Programmable expression control can determine whether a gene-therapy product remains spatially selective, dose-appropriate and controllable after delivery. This critical translational review examines regulatory circuits as a distinct engineering layer, rather than treating vector targeting or initial transduction as sufficient evidence of controlled therapy. Peer-reviewed experimental studies and focused methodological literature published through 1 November 2026 were selected purposively to compare tissue-restricted transcription, microRNA-mediated detargeting, inducible RNA and protein switches, and circuit architectures that suppress basal leakage. Evidence was interpreted according to the biological model, delivered construct, measured output and observation period. Across these approaches, specificity emerges from multiple non-equivalent barriers: entry into a cell, transcriptional competence, RNA fate and protein production. Large induction ratios may coexist with residual basal expression, heterogeneous cellular responses or incomplete reversibility. Studies in mice and nonhuman primates further show that persistence of vector genomes does not guarantee persistence of expression, while transient expression loss does not always mean permanent vector clearance. The central translational requirement is therefore a linked validation package: tissue-resolved exposure and output, basal and induced dose, withdrawal and rechallenge, and longitudinal measurements of circuit state, immunity and function. These considerations guide condition-specific design choices without implying clinical validation of preclinical switches.
