MK-0752

Lipid nanoparticle‐messenger RNA formulations have garnered significant attention for their therapeutic potential in infectious diseases, cancer and genetic disorders. However, effective mRNA delivery to the central nervous system (CNS) remains a formidable challenge. To overcome this limitation, a class of brain‐targeting lipids (BLs) is developed by incorporating brain‐targeting small molecules with amino lipids and formulated them with helper lipids to generate brain‐targeting lipid nanoparticles (BLNPs) for mRNA delivery. Screening studies led to a lead formulation, TD5 BLNPs, outperforming FDA‐approved DLin‐MC3‐DMA LNPs in delivering mRNA to the brain upon intrathecal injection. Specifically, a single intrathecal injection of TD5 BLNP‐GFP mRNA led to GFP expression in 29.6% of neurons and 38.1% of astrocytes across the brain. In an Ai14 mouse model, TD5 BLNP‐Cre recombinase mRNA treatment induced tdTomato expression in ≈30% of neurons and 40% of astrocytes across major brain regions. Notably, delivery of Cas9 mRNA/sgRNA complex using TD5 BLNPs achieved effective genome editing in the brain. Additionally, TD5 BLNPs showed comparable safety profiles to MC3 LNPs, indicating promising biocompatibility. Overall, this TD5 BLNP formulation effectively delivers mRNA to brain tissues via intrathecal injection and facilitates efficient expression in both neurons and astrocytes, presenting a potential strategy for treating CNS diseases.

Dysregulation of microRNAs (miRNAs) influences diverse hallmarks of cancer, including proliferative signaling, metastasis, and resistance to cell death. We explored the contribution of miR-92b-3p in oral squamous cell carcinoma (OSCC) and its potential as a monitoring biomarker. Analysis of TCGA, GEO, and our own cohort revealed dysregulation of miR-92b-3p in OSCC, which correlated with aggressive tumor characteristics. miR-92b-3p overexpression augmented proliferation and the epithelial-mesenchymal transition in both YD8 and SCC25 cell lines and xenograft models. Mechanically, augmented miR-92b-3p expression suppressed ATXN1 and CPEB3, activating the Notch signaling pathway and thereby promoting metastasis and cisplatin resistance. In our cohort, serum miR-92b-3p expression reflected the disease status, including relapse. Our results suggest that miR-92b-3p might be an onco-miR involved in OSCC through regulating the ATXN1/CPEB3/Notch pathway. These findings provide novel insights for treating and monitoring OSCC.