Currently, the frequent occurrence and complex treatment of fungal infections pose a serious threat to public health security [1], [2], [3]. Polyenes, azoles, flucytosine, and echinocandins are the primary antibiotics used to treat fungal infections, yet their use is associated with increasing antimicrobial resistance and an increase in adverse effects [4], [5], [6]. Innovative approaches to treat fungal infections are desperately needed in light of these issues with antibiotic resistance. [7], [8], [9], [10].

Copper ions served as cofactors for a variety of enzymes in the human body, playing a significant role in key physiological processes such as iron metabolism, energy production, and connective tissue cross-linking [11], [12], [13]. Recent research suggested that copper ion-mediated fungal cell death resembled cuproptosis, and this mechanism was considered a promising new strategy against fungal infections [14]. An excess of intracellular copper ions led to the impairment of the tricarboxylic acid (TCA) cycle, which causes the accumulation of lipoylated proteins and loss of iron-sulfur cluster proteins, thereby triggering a proteotoxic stress response and eventually leading to cell death [15]. Therefore, utilizing the mechanism of copper poisoning as a means to treat microbial infections was becoming an emerging and important therapeutic strategy. Unlike bacteria, fungal cells contained mitochondria where the TCA cycle took place, making fungi similarly susceptible to the effects of cuproptosis [16].

Nitric oxide (NO) gas therapy displayed great potential in combating fungal infections. [17] NO induced lipid peroxidation to damage fungal membranes and activated oxidative stress responses within fungi, achieving efficient antifungal effects. However, the stability of NO donors in the body and the precise control of release technologies remained challenging areas of research [18]. Researchers were exploring the use of external stimulation methods such as near-infrared laser to accurately control the release of NO, for example, N,N′-Di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine (BNN6) could release NO under photothermal effects, and in combination with nanotechnology, to enhance overall antimicrobial efficacy [19].

With the continuous advancement of nanotechnology, nanomotors were anticipated to become a key tool for future antifungal therapy [20], [21]. Nanomotors demonstrated significant advantages in antifungal treatment by utilizing chemical fuels and thermophoresis to achieve autonomous movement, thereby enhancing the penetration of biomembranes and enabling localized delivery of antifungal agents for effective fungal combat [22]. Thermophoresis was one of the key mechanisms driving the movement of nanomotors. Thus, selection of nanocomplexes with good photothermal conversion effects was crucial [23], [24]. Polydopamine (PDA) was an organic material with excellent photothermal conversion performance and biodegradability. Polydopamine possesses an extensive conjugated π-electron system, enabling it to effectively absorb light energy and convert it into heat, thus exhibiting excellent photothermal conversion capabilities. This material shows broad application potential in photothermal therapy (PTT) [25], [26]. PDA nanoparticles possessed satisfactory photothermal effects and drug loading capacity [27]. In contrast, gold could efficiently absorb near-infrared light and achieve photothermal conversion through surface plasmon resonance, with a photothermal conversion efficiency higher than that of PDA, making it an effective photothermal therapeutic agent [28], [29], [30]. When gold was combined with PDA, it enabled efficient photothermal conversion of the nanocomplex, thereby enhancing the performance of nanomotors. Therefore, by asymmetrically modifying gold on the surface of PDA, researchers can create a nanomotor with thermophoretic propulsion.

In this study, we developed a nanomotor named CPBHA. It is composed of polydopamine chelated with copper ions, loaded with BNN6, and coated with hyaluronic acid, followed by asymmetric gold modification. Under near-infrared light irradiation, the nanomotor moved in a directional manner due to thermophoresis. As the temperature increased, BNN6 activates and releases NO, which aided in the regulation of the nanomotor’s velocity. Precise control of the near-infrared light irradiation time and power allowed for the accurate regulation of the nanomotor’s movement (Fig. 1). Upon reaching the infection site, CPBHA effectively absorbed light energy at 808 nm under near-infrared light and converted it into heat energy, allowing for deep penetration into the infected area. Under the action of hyaluronidase secreted by Candida albicans (C. albicans) and photothermal therapy, CPBHA began to release copper ions and NO. NO and photothermal treatment together may change the microbial membrane's permeability, facilitating the absorption of Cu2+. After Cu2+ entered the fungal interior, it consumed the intracellular glutathione (GSH), leading to lipid peroxidation and affecting the TCA cycle, resulting in the cuproptosis of C. albicans. Excess NO could damage its DNA, effectively killing C. albicans rapidly. The combination of multiple lethal modes of action achieved an antifungal effect. This study, using C. albicans as a model, demonstrated how this nanocomplex could achieve a synergistic antifungal effect through gas sterilization, photothermal therapy and cuproptosis.