Incorporation of Molecular Nanoparticles Inside Proteins:The Trojan Horse Approach in Theranostics

CONSPECTUS:Molecular nanoparticles,MNPs,characterized by well-defined chemical formulas,structures,and sizes can interact with a variety of proteins.Fullerenes,carboranes,and gold nanoclusters well represent the diversity of MNPs properties available in nanoscience.They can have diameters smaller than 1.5 nm,be hydrophilic or hydrophobic,and can use a paraphernalia of means to establish local and global interactions with the amino acidic residues of proteins.Proteins,endowed as they are with an assortment of pockets,crevices,and gaps are natural supramolecular hosts to incorporate/hide/transport MNPs directly in water with a facile and“green”approach.This Account identifies and discusses the rules that govern the interactions and binding between MNPs and proteins.Fullerenes are composed solely by carbon atoms arranged to form hollow polyhedra.Hydrophobic interactions occur between aliphatic residues and the fullerene surface.The amino acids most effectively interacting with fullerenes are aromatic residues that establishπ−πstacking interactions with the cage.Amphiphilic and charged residues produce also cation−π,anion−π,and surfactant-like interactions with the cages.Carboranes are composed of boron,carbon,and hydrogen atoms,also arranged to form cages.They are hydrophobic with unusual properties originating from the presence of boron atoms.Hydride-like hydrogens bound to the boron atoms govern carborane chemistry.These negatively charged hydrogens do not participate in classic hydrogen bonding with water and promote hydrophobic interactions with proteins.On the contrary,the electronegativity of these hydrogens drives the formation of unconventional dihydrogen bonds with the acidic hydrogen atoms of positively charged amino acid.Carboranes also establish C−H…πand B−H…πinteractions with aromatic residues.Gold nanoclusters,AuNCs,are synthesizable with atomically precise stoichiometry.Amino acid residues with sulfur atoms or with nitrogen-containing heterocycles are the strongest Au binders.The proteins can act as supramolecular hosts but also as templates for the synthesis of AuNCs directly inside the protein core.Of the pristine amino acids,tryptophan,tyrosine,phenylalanine,and aspartic acid are the most efficient reducing groups.In a peptide sequence,the best Au-reducing moieties are obtained by nitrogencontaining residue such as glutamine,asparagine,arginine,and lysine.The investigation of the interactions between AuNCs and proteins therefore adds further complexity with respect to that of fullerenes and carboranes.The selection of the host proteins should consider that they will have to contain active sites for metal ion accumulation and ion reduction where AuNC can form and stabilize.This Account further discusses the hybridization of MNPs with proteins in view of creating innovative multifunctional theranostic platforms where the role of proteins is akin to that of“Trojan Horses”since they can(i)hide the MNPs,(ii)control their cellular uptake,(iii)drive their crossing of physiological barriers,and(iv)ultimately govern their biological fate.