<p>Tissue Nanotransfection (TNT) is an emerging and transformative platform for non-viral drug and gene delivery that enables highly efficient, precise, and rapid (millisecond-scale) transfer of molecular cargo into solid tissues. Using silicon nanochannels, TNT electrophoretically drives charged payloads (<i>e.g.,</i> plasmid DNA, miRNA, etc.) through transient membrane pores created by brief electric pulses. Beyond its capacity for localized delivery, TNT can induce systemic therapeutic effects by repurposing tissues in situ to function as biofactories. Recent studies demonstrate that TNT-engineered skin can be harnessed to release extracellular vesicles (EVs) enriched with delivered molecular cargo and functionalized with targeting ligands, as well as potent metabolites capable of modulating distant tissues. These engineered products can engage in inter-organ communication, extending the biological reach of localized interventions for both therapeutic and fundamental research applications. Moreover, TNT could conceivably be used to generate reprogrammed cells within the skin that migrate to extracutaneous sites, where they may contribute to tissue repair, immune modulation, or other systemic effects. Altogether, this precision-driven and benign delivery approach positions TNT as a transformative non-viral technology capable of converting accessible tissues into programmable bioactive hubs that modulate systemic physiology and disease, offering new avenues for novel therapies and mechanistic discovery.</p> Graphical Abstract <p></p>