Unlocking the Architecture and Component Distribution of Bioengineered and Derived Colloidal Structures from Blood with Neutron Scattering

Blood‐ and blood cell‐derived colloidal materials are gaining traction as platforms for targeted therapeutics, imaging, and theranostics. To fully exploit their potential, high‐resolution insight into their structural and compositional features is critical. Here, small‐ and ultra‐small‐angle neutron scattering (SANS/USANS) with contrast variation (CV) is applied to characterize red blood cell (RBC) ghosts, RBC‐derived extracellular vesicles (RBCEVs), vesicle‐depleted human plasma ( vd plasma), and human serum albumin (HSA). SANS identifies key contrast match points for lipids (0.5 × 10 − 6 Å − 2 ), proteins (2 × 10 − 6 Å − 2 ), and cell membrane mixed lipid–protein phases (≈1.4 × 10 − 6 Å − 2 ). The compositions, shapes, sizes, and thicknesses of these materials are revealed via structural analyses using model fitting. RBCEVs are resolved as spherical vesicles with a 257 nm diameter and a 3 nm lipid bilayer, supported by data from cryogenic electron microscopy, dynamic light scattering, and nanoparticle tracking analysis. For the first time, SANS reveals differences in structural organization between RBCEV membranes and RBC ghosts, as well as insights into the internal protein and water content of RBCEVs, offering new perspectives on their nanoarchitecture. This study highlights the power of SANS/USANS in resolving complex, hierarchical structures in bioinspired colloids, paving the way for rational design of functional blood‐derived nanomaterials.