Targeted, stimulus‐responsive DNA nanogels hold considerable promise for cancer therapeutics. To expand their functionality including thermoresponsiveness, here, multifunctional DNA nanogels are developed for potential application toward cancer‐targeted delivery and stimuli‐responsive release of cancer therapeutics. Three types of functionalized DNA nanobuilding units are formed into DNA nanogels of ≈200 nm via sequence‐dependent self‐assembly. The sequence‐dependent assembly of nanobuilding units is precisely designed for controlled assembly and thermal disassembly at physiological temperatures. The supramolecular structure exhibits multifunctionalities including temperature‐induced disassembly, aptamer‐mediated cancer cell targeting, and light‐triggered temperature increase. The nanogels support co‐loading of cancer therapeutics including anti‐sense oligonucleotides and doxorubicin along with stimuli‐responsive release of loaded drugs through temperature‐responsive structural disassembly and pH‐responsive deintercalation. The nanogels exhibit efficient aptamer‐mediated cancer‐specific intracellular delivery and combinational anticancer effects upon light triggering. The developed DNA nanogels, thus, constitute potential noncationic nanovectors for targeted delivery of combinational cancer therapeutics.

The cell surface can be engineered with synthetic DNA for various applications ranging from cancer immunotherapy to tissue engineering. However, while elegant methods such as click conjugation and lipid insertion have been developed to engineer the cell surface with DNA, little effort has been made to systematically evaluate and compare these methods. Resultantly, it is often challenging to choose a right method for a certain application or to interpret data from different studies. In this study, we systematically evaluated click conjugation and lipid insertion in terms of cell viability, engineering efficiency, and displaying stability. Cells engineered with both methods can maintain high viability when the concentration of modified DNA is less than 25–50 μM. However, lipid insertion is faster and more efficient in displaying DNA on the cell surface than click conjugation. The efficiency of displaying DNA with lipid insertion is 10–40 times higher than that with click conjugation for a large range of DNA concentration. However, the half-life of physically inserted DNA on the cell surface is 3–4 times lower than that of covalently conjugated DNA, which depends on the working temperature. While the half-life of physically inserted DNA molecules on the cell surface is shorter than that of DNA molecules clicked onto the cell surface, lipid insertion is more effective than click conjugation in the promotion of cell–cell interactions under the two different experimental settings. The data acquired in this work are expected to act as a guideline for choosing an approximate method for engineering the cell surface with synthetic DNA or even other biomolecules.

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