Hyperbranched Polymer-Based Multipath Proton Transmembrane Transport System with Redox-Switchable Characteristics for Cancer Cell Apoptosis

Natural channel proteins (NCPs) enable efficient and selective transport of specific species across cellular membranes and exhibit stimulus-responsive behaviors; however, replicating these features in their artificial counterparts poses significant challenges. Here, we report a hyperbranched polymer (HBP)-derived biomimetic multipath proton transport system, H3, by a straightforward “one-pot” cationic polymerization of 3-ethyl-3-(hydroxymethyl)-oxetane. H3 efficiently transports protons while rejecting other ions and water molecules by forming multiple hydrogen bonding chains like natural proton channels. Patch clamp experiments revealed that H3 facilitates rapid proton transport (γ_H+ = 181 ± 4 pS) comparable to that of natural gramicidin A (γ_H+ = 213 ± 4 pS) and demonstrates high H⁺-selectivity, with P_H+/P_K+, P_H+/P_Na+, and P_H+/P_Cl- values reaching 78.4, 233.2, and 167.8, respectively. H3-induced proton transport causes elevated lysosomal pH and mitochondrial damage, ultimately resulting in severe cancer cell apoptosis (IC₅₀: 0.23 µM for U87MG; 1.04 µM for B16F10). Interestingly, selenide moieties-containing H3-Se exhibits an unprecedented in situ redox-switchable “ON–OFF” of proton transport by regulating its hydrophilicity. This work will contribute to a deeper understanding of the intrinsic mechanisms of NCPs and treatments for cancer and other diseases.