Changliang Ren

Biological ion channels and pores frequently exhibit dynamic, concentration‐dependent adaptive assembly, yet synthetic systems that faithfully replicate this intriguing behavior remain rare. In this study, we present a novel class of tripeptide‐appended macrocyclic ion channels that undergo aromatic interaction‐driven adaptive transformation from unimolecular chloride channels into higher‐order nanopores. At low concentrations, analogues with aromatic tripeptide‐functionalized macrocycles ( MC‐F and MC‐W ) function as discrete and efficient chloride channels. Upon increasing the concentration, cooperative aromatic interactions among the tripeptide side chains promote their lateral self‐assembly into stable nanopores, enabling efficient transmembrane transport of small molecules, including carboxyfluorescein and glucose. In contrast, the aliphatic analogues ( MC‐A , MC‐L , and MC‐I ) remain restricted to unimolecular chloride channels. Single‐channel measurements combined with theoretical calculations further substantiate the structural stability and energetic preference of tetrameric and pentameric assemblies within lipid bilayers. Collectively, this work establishes cooperative aromatic interactions as a versatile and robust design principle for engineering adaptive artificial channels, thereby narrowing the functional gap between synthetic systems and the dynamic regulatory behavior of natural channels.

Biological ion channels and pores frequently exhibit dynamic, concentration‐dependent adaptive assembly, yet synthetic systems that faithfully replicate this intriguing behavior remain rare. In this study, we present a novel class of tripeptide‐appended macrocyclic ion channels that undergo aromatic interaction‐driven adaptive transformation from unimolecular chloride channels into higher‐order nanopores. At low concentrations, analogues with aromatic tripeptide‐functionalized macrocycles ( MC‐F and MC‐W ) function as discrete and efficient chloride channels. Upon increasing the concentration, cooperative aromatic interactions among the tripeptide side chains promote their lateral self‐assembly into stable nanopores, enabling efficient transmembrane transport of small molecules, including carboxyfluorescein and glucose. In contrast, the aliphatic analogues ( MC‐A , MC‐L , and MC‐I ) remain restricted to unimolecular chloride channels. Single‐channel measurements combined with theoretical calculations further substantiate the structural stability and energetic preference of tetrameric and pentameric assemblies within lipid bilayers. Collectively, this work establishes cooperative aromatic interactions as a versatile and robust design principle for engineering adaptive artificial channels, thereby narrowing the functional gap between synthetic systems and the dynamic regulatory behavior of natural channels.

Proton‐activated ion channels mediate ion transport in response to extracellular acidification, enabling cellular adaptation to acidic microenvironments. Despite their biological importance, mimicking proton‐activated functionality in artificial ion channels remains a significant challenge. Here, we present a novel class of proton‐activated artificial ion channels built from self‐assembled peptide chains integrated into a pH‐responsive 2,2′‐bipyridine scaffold. Protonation induces a conformational switch in the channel‐forming units, promoting one‐dimensional self‐assembly and subsequent hydrophobic packing into functional channels capable of transporting small molecules. As extracellular pH decreases from 7.4 to 6.5, C‐FF exhibits a 10.3‐fold enhancement in cytotoxicity against human colorectal carcinoma cells, boosting an IC ₅₀ of 2.8 µM, mediated through apoptosis induction and cell cycle arrest resulting from disruption of the autophagic process. Significantly, C‐FF demonstrates exceptional selectivity for cancer cells, achieving a selectivity index of 8.5, surpassing that of doxorubicin by one order of magnitude while maintaining comparable potency, highlighting its potential as a pH‐responsive platform for selective anticancer therapy in acidic tumor microenvironments.

Proton‐activated ion channels mediate ion transport in response to extracellular acidification, enabling cellular adaptation to acidic microenvironments. Despite their biological importance, mimicking proton‐activated functionality in artificial ion channels remains a significant challenge. Here, we present a novel class of proton‐activated artificial ion channels built from self‐assembled peptide chains integrated into a pH‐responsive 2,2′‐bipyridine scaffold. Protonation induces a conformational switch in the channel‐forming units, promoting one‐dimensional self‐assembly and subsequent hydrophobic packing into functional channels capable of transporting small molecules. As extracellular pH decreases from 7.4 to 6.5, C‐FF exhibits a 10.3‐fold enhancement in cytotoxicity against human colorectal carcinoma cells, boosting an IC ₅₀ of 2.8 µM, mediated through apoptosis induction and cell cycle arrest resulting from disruption of the autophagic process. Significantly, C‐FF demonstrates exceptional selectivity for cancer cells, achieving a selectivity index of 8.5, surpassing that of doxorubicin by one order of magnitude while maintaining comparable potency, highlighting its potential as a pH‐responsive platform for selective anticancer therapy in acidic tumor microenvironments.

