Huntingtin Aggregate‐Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice

ABSTRACT

The accumulation of mutant huntingtin (mHTT) aggregates drives the pathology of Huntington's disease (HD), yet therapies capable of distinguishing toxic species from wild‐type proteins remain elusive. Here, a synthetic gene circuit, termed ARAA, was engineered to couple the preferential recognition of aggregated polyQ species to the on‐demand activation of autophagy. Utilizing a repurposed bacterial NarX–NarL system fused with a conformation‐sensitive intrabody, the circuit detects pathological polyQ conformers and triggers the transcriptional expression of the master autophagy regulator TFEB. To enable systemic application, the ARAA plasmid is encapsulated in CD98‐targeted immunoliposomes (LIP‐CD98) that facilitate efficient blood‐brain barrier crossing via receptor‐mediated transcytosis. In the R6/2 HD mouse model, ARAA treatment significantly reduces mHTT burden, attenuates neuroinflammation, and rescues synaptic deficits. This closed‐loop intervention improves motor function and extends lifespan. Together, these findings provide proof‐of‐concept evidence that aggregate‐responsive regulation of autophagy can mitigate disease‐associated phenotypes in exon 1‐based HD models.