Thermoelectric Nanofluidics Probing Thermal Heterogeneity inside Single Cells

Accurate temperature measurement in one living cell is of great significance for understanding biological functions and regulation. Here, a nanopipet electric thermometer (NET) is established for real-time intracellular temperature measurement. Based on the temperature-controlled ion migration, the temperature change in solution results in altered ion mobilities and ion distributions, which can be converted to the thermoelectric responses of NET in a galvanostatic configuration. The exponential relationship between the voltage and the temperature promises highly sensitive thermoelectric responses up to 11.1 mV K^–1, which is over an order of magnitude higher than previous thermoelectric thermometry. Moreover, the NET exhibits superior thermal resolution of 25 mK and spatiotemporal resolution of 100 nm and 0.9 ms as well as excellent stability and reproducibility. Benefiting from these unique features, both thermal fluctuations in steady-state cells and heat generation and dissipation upon drug administration can be successfully monitored, which are hardly achieved by current methods. By using NET, thermal heterogeneities of single cancer cells during immunotherapy were reported first in this work, in which the increased intracellular temperature was demonstrated to be associated with the survival benefit and resistance of cancer cells in immunotherapy. This work not only provides a reliable method for microscopic temperature monitoring but also gains new insights to elucidate the mechanism of immune evasion and therapeutic resistance.