Programmable DNA Nanotoolbox-Engineered NK/T Cells for Logic-Gated Tumor Cell Targeting and Spatiotemporally Controlled Immunotherapy

High Resolution Image Download MS PowerPoint Slide Immune cell membrane engineering strategies, such as chimeric antigen receptors and multispecific antibodies, hold great promise for cancer therapy but are often limited by immune-related adverse effects caused by nonspecific antigen recognition and excessive activation. Here, we present a multifunctional DNA nanotoolbox (MDNT) for stable engineering of T/NK cell membranes, enabling dual-parameter-guided tumor targeting and light-controllable regulation of cellular activity. The MDNT, based on an amphiphilic DNA triangular prism with tetravalent cholesterol anchors, ensures robust membrane insertion. An ATP-activated Sgc8 aptamer module confers selective recognition of PTK7-positive tumor cells, while the photosensitizer chlorin e6 enables light-triggered reactive oxygen species generation for spatiotemporal control of immune cell activity, eliminating overactivated cells and reducing toxicity. By integrating immune cytotoxicity with photodynamic effects, MDNT significantly enhances antitumor efficacy. This work provides a modular, programmable, and controllable functional interface between DNA nanodevices and immune cells, offering a strategy to improve both safety and therapeutic performance in cancer immunotherapy.