Stimulus switches for spatial-temporal precision in therapeutic delivery systems

Precision treatment, which targets the molecular-based pathogenesis or the specific microenvironment of the focus, has become an established paradigm in current therapeutic agent development and delivery strategy design. However, current therapeutics lack spatial and temporal control, resulting in systemic side effects and suboptimal patient outcomes. Drug delivery systems that are site-specific, rate-specific, and time-specific can be designed to improve therapeutic precision by optimizing pharmacokinetics, developing stimulus-sensitive switches, and creating novel responsive biomaterials. Here, we discuss the engineering of stimulus switches at various scales to improve spatial-temporal precision in therapeutic delivery systems, release drugs in a controlled manner, and reduce adverse reactions. We further outline the use of biomaterials that respond to endogenous stimuli (pH, enzymes, prodrugs, and redox potential), and summarized the three key controllable release mechanisms of these stimulus switches: time, site and rate-specific. We also anticipate that the strategies summarized in this review will contribute to the development of neotype drug delivery strategies.