Biological ion channels exhibit switchable cation transport with ultrahigh selectivity for efficient energy conversion, such as Ca 2+ -activated TRPM4 channels tuned by cation−π interactions, but achieving an analogous highly selective function is challenging in artificial nanochannels. Here, we design a TRPM4inspired cation-selective nanochannel (CN) assembled by two poly(ether sulfone)s, respectively, with sulfonate acid and indole moieties, which act as cation-selective activators to manage Na + / Cl − selectivity via ionic and cation−π interactions. The cation selectivity of CNs can be activated by Na + , and thereby the Na + transference number significantly improves from 0.720 to 0.982 (Na + /Cl − selectivity ratio from 2.6 to 54.6) under a 50-fold salinity gradient, surpassing the K + transference number (0.886) and Li + transference number (0.900). The TRPM4-inspired nanochannel membrane enabled a maximum output power density of 5.7 W m −2 for salinity-gradient power harvesting. Moreover, a record energy conversion efficiency of up to 46.5% is provided, superior to most nanochannel membranes (below 30%). This work proposes a novel strategy to biomimetic nanochannels for highly selective cation transport and high-efficiency salinity-gradient energy conversion.