C. albicans, a major opportunistic and pathogenic fungus, can cause both superficial and systemic infections, posing a serious life-threatening risk to immunocompromised or immunodeficient patients [1]. To combat these infections, conventional antibiotics such as azoles, polyenes and allylamines are widely used in clinical practice. Unfortunately, inappropriate use of antibiotics has led to an increase in drug resistance, resulting in a higher mortality rate associated with C. albicans infections [2]. Therefore, there is an urgent need to explore alternative non-antibiotic therapeutic approaches.

One such promising alternative is aPDT, which offers a non-antibiotic method of treating localized fungal infections, particularly of the skin or mucosa [3]. aPDT is based on non-toxic photosensitizers (PSs) which, when exposed to light of the correct wavelength, induce the generation of reactive oxygen species (ROS) [4]. These ROS can degrade essential cellular components such as intracellular DNA, proteins and membrane lipids, effectively eradicating fungi [5]. The non-specific and multi-targeted action of aPDT is proving to be an effective approach against drug-resistant fungal infections.

Traditional Chinese medicine, known for its antimicrobial properties, offers potential solutions for various infectious diseases. Curcumin, the bioactive component of turmeric [6], has numerous health benefits and pharmacological effects. This non-toxic hydrophobic polyphenol (Fig. 1A) is also known for its antimicrobial photodynamic activity [7,8]. The potential of curcumin-mediated aPDT (Cur-aPDT) against C. albicans has been extensively investigated [9]. However, there are limitations to the clinical translation of Cur-aPDT for the treatment of C. albicans infections. For example, ROS generated during aPDT have a short lifespan (≈ 3 μs) and are readily quenched within a limited diffusion range (< 0.3 μm). Thus, the efficacy of aPDT in inactivating fungi is highly dependent on the ability of PSs to adhere to the outer cell membrane and facilitate transmembrane transport [10]. Unfortunately, the poor water solubility of curcumin in aqueous solutions limits its bioavailability and cellular uptake [11]. In addition, the fungal cell wall, composed mainly of glucans and chitin, acts as a barrier preventing curcumin from entering the fungal cytoplasm [12].

Synergistic drug screening is emerging as a promising strategy to combat drug-resistant fungal infections, potentially overcoming the limitations of individual drug efficacy. This approach offers numerous advantages, such as improved therapeutic efficacy, reduced drug dosage, minimal toxicity, improved patient compliance and mitigation of drug resistance [13]. It is also less time-consuming and costly than the development of novel PSs, such as cation-modified PS conjugates. In one successful example, polymyxin B, a cationic polypeptide with membrane disorganizing activity, significantly enhanced the bactericidal efficacy of Cur-aPDT against Pseudomonas aeruginosa [14]. However, peptides often face challenges such as high cost and susceptibility to degradation and inactivation.

Borneol, a natural extract, is characterized by a highly hydrophobic bicyclic monoterpene structure (Fig. 1B). This compound has been used in traditional Chinese medicine for over a millennium under names such as “bing pian” or “long nao” [15]. It is found in several medicinal plants including Dipterocarpus turbinatus, Rosmarinus officinalis and Salvia officinalis [16]. Borneol's stability and multiple biological effects such as antifungal, analgesic, anti-inflammatory and antioxidant properties [16,17] make it a valuable resource in various industries such as food, pharmaceuticals, perfumery and cosmetics [18]. Furthermore, borneol has shown the potential to enhance permeation, particularly in improving the bioavailability of poorly permeable drugs in the brain, eyes and nasal cavity [19]. Given this property, the primary objective of this study is to assess whether borneol can facilitate the cellular uptake of curcumin by C. albicans, thereby enhancing its photodynamic fungicidal efficacy. In addition, we aim to uncover the underlying mechanism of this combination using biochemical assessments and transcriptomic techniques. These efforts will provide a solid foundation for the development of novel therapeutic strategies tailored to superficial fungal skin infections.