Simpler DNA Form May Unlock Cheaper, Safer Non-Viral Gene Therapy

By Curie | Biotech Reporter

March 12, 2026 — The iconic double helix of DNA has been the centerpiece of molecular biology for decades. But new research suggests a simpler form of the molecule — a circular single strand — could be the key to making gene therapy cheaper, safer, and more accessible.

Scientists at Full Circles Therapeutics, in collaboration with Mass General Brigham, have developed a novel circular single-stranded DNA (cssDNA) technology that achieves up to 70% successful gene integration in various cell types — a dramatic improvement over current methods, according to a study published in Nature Biotechnology.

"When we use conventional double-stranded DNA as a donor, we typically achieve only single-digit percentage integration rates," said Howard Wu, PhD, co-founder and CSO at Full Circles Therapeutics and corresponding author of the study. "However, with cssDNA, we can achieve much higher efficiency, with integration rates of 50% to 70%."

The current gold standard for gene therapy delivery is viral vectors, particularly adeno-associated viruses (AAVs). But AAVs have significant limitations: they can only carry small genetic payloads (about 4.7 kb), they raise safety concerns including genotoxicity, and manufacturing is complex and expensive. Non-viral approaches using linear DNA have struggled with low efficiency and high cellular toxicity.

The new cssDNA approach, called GATALYST, addresses these challenges. The circular structure is inherently resistant to exonuclease degradation — a problem that plagues linear single-stranded DNA in the cytoplasm — and appears to bypass cellular pathways that recognize foreign double-stranded DNA, reducing toxicity. The system can also carry genetic sequences up to 20 kb in length, more than four times the capacity of AAVs.

The higher efficiency could translate to real cost savings. "This higher efficiency saves significant time and resources, potentially reducing the cost of therapeutic products," Wu said. "Ultimately, this makes the treatment more affordable and accessible to patients."

For CAR-T cell therapy manufacturing, where each dose costs hundreds of thousands of dollars, even modest efficiency gains could meaningfully reduce prices. The technology is also being explored for editing hematopoietic stem cells, which could enable durable gene therapies for blood disorders.