ABSTRACT Engineering intelligent interfaces on living cells is essential for precise cellular manipulation. Here, we developed a DNA framework nucleator (DFN)‐guided strategy for the controlled assembly of high‐fidelity stimuli‐responsive intelligent hydrogel interfaces (HIs) on living cell surfaces. Using a rigid tetrahedral DNA framework as the structural core, DFNs served as stable and ordered nucleation sites on the cell membrane, which directed localized branched hybridization chain reaction to form single‐cell HIs. For ATP‐responsive HIs, a response efficiency of ∼90.7% was achieved, representing an ∼2.9‐fold enhancement over the HIs guided by a flexible double‐stranded DNA nucleator (dsDN). Notably, this platform supports the integration of dual‐locked and crosstalk‐free logic gate function, triggering efficient disassembly exclusively when both ATP and microRNA‐122 are present. This AND‐gate function yielded a response efficiency of ∼98.5%, outperforming the dsDN‐guided control by 4.2‐fold, with a background crosstalk below ∼4.0%. These results demonstrate that ordered nucleation is essential for high‐fidelity signal processing at cellular interfaces, advancing the field from static encapsulation to dynamic, logic‐regulated systems and establishing a versatile platform for next‐generation programmable cell‐based applications.
Wu et al. (Sat,) studied this question.