Bio-interfacial design of CPP- and TPP-functionalized nanocarriers for barrier-limited delivery: Mechanisms, design...

Peptide functionalization offers a way to improve nanocarrier transport across tissue and cellular barriers, but performance remains limited by competing interfacial requirements across the delivery cascade. Surface shielding supports circulation, whereas peptide exposure is needed for stromal access, membrane interaction, or endosomal escape. Cell-penetrating peptides (CPPs) and tissue-penetrating peptides (TPPs) contribute to different steps of delivery, and their function depends not only on peptide sequence but also on carrier architecture, ligand presentation, and the barrier being addressed. This review addresses membrane-associated entry of CPP-functionalized carriers, tissue-level transport mediated by TPPs, and dynamic surface designs that separate systemic stability from local activity. It also examines why commonly used experimental measurements do not provide equivalent evidence of delivery, and why accumulation, penetration, uptake, and functional intracellular access should be interpreted separately. Formulation heterogeneity, model dependence, reproducibility, and translational safety are discussed as practical constraints on the development of peptide-functionalized nanocarriers.