Researchers led by Ben Kleinstiver developed a circular single-stranded DNA donor (INSTALL) that supports kilobase-scale genome insertions while evading cytosolic DNA sensors that trigger toxic immune responses. The work, reported in Nature and related venues, demonstrates non-viral, LNP-mediated delivery of immune-evasive donors that enabled large payload integration in mouse liver without the fatal reactions observed with conventional double-stranded DNA donors. The team collaborated with Full Circles Therapeutics to show that circular ssDNA donors with short double-stranded recognition regions remain recombinase-compatible but avoid detection by cGAS and downstream innate immunity. In murine experiments, INSTALL-supported integrations were efficient and non-toxic, addressing a major barrier to scalable genetic medicines that require gene-sized payloads rather than point edits. Kilobase-scale insertion is the process of integrating large DNA sequences into genomes to restore or replace entire genes. These results remove a key immunogenicity hurdle for therapies aiming to treat genetically heterogeneous diseases where single-mutation fixes are impractical.