Circular RNA Calls for a Different Delivery Material
A Stanford study by Paul Wender and collaborators shows how ionizable lipid design can be tailored to circular RNA.
When the payload changes, the material matters
Circular RNA has a closed structure that differs from the linear RNA used in many delivery studies. Its stability creates possibilities for protein expression, while its physical properties raise a practical question: which delivery materials work well with this payload?
In a 2026 Journal of the American Chemical Society study, Stanford’s Paul A. Wender, an N1 Life co-founder, and collaborators designed ionizable lipids for circular RNA delivery. They connected changes in lipid structure with protein-expression results in cells and mice. [1]
Design the lipid around the RNA
The team examined features of the lipid head, linker and tail, then combined favorable elements in a lead molecule called iL-19. The design included aminoethoxy head units, doubly branched tails and linkers tuned for hydrogen bonding and biodegradability. A step-economical synthesis helped the team adjust molecular structures and systematically compare lipid design with delivery performance. [1]
The principle is useful beyond one molecule: a carrier and its payload form a working system. Changing the RNA can affect how particles assemble and perform, so an existing formulation offers a starting point for further optimization around circular RNA.
Read the comparison in its model
In cultured C2C12 mouse muscle cells, the iL-19 formulation produced approximately 28 times the reporter protein expression of the SM-102 comparator formulation. After intramuscular administration in BALB/c mice, expression was approximately 2.5 times the SM-102 comparison. The study also reported higher expression relative to formulations containing ALC-0315 and DLin-MC3-DMA in the mouse experiment. [1]
Across both experimental settings, the iL-19 formulation produced higher reporter protein expression. Those results connect lipid design with a functional readout and offer a starting point for exploring materials for other payloads and applications.
What the next experiment needs to resolve
For a development team, the findings make the material–payload relationship tangible. The next decision is to test whether the observed expression can be reproduced with the intended RNA, tissue and formulation, then evaluate duration, tolerability and manufacturing consistency for that use.
The same discipline applies when evaluating a different delivery setting: define the payload, target tissue and functional readout together before deciding which formulation is ready to advance.
Explore N1 Life’s delivery programs.