Transient let-7/miR-98 reprograms primed pluripotency to induce naive human PSCs

We identify an unexpected role for miR-98-5p, a let-7 family microRNA (miRNA) typically linked to differentiation, in promoting naive induction. Using a synthetic mRNA screen containing diverse miRNA-responsive elements, we uncovered miR-98-5p as a potent enhancer of resetting.

Single-cell RNA sequencing and targeted perturbations show that miR-98-5p directly represses NR6A1 while transiently activating BMP2/4 signaling, triggering network transitions. These changes destabilize the primed gene-regulatory network and enable acquisition of a naive state. Leveraging this mechanism, we establish a feeder-free, miRNA-based, editing-free protocol that boosts resetting efficiency from <10% to ~80%.