i-Motifs in cancer diagnosis and treatment: fabrication and functionalization

As a four-stranded DNA structure which forms within cytosine (C)-rich sequences, the i-motif introduces a state-of-the-art pH-responsive targeting agent having remarkable ability in drug delivery systems (DDSs). Upon exposure to slightly acidic environments, these sequences exhibit a significant tendency to fold into the intramolecular i-motif structure, normally with three loop style, supplying potent drug carriers. The conformational flexibility, easy modification, symmetrical architecture, and intrinsic biocompatibility of C-rich sequences strongly support their usage in drug delivery applications. Particularly, conjugation of C-rich sequences with different inorganic nanoparticles or organic fragments improves their efficacy as nanocarriers by providing increased biocompatibility, reduced cytotoxicity, and enhanced stability. The i-motif-based systems are utilized for both their cancer detection and therapeutic interventions. Although i-motifs have become a promising platform for exploring pH-responsive systems, comprehensive reviews discussing their progress in developing targeted and non-targeted drug delivery systems and biosensors are still lacking. In this timely update we aim to supply an in-depth analysis of the progress, with the goal of inspiring innovative strategies for designing targeting/non-targeting systems that benefit from i-motifs as pH-responsive agents in combination with different types of nanocarriers for enhanced cancer diagnosis and treatment.