Lipid Tail Length Determines Nano‐Bio Interactions of Peptide Amphiphile Nanostructures

ABSTRACT Understanding the interactions of nanomaterials with biological systems is essential to designing effective nanomedicines. However, most of our understanding originates from studies with solid nanoparticles, and nano‐bio interactions of self‐assembled nanomaterials have remained largely unexplored. To address this knowledge gap, we develop a series of self‐assembling peptide amphiphiles (PAs) with different lipid modifications and investigate their interactions with biological systems. We find that PA nanostructures rapidly disassemble and reassemble with albumin and lipoproteins in blood plasma. While PAs with shorter lipid tails mainly assemble with albumin, increasing lipid length shifts binding to lipoproteins. All PAs show strong tumor accumulation in 4T1 tumor‐bearing mice with tumor to liver ratios of ∼3–6. Overall, albumin‐binding improves blood circulation (up to 1.6‐fold) and tumor accumulation (up to 3‐fold) compared to lipoprotein‐binding, but also shows slower healthy tissue clearance. This study shows that the biointeractions of self‐assembled nanomaterials can be controlled through molecular design, which may lead to the development of effective nanomedicines.