In nature, hypoxia‐sensitive ion channels regulate the ion transport in response to oxygen levels, which are critical for cellular adaptation to low‐oxygen environments. However, this intriguing stimuli‐responsive property has yet to be replicated in artificial ion channels designed to mimic the essential functions of their natural counterparts. Herein, we introduce a novel class of adaptive artificial channels activatable under hypoxic conditions in cancer cells. Reductase‐mediated reduction of nitro and/or azo groups triggers the rapid release of channel‐forming units, which dimerize into chloride channels or further assemble into nanopores of varying cavity sizes at high concentrations in the presence of cholesterol. Upon activation, the most sensitive channel, C1 , demonstrates an 18.1‐fold enhancement in cytotoxicity against HepG2 cells with an IC ₅₀ of 2.9 µM. Remarkably, C1 exhibits exceptional selectivity for liver cancer cells over normal liver cells, with a selectivity index of 17.9, surpassing that of doxorubicin by 44.8 folds while maintaining comparable anticancer efficacy.

In nature, hypoxia‐sensitive ion channels regulate the ion transport in response to oxygen levels, which are critical for cellular adaptation to low‐oxygen environments. However, this intriguing stimuli‐responsive property has yet to be replicated in artificial ion channels designed to mimic the essential functions of their natural counterparts. Herein, we introduce a novel class of adaptive artificial channels activatable under hypoxic conditions in cancer cells. Reductase‐mediated reduction of nitro and/or azo groups triggers the rapid release of channel‐forming units, which dimerize into chloride channels or further assemble into nanopores of varying cavity sizes at high concentrations in the presence of cholesterol. Upon activation, the most sensitive channel, C1 , demonstrates an 18.1‐fold enhancement in cytotoxicity against HepG2 cells with an IC ₅₀ of 2.9 µM. Remarkably, C1 exhibits exceptional selectivity for liver cancer cells over normal liver cells, with a selectivity index of 17.9, surpassing that of doxorubicin by 44.8 folds while maintaining comparable anticancer efficacy.

Peptide transporters are integral membrane proteins responsible for the cellular uptake of dipeptides and tripeptides from the extracellular environment, which play pivotal roles in nutrient absorption, antigen presentation, and cellular signaling. Despite their essential biological functions, the development of artificial peptide transporters capable of efficiently transporting charge-neutral peptides, which are highly polar and prone to aggregation, remains a significant challenge. Herein, we introduce a novel class of peptide transporters involving the integration of anion and cation transport functionalities. Notably, 5F–C12, which functions as a molecular tweezer, forms a stable 1:1 complex with the charge-neutral peptide tyroserleutidean anticancer agent currently in Phase III clinical trialsand actively facilitates its transmembrane transport by shielding it from the membrane’s hydrophobic core, achieving an EC₅₀ value of 7.5 μM. For the first time, 5F–C12 could remarkably enhance the peptide’s bioavailability and exhibit a pronounced enhanced anticancer effect against MCF-7 breast cancer cells both in vitro and in vivo.

Reactive oxygen species (ROS)‐responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS‐responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H⁺/Cl⁻ ion channels activatable by elevated ROS levels in cancer cells. ROS‐induced decaging of the phenylboronate group triggers the rapid release of the channel‐forming units, leading to self‐assembly of the H‐bonded cascades facilitating the synergistic transport of H⁺ and Cl⁻ ions, with H⁺/Cl⁻ ion transport selectivity of 7.7. Upon activation, ROS‐C‐Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC₅₀ of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H⁺/Cl⁻ co‐transport, ROS‐C‐Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.

Reactive oxygen species (ROS)‐responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS‐responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H⁺/Cl⁻ ion channels activatable by elevated ROS levels in cancer cells. ROS‐induced decaging of the phenylboronate group triggers the rapid release of the channel‐forming units, leading to self‐assembly of the H‐bonded cascades facilitating the synergistic transport of H⁺ and Cl⁻ ions, with H⁺/Cl⁻ ion transport selectivity of 7.7. Upon activation, ROS‐C‐Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC₅₀ of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H⁺/Cl⁻ co‐transport, ROS‐C‐Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.