Engineering of Living Cells with Polyphenol‐Functionalized Biologically Active Nanocomplexes

Abstract Approaches to safely and effectively augment cellular functions without compromising the inherent biological properties of the cells, especially through the integration of biologically labile domains, remain of great interest. Here, a versatile strategy to assemble biologically active nanocomplexes, including proteins, DNA, mRNA, and even viral carriers, on cellular surfaces to generate a cell‐based hybrid system referred to as “Cellnex” is established. This strategy can be used to engineer a wide range of cell types used in adoptive cell transfers, including erythrocytes, macrophages, NK cells, T cells, etc. Erythrocyte nex can enhance the delivery of cargo proteins to the lungs in vivo by 11‐fold as compared to the free cargo counterpart. Biomimetic microfluidic experiments and modeling provided detailed insights into the targeting mechanism. In addition, Macrophage nex is capable of enhancing the therapeutic efficiency of anti‐PD‐L1 checkpoint inhibitors in vivo. This simple and adaptable approach may offer a platform for the rapid generation of complex cellular systems.