Synthetic nanoparticles for cell-type specific, spatially resolved miRNA loading and export in neural cells

Brain development and plasticity depend on specific microRNA (miRNA) expression patterns across cell types and subcellular compartments. Nevertheless, comprehensive profiling of localized brain miRNAs is still limited by challenges in isolating individual cell types or compartments and in detection sensitivity. To overcome these limitations, we advanced HIV-1 Gag’s ability to bind host miRNAs within Virus-like Particles to develop Synthetic Nano-Particles for Precise miRNA loading and export (SNaP). Our data establish SNaP’s modularity and portability to clinically-relevant neural cells, with particle yields matching benchmark packaging cells. SNaP integration with a cell-specific promoter enabled lineage-restricted miRNA export, while incorporating a Dendritic Localization Signal improved the specificity of postsynaptic miRNA recovery over traditional synaptosomes. Additional engineering with a miRNA-binding module synergistically boosted synaptic miRNA packaging in a sequence-independent manner. Collectively, our work positions SNaP as a technological advancement supporting the high-resolution, spatially resolved profiling of non-coding RNAs, adaptable to diverse polarized or heterogeneous tissues.