Crafting Immune-Cancer Cell Crosstalk via Modular Multilayer Logic DNA Nanoadaptors

Synthetic molecular recognition tools offer a promising approach to reconfigure cell-cell interactions, but engineering user-defined logic circuits to control intercellular communication in heterogeneous microenvironments endures as a critical barrier. Herein, we present a multilayer logic DNA nanoadaptor (Magic-NA) to define immune-cancer cell crosstalk by a customized logic operation of multiple variables, including cell surface antigens and microenvironmental characteristics. The modular Magic-NA consists of a DNA di-tetrahedral scaffold featuring three ports at each terminal. These ports can be interfaced with a library of plug-and-play logic connectors specifically activated by molecular triggers and targeted to desired cells, enabling programmable design of both logic circuits and inputs. We demonstrated an AND-AND logic network in Magic-NA that guides natural killer (NK) cells to target cells for selective cytotoxicity, based on tumor microenvironment (TME) acidic pH, and cellular antigens PTK7 and MUC1. Furthermore, leveraging the multi-port design, we implemented an OR-AND logic gate system to achieve on-demand cell targeting and broad-spectrum cell killing. This nanoplatform provides a paradigm for manipulating cellular interactions through Boolean integration of cell-intrinsic markers and microenvironmental cues, advancing the development of precision cancer immunotherapy.