Researchers reported CRISPR–Cas3 genome editing as an alternative to Cas9 for transthyretin (TTR) amyloidosis, using Cas3 to generate long-range deletions that abolished TTR expression. In vitro optimization achieved ~59% editing at the TTR locus; a single lipid‑nanoparticle (LNP) treatment in mice produced 48.7% hepatic editing and an ~80% reduction in circulating TTR. Cas3 primarily generated directional deletions up to 75 kb in vitro and achieved large deletions without reproducible off‑target mutations contrasted with Cas9’s indel profile. In humanized exon mice Cas3 treatment reduced serum TTR and attenuated macrophage‑associated deposition. The work positions Cas3 as a mechanistically distinct tool for systemic proteinopathies where long deletions and durable knockout are desirable; translation will require further safety and delivery optimization, but the in vivo LNP results signal a potentially durable gene‑editing strategy for ATTR.