Living cells have the irreplaceable capability to achieve a wide range of complex biochemical reactions precisely and efficiently, which makes them attractive materials for therapeutic applications. In lieu of the traditional biochemical and biological approaches primarily focused on the augmentation of the innate functions of cells, there has been appreciable progress in the development of engineered therapeutic cells, mainly based on the chemical modifications of cell surfaces, at the single‐cell level, which empowers individual living cells with designed therapeutic functions in a cytocompatible manner. This review highlights the latest advances in the development of therapeutic living cells using single‐cell surface engineering, for potential applications in blood transfusion, drug delivery, cancer therapy, probiotic therapy, and tissue engineering and regenerative medicine. The methodological strategies for functionalizing cell surfaces with biomolecules, and inorganic and organic materials, to endow living cells with extrinsic physicochemical and biological properties as well as to increase the durability and efficacy of engineered therapeutic cells, are also briefly overviewed. The review ends with a perspective that discusses the construction of active cell‐in‐shell nanobiohybrid systems, in which exogenous materials formed on cell surfaces mutually and intimately communicate with the cells inside, as a future research direction for single‐cell surface engineering.

Cannabidiol (CBD), a main nonpsychoactive phytocannabinoid in the Cannabis genus, has been in the limelight for its potential health benefits in various neurological diseases. However, the safety issue of CBD in the nervous system has not been settled fully, while CBD has been reported to have mild side effects including dizziness and somnolence. In this work, a platform of neuron‐astrocyte sandwich coculture to investigate the neurotoxicity of CBD, as well as the neuronal responses to CBD, in a more in vivo relevant mode is constructed. CBD (15 and 30 µm) causes the viability decrease, along with morphological damage, in the neuron‐alone culture, whereas its neurotoxic effects are significantly attenuated by the supports of astrocytes in the neuron‐astrocyte coculture. In addition, it is found that CBD‐induced increase of intracellular Ca2+ concentration and depolarization of mitochondrial membrane potential, via activation of transient receptor potential vanilloid 1, are noticeably ameliorated by coculturing neurons with astrocytes. This work provides crucial information in the development of CBD as therapeutics for neurological disorders, as well as in a fundamental understanding of how CBD works in the nervous system.

Manipulation and control of cell chemotaxis remain an underexplored territory despite vast potential in various fields, such as cytotherapeutics, sensors, and even cell robots. Herein is achieved the chemical control over chemotactic movement and direction of Jurkat T cells, as a representative model, by the construction of cell‐in‐catalytic‐coat structures in single‐cell nanoencapsulation. Armed with the catalytic power of glucose oxidase (GOx) in the artificial coat, the nanobiohybrid cytostructures, denoted as Jurkat[Lipo_GOx], exhibit controllable, redirected chemotactic movement in response to d‐glucose gradients, in the opposite direction to the positive‐chemotaxis direction of naïve, uncoated Jurkat cells in the same gradients. The chemically endowed, reaction‐based fugetaxis of Jurkat[Lipo_GOx] operates orthogonally and complementarily to the endogenous, binding/recognition‐based chemotaxis that remains intact after the formation of a GOx coat. For instance, the chemotactic velocity of Jurkat[Lipo_GOx] can be adjusted by varying the combination of d‐glucose and natural chemokines (CXCL12 and CCL19) in the gradient. This work offers an innovative chemical tool for bioaugmenting living cells at the single‐cell level through the use of catalytic cell‐in‐coat structures.

In article number 2300037, Hojae Lee, Insung S. Choi, and co‐workers review recent advances in single‐cell surface engineering for therapeutic applications of living cells. This image illustrates the process of single‐cell nanoencapsulation (SCNE), in which a nanoshell is created around a cell using extrinsic compounds, such as trimesic acid, dopamine, and tetramethyl orthosilicate.

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