A new genome-editing strategy could sidestep one of the field’s biggest bottlenecks: the immune response triggered by double-stranded DNA (dsDNA). Researchers have developed “INSTALL,” a system that pairs recombinases with circular single-stranded DNA (cssDNA) donors to enable kilobase-scale gene insertion with reduced toxicity.
Traditional recombinase approaches rely on dsDNA templates, which activate innate immune sensors such as cGAS–STING, limiting efficiency and confining applications largely to ex vivo or immune-deficient settings. By contrast, cssDNA largely evades these pathways. The team engineered partially duplexed cssDNA constructs – allowing recombinases to recognize their target sites – while retaining immune stealth.
The result: high-fidelity DNA integration across multiple recombinase systems, with improved efficiency in human cells and dramatically better tolerability in mice. In vivo, lipid nanoparticle delivery of cssDNA-based donors enabled systemic dosing and even repeat administration – something not feasible with dsDNA or viral vectors. At equivalent doses, dsDNA triggered severe immune activation and lethality, whereas INSTALL-treated animals showed minimal inflammation and sustained integration.
By combining immune-evasive nucleic acids with recombinase precision, INSTALL offers a potential path toward non-viral, in vivo genome writing – expanding the therapeutic scope of gene insertion technologies.
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