Directing the Encapsulation of Single Cells with DNA Framework Nucleator‐Based Hydrogel Growth

Abstract

Encapsulating individual mammalian cells with biomimetic materials holds potential in ex vivo cell culture and engineering. However, current methodologies often present tradeoffs between homogeneity, stability, and cell compatibility. Here, inspired by bacteria that use proteins stably anchoring on their outer membranes to nucleate biofilm growth, we develop a single‐cell encapsulating strategy by using a DNA framework structure as a nucleator(DFN) to initiate the growth of DNA hydrogels under cell‐friendly conditions. We find that among the tested structures, the tetrahedral DFN can evenly and stably reside on cell membranes, effectively initiating hybridization chain reactions, thus generating homogenously dense yet flexible single‐cell encapsulation for diverse cell lines. The encapsulation purely consisting of DNA persists for up to 72 hours in a serum‐containing cell culture environment, which is a ~70‐fold improvement compared to that mediated by a single‐stranded DNA nucleator. The metabolism and proliferation of the encapsulated cells are found suppressed, which however can be restored to the original efficiencies upon release, suggesting superior cell compatibility of the encapsulation. We also find that compared to naked cells, the encapsulated cells exhibit a lower autophagy level after undergoing mechanical stress, suggesting the protective effect of the DNA encapsulation.