Since the rapid development of nanoscience and nanotechnology, nanomedicine, as an important branch of nanomaterial applications, has flourished in the past two decades. Nanomedicine has also evolved from the initial stage of liposome-encapsulated nanodrugs to develop advanced drug delivery systems designed as multifunctional therapy platforms targeting various diseases. Tracing the history of nanomedicine’s development, the development of inorganic nanomedicine has witnessed a transformative shift from initially focusing on biological medical imaging towards the design of targeted platforms for disease therapies, and eventually culminating in the establishment of an integrated system that combines the regulation of the immune microenvironment with targeted therapy to achieve effective disease treatment [1]. While the advantages of targeted delivery, active targeting design, the passive targeting effect of the enhanced permeability and retention (EPR) effect, combination therapy effects, and favorable pharmacokinetics have profoundly improved therapeutic outcomes in nanomedicine [2], there are still challenges to overcome and explore, such as precise composition information, low drug utilization, and the balance between toxicity and efficacy. Among these challenges, the good dispersion, uniformity, and precise composition information of the nanomedicine is critical for nanomedicine to be recognized as a viable option for drug development. Fortunately, the advent of atomically precise metal NCs has turned this fascination into a reality, where no two nanoparticles are the same.
Metal NCs with a metal core of less than 2 nm typically contain several to hundreds of metal atoms. The ultrasmall size reaching the Femi wavelength of electrons makes the metal NCs exhibit discrete electronic structures, tunable HOMO-LUMO transitions, and size-dependent tuned optical properties [3], [4], [5]. Meanwhile, the size of metal NCs bridges the gap between metal atoms and traditional nanoparticles. Studying the metal NCs’ structure and growth process is beneficial for our understanding of the evolution and growth processes of nanoparticles. It also helps us comprehend the ultimate fate and interaction mechanisms of metal ions or nanoparticles within biological systems. The fluorescence properties are owned by the highest occupied orbital and the lowest unoccupied orbital (HOMO-LUMO) transition of the electrons between the occupied d bands and sp bands, the selective enzyme-like catalytic activity, and the immune regulation performance make metal NCs ideal candidates for next-generation materials in diverse areas of biomedical science. Though some metal NCs possess the potential to kill tumor cells, inhibit bacteria, combat viruses, and regulate immune activities, the further application of these metal NCs is restricted by their potential toxicity. For instance, the Ag NCs could exhibit potential toxicity, leading to damage or even death of normal cells, disrupting the balance of normal flora, and even exhibiting neurotoxic effects [6]. Similarly, Pt NCs have exhibited good biological safety at the same concentration as first-line antitumor drugs. However, it is crucial to carefully assess and investigate the availability and potential toxicity of Pt NCs since it depends on DNA damage through the production of Pt ions during metabolism [7]. Hence, both the bioeffect and biological toxicity should be carefully balanced when considering metal NCs as a biological medical treatment.
Au NCs generally exhibit favorable in vivo biosafety profiles, a key advantage underpinned by their efficient renal clearance. This clearance capability minimizes long-term systemic retention and reduces off-target accumulation in vital organs, thereby lowering toxicity risks [8], [9]. Recent mechanistic insights have further elucidated this process. For instance, ultrasmall Au NCs can be efficiently filtered and excreted, bypassing extensive sequestration by the mononuclear phagocyte system [10]. More profoundly, paradigm-shifting studies reveal that renal clearance is an actively regulated process. At the glomerulus, the barrier functions as an atomically precise “bandpass filter” for sub-nanometer clusters, where size-dependent interactions with the glycocalyx dictate clearance rates [11]. Concurrently, proximal tubules employ a charge-dependent “organelle extrusion” mechanism to actively eliminate endocytosed nanoparticles, ensuring the removal of even biotransformed materials [12]. These foundational insights into charge- and size-specific clearance pathways provide a critical framework for the rational design of safe, clinically translatable Au NC-based nanomedicines.
The structurally tunable optical properties, ranging from the ultraviolet (UV) region to the near-infrared Ⅱ (NIR-Ⅱ) region, make it a promising candidate for biosensors and bioimaging applications. The most promising clinical application is the utilization of near-infrared fluorescence for tumor surgery. In the near-infrared region, the combination of weak biological background and high tissue permeability facilitates improved imaging and guided surgery at the site of the lesion. Moreover, due to the enhanced fluorescent quantum yields of Au NCs, singlet oxygen (1O2) can be generated through the intersystem crossing and subsequent relaxation from the triplet state to the ground state. This property can facilitate the realization of fluorescence imaging-assisted photodynamic therapy. As a high-Z element, Au is commonly utilized as a radiosensitizer to enhance the local radiation dose by absorbing, scattering, and emitting radiation energy for radiation therapy. Compared to normal tissue, it can be increased by 100 times in the keV energy range and is used for radiation therapy [13]. Scattering photons, electrons, electron-positron pairs, or fluorescence generated by X-ray radiation may also cause secondary effects, ultimately leading to damage and killing cancer cells. Compared with traditional Au nanoparticles, the atomically precise Au NCs tend to have faster kidney clearance from the body, which reduces accumulation in the liver and spleen, thereby reducing changes in gene expression and the occurrence of liver necrosis [14]. The stability of the simultaneous structure also decreases the potential damage to the body caused by ions generated from the degradation of Au NCs. Besides, on the one hand, Au NCs can inhibit virus replication and amplification by regulating key enzyme activity or influencing viral transfection and replication processes. On the other hand, Au NCs can exhibit antibacterial activities by diffusing into bacteria and inducing a burst of reactive oxygen species (ROS), resulting in the oxidation of bacterial membranes and disruption of bacterial metabolism. Most importantly, Au NCs also exhibited antioxidant and immune regulation activities by upregulating the expression level of antioxidant enzymes and inhibiting proinflammatory cytokines [15].
Collectively, Au NCs have demonstrated unique bioeffect performance and have enormous potential for application in the biomedical field. Numerous reviews on Au NCs have been published, focusing on specific optical properties, synthesis methods, or their broad diagnostic and therapeutic roles [16], [17], [18], [19], [20]. However, a comprehensive systematic review is needed to elucidate its applications in the field of biomedical research from a perspective of biological effects. Therefore, this review aims to explore the mechanisms of its biological effects and derive its biological applications, particularly focusing on its applications in the prevention, control, and treatment of diseases and pathogenic microorganisms. Given this, as described in Scheme 1, this review primarily focuses on the following aspects: Firstly, the design strategies for preparing the atomically precise Au NCs with good biocompatibility and biosafety. Secondly, review the mechanisms of its biological effects and the biomedical applications in the prevention, control, and treatment of diseases and pathogenic microorganisms. Moreover, this article will systematically review the application prospects and challenges of Au NCs, including our optimistic views and thoughts on the future applications of Au NCs in the biomedical field.