"Actual" peptide properties required for nanoparticle development in precision cancer therapeutic delivery

Functionalizing nanoparticles with peptides (3-30 amino acids) reduces premature clearance and increases colloidal stability and targeting capacity of cancer therapeutics. Glutamate/lysine-rich zwitterionic and hydrophilic/neutral peptides minimize reticuloendothelial digestion of nanomedicine through reducing particle hydrophobicity and depressing plasma anti-PEG immunoglobulin that disrupts the PEG-based particle stealth. Anionic peptides negate protein corona formation and subsequent particle aggregation in vivo enabling efficient nanoparticles biodistribution and drug targeting by facilitating their endothelial/extracellular matrix pore diffusion. Cationic and hydrophobic peptides display a strong affinity for anionic cancer cell membrane and mediate membrane porosification or receptor binding leading to particle uptake and endocytosis. The peptide ionic and hydrophobicity/hydrophilicity attributes collectively facilitate endosomal escape, and nuclear and mitochondria targeting of nanoparticles. Peptides are required to present with different physicochemical attributes from administration site, through blood and extracellular matrix, to cancer site of action. Charge/hydrophilicity-hydrophobicity switching and projection of receptor-specific domain of peptides are attainable through pH-pKa interplay and labile bond hydrolysis of "unwanted" domain to give rise to new functional domains in response to pH, thermal and enzymatic stimuli. Co-introducing all functional attributes on a single peptide is challenging. Use of peptide blends risks leaching during nanoparticles production. Peptides-nanoparticles conjugation risks peptide conformational alterations and loss of acidic/basic termini affecting their roles in nanoparticle stabilization, targeting, membrane permeabilization and subcellular delivery.