Three RNA Vaccine Formats and the Lipid Problem Underneath Them

Six years after the first licensed mRNA vaccine, the argument in the field is no longer whether RNA can be delivered. It is which RNA, for how long, and at what cost in reactogenicity. Three molecular formats carry most of the work now: nucleoside-modified linear mRNA, self-amplifying RNA (saRNA) and circular RNA (circRNA). Each has produced human or near-human data since 2021, and each is limited at a different step-cytosolic lifetime, innate sensing of replication intermediates, and manufacturing. Beneath all three sits the ionizable lipid, whose discovery process has itself been redesigned: combinatorial libraries, machine learning and iterative chemical evolution have compressed what once took years into months, without yet producing a molecule that separates potency from inflammation. This Review follows the three formats through their mechanistic constraints and their clinical readouts, then examines what the lipid literature of the past five years does and does not establish. We give particular weight to results that conflict, to effect sizes measured in the wrong species, and to claims that circulate without a same-condition comparison behind them.