Kaiyuan Zheng

Genetic medicine has established a transformative paradigm for precision therapy. To date, most advances have relied on viral vectors and non‐viral lipidic and polymeric nanocarriers. Although metal nanomaterials have not achieved clinical approval for gene therapy, recent progress in precise synthesis and versatile functionalization has made them promising candidates, together with their unique physicochemical characteristics and intrinsic theranostic properties. This review first summarizes recent advances in the most widely studied metal nanomaterials, gold nanoparticles, for delivery of diverse genetic cargoes through covalent conjugation and electrostatic assembly, emphasizing the rational design of hybrid nanoplatforms for stimuli‐responsive release and synergistic gene therapy effects. Distinctive internalization mechanisms and key physicochemical properties governing therapeutic efficacy are also discussed. Subsequently, emerging ultrasmall metal nanoclusters are highlighted, which can be engineered at the atomic level and exhibit unique in vivo performance, including efficient renal clearance, intrinsic luminescence, theranostic capability, and gene therapy efficacy. Other metal‐based platforms, such as metal–organic frameworks and iron oxide nanoparticles, are also covered. Finally, key challenges and future opportunities for engineering metal nanomaterials in genetic medicine are identified, with particular emphasis on the role of artificial intelligence and modular design in overcoming manufacturing scalability and regulatory barriers to clinical translation.

Bacterial resistance toward antibiotics is a world‐wide problem, and one potential solution to fight against the resistance is to develop multi‐mechanism antimicrobial agents to achieve synergistic performance. Titanium carbide (MXene) is an emerging 2D nanomaterial with antimicrobial ability to physically damage bacterial membrane and chemically induce oxidative stress, and it can be further conjugated with nanomaterials to improve its antibacterial performance. Herein, a synergistic antimicrobial agent is developed through conjugation of the ultra‐small gold nanoclusters (AuNCs) on MXene nanosheets. The conjugated AuNCs are effectively delivered into bacteria after bacterial membrane damage caused by MXene, generating localized reactive oxygen species (ROS) of high concentration to effectively oxidize bacterial membrane lipid for enhanced membrane broken, as well as bacterial DNA for violent fragmentation. Thus, the synergistic physical (via MXene) and chemical (via MXene and AuNCs) antimicrobial mechanisms lead to eventual bacterial death of both Gram‐positive and Gram‐negative bacteria, with low IC₅₀ values of 11.7 µg mL⁻¹ of MXene and 0.04 µm of AuNCs. Moreover, the crumpled MXene‐AuNCs structure is constructed to inhibit biofilm formation, which hold synergistic antibacterial ability of MXene‐AuNCs conjugation, hydrophobic surface to prevent bacterial attachment, and large surface area containing higher density of bactericides.

Alloying is an efficient chemistry to diversify the properties of metal nanoparticles, however the atomic-level understandings of the composition dependent physicochemical properties and their related biological performance are presently lacking. Here, we developed a full spectrum of alloy metal nanoclusters (NCs): AuxAg25-x(MHA)18 (MHA = 6-mercaptohexanoic acid) with x = 0 – 25, and investigated their composition dependent antimicrobial performance. Interestingly, we observed a U-shape antimicrobial behavior of AuxAg25-x(MHA)18 NCs, where the alloy NCs showed decreased antimicrobial ability instead of the common trend of increasing. Detailed atomic-level characterizations of the AuAg NCs suggest that the decreased performance of alloy NCs is due to their enhanced stability after alloying, which can deactivate their capability in generating reactive oxygen species (ROS) that can kill the bacteria. More interestingly, the transition point of the antimicrobial performance was only obtained with our full-spectrum AuxAg25-x(MHA)18 NCs, which indicates the importance of exploring the composition dependent properties and application performance in a full-spectrum composition range. A library of full-spectrum alloy NCs also provides a good platform to investigate other composition dependent physicochemical and biological properties of metal NCs.

