Amyloid-mediated RNA uptake by sperm for embryonic delivery.

Previously, sperm-carried small noncoding RNAs were considered closely related to offspring development and adult phenotypes, and environmental changes can remodel the RNA pool of epididymal sperm; among these, mitochondrial tRNAs and their fragments were identified as sperm-carried factors, and single-embryo transcriptome studies further suggested transfer of mitochondrial tRNAs from sperm to oocytes at fertilization ^[3]. However, how extracellular RNA in seminal plasma enters sperm remains mechanistically unclear. Phase-separation studies have shown that FUS-family proteins can form liquid condensates that further harden, driven mainly by multivalent interactions between tyrosine residues in low-complexity domains and arginine residues in RNA-binding domains ^[1]. Meanwhile, cryo-EM has resolved patient-derived tau amyloid fibrils at 3.4–3.5 Å resolution ^[2], and cellular cryo-electron tomography has been used to reconstruct the 6.0 Å structure of mouse sperm axonemal microtubules ^[4], providing a technical basis for observing sperm uptake of exogenous fibrils.

This paper focuses on functional amyloid fibrils in seminal plasma. The researchers found that highly cationic peptides can phase-separate with RNA and form amyloid fibrils; these fibrils bind RNA and act as transport carriers, delivering RNA into mammalian sperm and further into the zygote at fertilization. Cryo-electron tomography, volume electron microscopy, and fluorescence live-cell imaging jointly showed that fibrils can be taken up by sperm and enter the cell interior. Biophysical experiments and in vitro fertilization experiments further demonstrated that amyloid-bound RNA can reach the zygote, and molecular chaperones can regulate RNA dissociation from the fibrils.

Relative to existing structural analyses of amyloid fibrils ^[2] and clues about sperm RNA transfer ^[3], the advance of this study is that it provides a relatively complete mechanistic chain of “fibril binding—sperm uptake—post-fertilization delivery” and proposes amyloid fibrils as potential tools for RNA delivery during fertilization. In other words, the amyloid fibrils here are not merely supramolecular objects awaiting characterization, but are assigned a clear transport function.

However, the abstract does not yet specify the identities or structures of the seminal plasma peptides that form the fibrils, the selectivity of RNA binding and loading, or delivery efficiency; nor does it explain which receptors or pathways sperm uptake depends on, or the precise timing by which molecular chaperones promote RNA dissociation within the zygote. The paper currently emphasizes RNA delivery and has not yet provided specific embryonic developmental phenotypes or safety endpoints in the abstract, so the in vivo applicability and controllability of this delivery approach remain to be further validated.