The progress and future of the treatment of Candida albicans infections based on nanotechnology

Abstract

Systemic infection with Candida albicans poses a significant risk for people with weakened immune systems and carries a mortality rate of up to 60%. However, current therapeutic options have several limitations, including increasing drug tolerance, notable off-target effects, and severe adverse reactions. Over the past four decades, the progress in developing drugs to treat Candida albicans infections has been sluggish. This comprehensive review addresses the limitations of existing drugs and summarizes the efforts made toward redesigning and innovating existing or novel drugs through nanotechnology. The discussion explores the potential applications of nanomedicine in Candida albicans infections from four perspectives: nano-preparations for anti-biofilm therapy, innovative formulations of "old drugs" targeting the cell membrane and cell wall, reverse drug resistance therapy targeting subcellular organelles, and virulence deprivation therapy leveraging the unique polymorphism of Candida albicans. These therapeutic approaches are promising to address the above challenges and enhance the efficiency of drug development for Candida albicans infections. By harnessing nano-preparation technology to transform existing and preclinical drugs, novel therapeutic targets will be uncovered, providing effective solutions and broader horizons to improve patient survival rates.

Keywords: Candida albicans; Drug resistance; Hyphae; Nanomedicine; Subcellular organelles.

Fig. 1

Schematic overview of the targeted drugs for the treatment of Candida albicans infections discussed in this article. These targeted nanomedicines primarily target different organelles within Candida albicans. The outermost layer shows the mechanism of action of the individual targeted drugs on the respective organelles

Fig. 2

(A) Schematic illustration of Chitosan-modified photodynamic nanoparticles destroying biofilm. (B) Inhibition efficiency of biofilm formation with PDT. The biomass was measured immediately after PDT (+ Laser) and 21.5 h after PDT (+ Laser + 24 h). Reproduced with permission [40]. Copyright 2023, American Chemical Society. (C) Schematic illustration of MLPGA antifungal strategy assisted by targeted degradation exopolysaccharides in the biofilms. (D) 3D confocal images of SYTO 9 stained mature Candida. albicans biofilms after different treatments. Reproduced with permission [46]. Copyright 2022, Wiley-VCH

Fig. 3

Schematic illustration of the most important resistance mechanisms of current drugs in Candida albicans infections. Mutations in certain genes, including the ERG and FKS genes, result in alterations to the drug targets encoded by these genes. Additionally, mutations in two specific transcription factors trigger the upregulation of ABC transporters and MF transporters, ultimately leading to the overexpression of the drug efflux pump. Over-expression of genes leads to an increase in the number of targets for drugs, such as ergosterol, thereby diminishing the therapeutic effectiveness of the drugs. When drugs act on the cell membrane, it generates pressure, and this cell membrane stress can also impact certain regulators and upregulate certain genes, thereby promoting drug tolerance

Fig. 4

(A) Schematic illustration of fabrication process of the liposomes and decoration with red blood cell membrane. The transmembrane domain of Band3 on the red blood cell membrane can connect the P4.2-derived peptide on the surface of nanoparticles. Once anchored onto the liposome surface, the nanoparticle engages with the isolated RBC membrane using a “molecular affinity” strategy. This interaction serves to orient the right side outward and enhances AmB targeting capability towards the cell membrane. Reproduced with permission [56]. Copyright 2019, American Chemical Society. (B) Schematic illustration of a nanoparticle conjugated with histatin 5 and AmB. Antifungal peptide histatin 5 as a novel ligand that targets fungal pathogens specifically in infected animal models. pH-sensitive histatin 5 and AmB with a redox-sensitive linker were self-assembled into nanoparticle to enhance ability of targeting infection site. The accuracy of AmB delivery to cell membrane is improved, which can reduce the toxicity and adverse reactions of drugs. Reproduced with permission [64]. Copyright 2017, Elsevier

Fig. 5

Schematic illustration of main organelles in Candida albicans as antifungal targets and their physiological functions

Fig. 6

The process of antifungal drugs targeting specific organelles and their subsequent effect on those organelles. (A) Certain drug molecules inhibit the proteasome, preventing the proteasome from degrading faulty proteins. (B) Many drugs can disrupt the structure of the mitochondria, damage the respiratory chain, and inhibit ATP synthesis, which ultimately leads to depletion of the energy supply. (C) Modified drugs show improved targeting of the endoplasmic reticulum and exert pressure on it. In addition, specific inhibitors of endoplasmic reticulum regulatory factors can attenuate drug resistance. (D) Drugs that target the cell nucleus are primarily aimed at destroying nuclear and DNA structures. They can also inhibit certain DNA-related enzymes, such as DNA repair enzymes. (E) Antifungal drugs hinder the transport of substances via extracellular vesicles and prevent the formation of biofilms by suppressing vesicle-related proteins

Fig. 7

(A) Schematic illustration of Candida albicans hypha and its physiological functions. (B) Inhibition of the phenotypic transformation can deprive Candida albicans of virulence by lowering the content of iron ions and oleic acid and controlling the gene expression of hyphae

Fig. 8

(A) Schematic diagram illustrating the role of hyphae in mediating macrophage death and facilitating Candida albicans escape from macrophages. Reproduced with permission [178]. Copyright 2021, Springer Nature. (B) The filamentation morphology of positive controls, NPsAg-31 and NPsAg-43 of both Candida albicans SC 5314 and ATCC 10,231, using fluorescence with Calcofluor white. Reproduced with permission [148]. Copyright 2021, Springer Link. (C) Signal transduction pathways leading to expression of hypha-specific genes. Reproduced with permission [176]. Copyright 2011, Springer Nature. (D) The filamentation morphology of Candida albicans after co-incubation with YM medium (control) and FeCl_3, using fluorescence with Calcofluor white (unpublished data). (E) SEM images of Candida albicans after co-incubation with YM medium (control), and DFS with the concentration of 128 µg mL^− 1 (unpublished data)