High-fidelity nanoflares: design strategies, response mechanisms, and biomedical applications.

Nanoflares, built from a nanoparticle core and a functional nucleic acid shell, have been widely used in various fields, such as programmable DNA assembly, biosensing, drug delivery and therapy. However, rigorous physiological environments (e.g. pH, polarity, biothiols and nucleases) can affect the stability of nanoflares, causing false positive signals, side-effects and off-target responses, thereby severely limiting their biological applications. Thus, the improvement of signaling accuracy is critical to breaking through the barriers for practical applications of nanoflares. In recent years, various methods including signal transduction, surface passivation of nanoparticles, replacement of the anchoring group, and spatial isolation of nanoflares, were proposed to improve the signal fidelity in biosensing and therapy. This review summarizes the development of high-fidelity nanoflares, systematically elaborates the design principles and sensing mechanisms, and outlines the obstacles remaining in this field, aiming to improve practical applications of nanoflares in biological systems.