A transistor-like pH-sensitive nanodetergent for selective cancer therapy

Plasma membrane rupture is a promising strategy for drug-resistant cancer treatment, but its application is limited by the low tumour selectivity of membranolytic molecules. Here we report the design of 'proton transistor' nanodetergents that can convert the subtle pH perturbation signals of tumour tissues into sharp transition signals of membranolytic activity for selective cancer therapy. Our top-performing 'proton transistor' nanodetergent, P(C6-Bn₂₀), can achieve a >32-fold change in cytotoxicity with a 0.1 pH input signal. At physiological pH, P(C6-Bn₂₀) self-assembles into neutral nanoparticles with inactive membranolytic blocks shielded by poly(ethylene glycol) shells, exhibiting low toxicity. At tumour acidity, a sharp transition in its protonation state induces a morphological transformation and an activation of the membranolytic blocks, and the cation-π interaction facilitates the insertion of benzyl groups-containing hydrophobic domains into the cell membranes, resulting in potent membranolytic activity. P(C6-Bn₂₀) is well tolerated in mice and shows high anti-tumour efficacy in various mouse tumour models.