TSPAN14 is a tetraspanin that functions as a key regulator of ADAM10 metalloprotease trafficking and substrate specificity. As a member of the TspanC8 subgroup, TSPAN14 directly interacts with ADAM10 to facilitate its exit from the endoplasmic reticulum, enzymatic maturation, and trafficking to the cell surface 1. This interaction is essential for ADAM10 to access its substrates; TSPAN14 negatively regulates ADAM10-mediated cleavage of GP6 while promoting cleavage of CDH5 2. TSPAN14 has emerged as clinically relevant in multiple disease contexts. Genome-wide association studies identified TSPAN14 as a novel Alzheimer's disease risk gene 3, with functional studies demonstrating that the AD-associated variant rs7922621 reduces ADAM10 cell surface expression and alters soluble TREM2 shedding in microglia 4. TSPAN14 is also implicated in rheumatoid arthritis and cardiovascular disease, with the rs7098414 variant identified as a pleiotropic locus 5. Additionally, TSPAN14 functions as a restriction factor for Venezuelan equine encephalitis virus entry 6. As an efficient extracellular vesicle-sorting protein, TSPAN14 accumulates 50-170 GFP molecules per vesicle, making it valuable for EV engineering applications 7.