Alloying metal materials with heterometal atoms is an efficient way to diversify the function of materials, but in-depth understanding of the dynamic heterometallic diffusion inside the alloying materials is rather limited, especially at the atomic level. Here, we report the real-time monitoring of the dynamic diffusion process of a single gold (Au) atom into an atomically precise silver nanocluster (Ag NC), Ag25(MHA)18 (MHA = 6-mercaptohexanoic acid), by using in situ UV-vis absorption spectroscopy in combination with mass and tandem mass spectrometry. We found that the Au heteroatom first replaces the Ag atom at the surface Ag2(MHA)3 motifs of Ag25(MHA)18. After that, the Au atom diffuses into the surface layer of the icosahedral Ag13 kernel, and finally occupies the center of the alloy NCs to form the thermodynamically stable [email protected](MHA)18 product. Density functional theory (DFT) calculations reveal that the key thermodynamic driving force is the preference of the Au heteroatom for the central site of alloy NCs. The real-time monitoring approach developed in this study could also be extended to other metal alloy systems to reveal the reaction dynamics of intra-cluster diffusion of heteroatoms, as well as the formation mechanisms of metal alloy nanomaterials.

Bacterial resistance toward antibiotics has been a worldwide threat; one way to fight against the resistance is to develop a multimechanism antibacterial agent to achieve synergistic performance. Graphene oxide (GO) is an emerging antibacterial agent combining multiple mechanisms (physical insertion and chemical disruption), and its rich functional groups enable the complexation/conjugation of nanomaterials to further improve antibacterial performance. Herein, a synergistic antimicrobial agent is established through the assembly of paramagnetic holmium ions and gold nanoclusters (AuNCs) onto GO nanosheets. The assembled nanosheets can be vertically aligned under weak and practical magnetic fields (T ), providing high‐density sharp edges with preferential orientation to effectively pierce the bacterial membrane. Also, the conjugated AuNCs are efficiently delivered into bacteria to induce high oxidative stress, which strongly disturbs bacterial metabolism, leading to the death of both Gram‐positive and Gram‐negative bacteria. The antibacterial agent uses both physical (via oriented GO) and chemical (via GO and AuNCs) mechanisms to achieve synergistic antimicrobial performance with low IC₅₀ values of 9.8 µg mL⁻¹ on the basis of GO and 0.39 × 10⁻⁶ m on the basis of AuNCs. This multicomponent agent with dual antimicrobial mechanisms is expected to be a promising multifunctional‐antimicrobial agent with high biosafety.

Ligand structure could control the size and structure of thiolate-protected silver nanoclusters (Ag NCs) in water. Small alkane-thiols, medium-sized aromatic-thiols, and bulky thiol-containing tri-peptides direct the formation of Ag₂₅(SR)₁₈, Ag₄₄(SR)₃₀, and Ag_9–15(SR)_5–10, respectively. In addition, small alkane-thiol collocates well with other types of thiolate ligand to generate bi-thiolate-protected Ag₂₅ NCs with controlled ligand landscapes on their surfaces.

Bulk gold (Au) is known to be chemically inactive. However, when the size of Au nanoparticles (Au NPs) decreases to close to 1 nm or sub-nanometer dimensions, these ultrasmall Au nanoclusters (Au NCs) begin to possess interesting physical and chemical properties and likewise spawn different applications when working with bulk Au or even Au NPs. In this study, we found that it is possible to confer antimicrobial activity to Au NPs through precise control of their size down to NC dimension (typically less than 2 nm). Au NCs could kill both Gram-positive and Gram-negative bacteria. This wide-spectrum antimicrobial activity is attributed to the ultrasmall size of Au NCs, which would allow them to better interact with bacteria. The interaction between ultrasmall Au NCs and bacteria could induce a metabolic imbalance in bacterial cells after the internalization of Au NCs, leading to an increase of intracellular reactive oxygen species production that kills bacteria consequently.