Understanding the interaction of nanomaterials with biological systems has always been of high concern and interest. An emerging type of nanomaterials, ultrasmall metal nanoclusters (NCs, < 2 nm in size), are promising in this aspect due to their well-defined molecular formulae and structures, as well as unique physical and chemical properties that are distinctly different from their larger counterparts (metal nanoparticles). For example, metal NCs possess intrinsic strong luminescence, which can be used for real-time tracking of their interactions with biological systems. Herein, luminescent gold (Au) NCs were used as traceable antimicrobial agents to study their interactions with the bacteria and to further understand their underlining antimicrobial mechanism. It is shown for the first time that the Au NCs would first attach on the bacterial membrane, penetrate, and subsequently accumulate inside the bacteria. Thereafter, the internalized Au NCs would induce reactive oxygen species (ROS) generation and damage the bacterial membrane, resulting in the leakage of bacterial contents, which can finally kill the bacteria. Traceable Au NCs (or other metal NCs) provide a promising platform to study the antimicrobial mechanisms as well as other fundamentals on the interfacing of functional nanomaterials with the biological systems, further increasing their acceptance in various biomedical applications.

A polymer-based nanocarrier was developed for the co-delivery of epigenetic and chemotherapeutic drugs. The sterically stabilized hybrid micelle system uses micelles composed of D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) and 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000). In this study, suberoylanilide hydroxamic acid (SAHA) and paclitaxel were used as model drugs for combination chemotherapy to enhance therapeutic efficiency in targeting mesenchyme-like triple negative breast cancer (TNBC) cells. Combination therapy of paclitaxel and SAHA in a dual drug micelle system, (P + S)_mic, exhibited an IC50 value of 0.52 μg/mL, which is about 5.91-fold more cytotoxic than the mere combination of free drugs (P + S). Furthermore, the (P + S)_mic formulation was far more effective at inhibiting cell migration by more than 3.4-fold than the control. Thus, our findings show that the co-delivery of these drugs using the micelle system greatly enhances their therapeutic effect at a lower dosage, thereby minimizing toxicity. In addition, this formulation is proved to be remarkably effective in preventing cell migration at low dosage.

Au nanoclusters (AuNCs) hold tremendous potential to be employed in a wide variety of biological applications. Despite the rapid development in the field of NCs synthesis, a comprehensive understanding of how cells interact with this class of ultra-small nanoparticles (< 2 nm) having defined sizes and surface chemistry, remains poorly understood. In this study, we show that the choice of the surface ligand used to protect AuNCs can significantly perturb cellular uptake and intracellular redox signaling. A panel of monodisperse, atomically precise AuNCs with different core Au atom number (i.e., Au₁₅, Au₁₈ and Au₂₅) protected with either mercaptopropionic acid (MPA) or glutathione (GSH) capping agent were synthesized and their effects on the generation of intracellular reactive oxygen species (ROS), cytotoxicity and genotoxicity of the NCs were assessed. Both mitochondrial superoxide anion (O₂^•–) and cytoplasmic ROS were found to be higher in cells exposed to MPA but not GSH capped AuNCs. The unregulated state of intracellular ROS is correlated to the amount of internalized AuNCs. Interestingly, MPA–AuNCs induction of ROS level did not lead to any detrimental cellular effects such as cell death or DNA damage. Instead, it was observed that the increase in redox status corresponded to higher cellular metabolism and proliferative capacity. Our study illustrates that surface chemistry of AuNCs plays a pivotal role in affecting the biological outcomes and the new insights gained will be useful to form the basis of defining specific design rules to enable rational engineering of ultra-small complex nanostructures for biological applications.

Metallic silver (Ag) and its ability to combat infection have been known since ancient history. In the wake of nanotechnology advancement, silver's efficacy to fight broad spectrum bacterial infections is further improved in the form of Ag nanoparticles (NPs). Recent studies have ascribed the broad spectrum antimicrobial properties of Ag NPs to dissociation of Ag⁺ ions from the NPs, which may not be entirely applicable when the size of Ag NPs decreases to the sub-2 nm range [denoted Ag nanoclusters (NCs)]. In this paper we report that ultrasmall glutathione (GSH)-protected Ag⁺-rich NCs (Ag⁺-R NCs for short, with a predominance of Ag⁺ species in the NCs) have much higher antimicrobial activities towards both gram-negative and gram-positive bacteria than the reference NC, GSH–Ag⁰-R NCs. They have the same size and surface ligand, but with different oxidation states of the core silver. This interesting finding suggests that the undissociated Ag⁺-R NCs armed with abundant Ag⁺ ions on the surface are highly active in bacterial killing, which was not observed in the system of their larger counterpart, Ag NPs.