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

Abstract 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.