Cross-kingdom delivery and putative gene modulation of androgen pathways by plant-derived exosome-like nanoparticles from polygoni multiflori radix promotes hair growth via miRNA cargo.

Plant-derived exosome-like nanoparticles (PENs) have emerged as promising nanocarriers for cross-kingdom delivery and putative gene modulation, yet their functional role in human physiology remains largely unexplored. Here, we isolate and characterize exosome-like nanoparticles from Polygoni Multiflori Radix (PMENs) and demonstrate their capacity to promote hair growth through cross-kingdom delivery and putative gene modulation of androgen signaling. PMENs are efficiently internalized by dermal papilla cells via caveolin- and heparan sulfate proteoglycan-mediated endocytosis, delivering plant-derived miRNAs that directly target the human androgen receptor (AR). This leads to downregulation of AR expression and downstream suppression of DKK1, a key inhibitor of the Wnt/β-catenin pathway. PMENs concurrently increase GSK3β phosphorylation and stabilize β-catenin, fostering hair follicle regeneration. In testosterone-induced delay in hair regrowth in C57BL/6 mice, PMENs outperform Minoxidil in restoring hair growth. High-throughput sequencing identifies aof-miR168a and osa-miR164a as core miRNA effectors, confirmed to repress AR via conserved 3'UTR binding sites. These findings establish PMENs as a novel, miRNA-mediated nanotherapy that enables putative cross-kingdom gene modulation and provides a compelling strategy for treating androgen-driven conditions such as AGA.