Abstract

Intracellular bacteria can evade the attack of the immune system and the bactericidal effects of most antibiotics due to the protective effect of the host cells. Herein, inspired by the stimuli-responsive behaviors of biological ion channels, a kind of synergistic cascade potassium ion (K+)-responsive nanoparticles gated with K+-responsive polymers is ingeniously designed to target intracellular bacteria and then control drug release. Due to the cooperative interaction of host–guest complexation and conformational transition of K+-responsive polymers, the grafted gates based on these polymers could recognize high K+ concentration to reverse the negatively charged nanoparticles into positively charged ones for targeting bacteria and subsequently inducing a switch from the hydrophobic shrinking "off" state to the hydrophilic stretching "on" state for drug release. The K+-responsive nanoparticles can effectively load antibiotics and be endocytosed into the infected cells, and K+-responsive gates can be actuated by a high intracellular K+ concentration. With the efficient synergistic cascade strategy, these K+-responsive nanocarriers can deliver antibiotics to the subcellular region where intracellular bacteria reside and show superior elimination efficiencies in vitro and in vivo than the free drug in delivering vancomycin. The K+-responsive nanocarriers are expected to improve the bioavailability of drugs and enhance their antibacterial efficacy.