Synthesis And Biological Application Of Noble Metal Nanoclusters

Recently,ultrasmall noble metal nanoclusters（NCs）composed of several to hundreds of noble metal atoms such as gold,silver and platinum,have emerged as a new type of functional nanomaterials and attracted increasing research interest.Metal NCs are highly sensitive to their size,surface and structure.Moreover,metal NCs have sizes close to the electron fermi wavelength,which enables them to have discrete electronic states,exhibiting many molecule-like properties such as HOMO-LUMO transition,tunable luminescence,large stokes shift,quantized charging,molecular chirality and magnetism.Owing to such attributes,metal NCs have been widely used in sensing,bio-imaging and theranostic applications.In the NCs field,various wet chemical methods have been developed for the synthesis of metal NCs in polar and nonpolar solvents.For example,the classical two-phase Brust-Schiffirin（B-S）method has achieved great success in synthesizing atomically precise metal NCs.However,the synthesis of noble metal NCs of different sizes and compositions remains a major challenge due to the lack of in-depth understanding of the two-phase method.Meanwhile,compared to the successful advancement of homoleptic metal NCs,the same cannot be said of heteroleptic metal NCs due to their relatively complicated synthesis process as well as the possible incompatibility of binary ligands.In fact,heteroleptic metal NCs may be even more important in some fundamental and applied fields than homoleptic metal NCs because of their richer yet modifiable surface functionalities and improved physiochemical properties.There is,therefore,a pressing need to fundamentally understand the synthesis of heteroleptic metal NCs,which can be beneficial to their advancement in method design,NC synthesis,and applications.In terms of biological application of NCs,owing to their inherent ultra-small size,benign biocompatibility and good renal clearance,metal NCs showcase promising applications in fields of biological imaging,biosensing,antimicrobial and disease theranostics.Among them,Ag NCs show high-efficiency and broad-spectrum bactericidal performance in the antibacterial field,which is even better than that of the commercial Ag-based antibacterial agents（core size of>2 nm）.In addition,considering that reliable recovery of skin appendages including hair follicle,capillary vessels,and sweat glands remains the“holy grail”of skin tissue engineering and skin wound regeneration,developing an injectable Ag NCs-based hydrogel with broad-spectrum and long-term bactericidal efficacy for promoting hair follicle/tissue regeneration provides a new way to solve this problem.Taken together,the main content of this paper is as follows:1)Aiming at the problem that the cluster size can not be tailored due to the excessive usage of the phase transfer agent tetramonium bromide（TOAB）in the B-S method,this project reports the identification of two roles of TOAB in the two-phase B–S method:TOAB not only transfers Au（III）precursors but also transfers the reducing agent Na BH₄ from the aqueous to the organic phase.On this basis,a novel two-phase synthetic strategy is developed by decoupling the roles of the TOAB:（1）using the hydrophobic selenolate ligand to transfer Au（III）precursors from the aqueous to the organic phase via the formation of selenolate–Au（I）complexes and（2）deploying a small amount of TOAB as“shuttles”to transfer Na BH₄ into the organic phase for controlled reduction of selenolate–Au（I）complexes in organic phase.Using this strategy,size tuning of Au NCs at the atomic level could be achieved by simply varying the amount of TOAB.The high yields of Au NCs（≥76%）together with the short synthetic time（≤3 h）and size-tuning capability further illustrate the attractiveness of this synthetic strategy in the synthesis of atomic-precision metal NCs.2)To study the effect of hetero-ligands on the size of Au NCs,the affinity of different ligands to Au is studied in this study and it is found that（1）the binary ligands could exhibit an eclectic effect on the size control of Au NCs if the binding affinities of such hetero-ligands with Au are comparable and（2）the binary ligands could exhibit a competitive effect on the size control of Au NCs,and the size of the Au NCs could be determined by the ligand with stronger binding affinity to Au.Secondly,the formation mechanism of the heteroleptic Au NCs that originated from the complex precursors is unprecedentedly studied.The complex precursors of the heteroleptic Au NCs are identified to be the predominant hybridized ligand#1–Au（I）–ligand#2 species,which is helpful for understanding the synthetic mechanisms in depth.Moreover,the growth processes of the heteroleptic Au NCs are also monitored,and some fundamental perceptions about the growth pathway and the structures of the Au NCs are obtained.3)Reliable recovery of sweat glands and hair follicle as well as scar removal remain the major challenges in skin tissue engineering and skin wound regeneration.In view of this,an injectable antibacterial hydrogel is designed for wound healing via integrating antibacterial Ag₂₉ NCs and mangiferin（MF）molecules into the 3D network-structured chitosan（CH）hydrogel to eliminate bacterial infection and promote hair follicle/tissue regeneration.This design not only endows the hydrogel with excellent widespectrum antibacterial activities,superior biocompatibility,decent injectability,adequate swelling,and good degradability,but also favors the regeneration of capillary vessels/hair follicles/sweat glands for wound healings,which is the“holy grail”of skin tissue engineering.The antibacterial performance of the hydrogel is further improved through the controlled release of Ag species,the formation of a high local concentration of antibacterial Ag species on the hydrogel surface,as well as the capture of bacteria on the hydrogel surface via electrostatic interaction.In vivo experiments reveal that the hydrogel could eliminate bacterial infections and prompt the regeneration of hair follicles/capillaries of wounds,which significantly promotes the skin flap wound healing.This study could shed light on the design of multi-functional Ag NCs-based hydrogel for applications of skin tissue engineering and wound treatments.