Cell‐Membrane‐Derived Nanoparticles with Notch‐1 Suppressor Delivery Promote Hypoxic Cell–Cell Packing and Inhibit Angiogenesis Acting as a Two‐Edged Sword

Abstract Cell–cell interactions regulate intracellular signaling via reciprocal contacts of cell membranes in tissue regeneration and cancer growth, indicating a critical need of membrane‐derived tools in studying these processes. Hence, cell‐membrane‐derived nanoparticles (CMNPs) are produced using tonsil‐derived mesenchymal stem cells (TMSCs) from children owing to their short doubling time. As target cell types, laryngeal cancer cells are compared to bone‐marrow‐derived MSCs (BMSCs) because of their cartilage damaging and chondrogenic characteristics, respectively. Treating spheroids of these cell types with CMNPs exacerbates interspheroid hypoxia with robust maintenance of the cell–cell interaction signature for 7 days. Both cell types prefer a hypoxic environment, as opposed to blood vessel formation that is absent in cartilage but is required for cancer growth. Hence, angiogenesis is inhibited by displaying the Notch‐1 aptamer on CMNPs. Consequently, laryngeal cancer growth is suppressed efficiently in contrast to improved chondroprotection observed in a series of cell and animal experiments using a xenograft mouse model of laryngeal cancer. Altogether, CMNPs execute a two‐edged sword function of inducing hypoxic cell–cell packing, followed by suppressing angiogenesis to promote laryngeal cancer death and chondrogenesis simultaneously. This study presents a previously unexplored therapeutic strategy for anti‐cancer and chondroprotective treatment using CMNPs.