Elucidation of the Structure Determinants for the Delivery Process of Phospholipid-Based Nanomaterials Using a Combinatorial Nanoparticle Library Approach.

Phospholipids are biocompatible and versatile materials commonly used in the design of nanodelivery systems. However, the relationship between the structural characteristics of phospholipids and the physiological behavior of lipid-based nanoparticles remains inadequately understood. To explore the key structural features influencing efficient and targeted delivery, we created a library of phospholipid-coated gold nanoparticles (Lip@AuNPs), comprising 12 distinct formulations. These nanoparticles varied systematically in their headgroups (PA, PS, PC, and PE) and aliphatic chain lengths (6:0, 12:0, and 18:0). We investigated their effects on protein adsorption, cellular uptake, and in vivo delivery. Our findings showed that phospholipids with zwitterionic headgroups (PC and PE) reduced complement protein adsorption, enhanced selective uptake by nonphagocytic cells, and promoted increased accumulation in the spleen. Conversely, AuNPs coated with phospholipids containing shorter aliphatic chains exhibited higher serum protein adsorption, resulting in decreased and nonselective cellular uptake, which extended the circulation time of the nanoparticles in the bloodstream. This combinatorial approach provides valuable insights into the role of the phospholipid structure in nanoparticle design and offers practical guidance for developing lipid-based delivery systems with improved targeting and therapeutic efficacy.