Biofluid-Programmed Biological Identity of Nanocarriers: Consequences for Drug Targeting and Reproducible Delivery

Nanocarriers are commonly designed and evaluated based on their physicochemical properties, including size, morphology, surface charge, composition, ligand density, drug loading, and release behavior. After administration, however, nanocarrier surfaces are rapidly remodeled by proteins, lipids, metabolites, enzymes, mucins, salts, and immune components present in systemic, mucosal, luminal, and disease-associated biofluids, thereby generating an acquired biological identity. Rather than focusing predominantly on plasma protein coronas or individual exposure environments, this review integrates biofluid-specific biological identity across administration routes and pathological states with the dynamic evolution of hard and soft coronas and its consequences for colloidal stability, immune recognition, and therapeutic performance. A further distinguishing emphasis is the translation of these nano-bio interactions into biological-identity-by-design strategies, standardized biofluid testing, and formulation and quality-control considerations. Strategies for biological-identity-by-design, including controlled corona formation, albumin and apolipoprotein pre-coating, ligand-protein co-design, antifouling interfaces, biomimetic camouflage, and disease-fluid programming, are evaluated. Treating biological identity as a formulation and quality attribute may improve the predictability, reproducibility, safety, and clinical translation of advanced drug-delivery systems.