colorectal luminal surface (CLS)‐targeting ligand‐functionalized nanoparticles selectively accumulate in CRC tissues without systemic distribution, resulting in successful local CRC therapy. The findings suggest that CLS‐targeted lumen‐to‐tumor delivery can be a suitable strategy for highly CRC‐specific drug delivery for precise local CRC therapy.