A DNA-Scaffolded Natural Killer Cell with Adaptable Multimodules for Enhanced Immunotherapy and Early Efficiency Reporting

Abstract

Adoptive cell therapy is promising with many clinical trials, but its application efficiency is significantly influenced by individual immune microenvironments and the varied responses of different patients. Equipping adoptive cells with multifunctional modules for function enhancement and real-time efficacy readouts is a key solution but remains challenging due to the dynamic nature of the cell membrane and the limited accessibility of available binding sites on the membrane. Herein, we report a multimodule intelligent NK (MI-NK) cell that encapsulates NK cells within a durable DNA scaffold anchored with multiple adaptable functional modules, including a barrier penetration module (glucose oxidase-catalase cascade enzymes), an activity boosting module (IL-21 nanoparticles), and an efficiency reporting module (granzyme B-activatable hemicyanine NIR fluorescent probe). Oxygen generated from cascade enzymatic reactions drives MI-NK cells and promotes their tumor infiltration. IL-21 nanoparticles are disintegrated by GSH to release IL-21 for on-site NK cell activation and expansion. Activated NK cells secrete granzyme B, which restores the NIR fluorescence of the efficiency-reporting module to enable response reporting as early as 6 h after adoptive cell administration. The as-obtained MI-NK effectively enhances the in vivo immunotherapeutic efficiency. The types and proportions of adaptable modules can be expanded, offering a universal approach for adoptive cell therapy efficiency.