The scale of the problem the review addresses is difficult to overstate. Candida species are the leading cause of opportunistic fungal infections, ranging from superficial mucosal disease such as thrush and vulvovaginal candidiasis to life-threatening bloodstream infections in intensive care patients, organ transplant recipients, and the immunocompromised. While Candida albicans remains the dominant pathogen, non-albicans species such as C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei are increasingly prevalent, and C. auris has emerged over the past decade as a genuine global public health threat. Its ability to adhere tenaciously to environmental surfaces and persist in hospitals makes it extraordinarily difficult to eradicate once it takes hold in a healthcare setting.

Part of what makes Candida so formidable is its arsenal of resistance mechanisms. The fungus can mutate target genes, ramp up efflux pumps that expel drugs, alter the sterol composition of its membranes, activate stress responses, and—perhaps most troublingly—form biofilms. These structured communities of cells encased in protective matrix can tolerate antifungal drugs at concentrations up to 1,000 times higher than free-floating cells, which is why biofilms on catheters, prosthetic heart valves, dentures, and implants are such a clinical nightmare. The four existing drug classes—azoles, polyenes, echinocandins, and pyrimidine analogues—all suffer from limitations including toxicity, poor tissue penetration, harmful drug interactions, and the rapid emergence of resistance.

Zinc oxide nanoparticles attack the fungus in a fundamentally different way. Rather than targeting a single molecular pathway, they deploy a multi-pronged assault that the review identifies as the key to their promise. The primary mechanism is the generation of reactive oxygen species, which induces oxidative stress that damages DNA, oxidizes proteins, and disrupts mitochondrial function. Simultaneously, the nanoparticles physically compromise the fungal cell wall and plasma membrane, forming pores, rupturing membranes, and causing leakage of intracellular contents. Dissolution of the particles releases zinc ions that further interfere with intracellular enzyme systems and metabolic pathways. Because this attack hits multiple cellular targets at once, the likelihood of Candida evolving effective resistance is substantially reduced compared with single-target drugs.

Beyond outright killing, ZnO NPs also disarm the fungus’s virulence machinery. Studies included in the review showed that the nanoparticles reduce biofilm formation, inhibit the yeast-to-hypha transition that underpins tissue invasion, block quorum sensing, and downregulate key virulence genes including HWP1, ALS1, ALS3, ERG11, SAP, and RAS1. Electron microscopy evidence is particularly vivid: treated C. albicans cells exposed to nanoparticle concentrations of 80 and 160 micrograms per milliliter displayed hyphal breakdown, surface pitting, membrane invagination, and complete membrane rupture, while untreated cells retained their smooth, intact morphology. Spectroscopic analysis confirmed that zinc accumulated on the surface of treated fungal cells, supporting a model in which direct adhesion of nanoparticles triggers membrane disruption, oxidative stress, and lethal leakage.

How the nanoparticles are made matters enormously, and here the review highlights the rise of green synthesis. Conventional chemical and physical production of nanomaterials relies on toxic reducing agents, volatile organic solvents, high temperatures, and energy-intensive processes that generate hazardous waste. Green synthesis instead uses plant extracts, bacteria, fungi, and algae as natural reducing, capping, and stabilizing agents, converting zinc salts into nanoparticles under mild conditions. The review catalogs an impressive range of biological sources that have successfully yielded antifungal ZnO NPs, from fenugreek seeds and green tea leaves to sage, lemon peel, mango leaves, cashew apple juice, bay leaf, garden cress, egg albumin, and even lignin biotemplates, alongside microbes such as Lactobacillus gasseri, Pseudomonas putida, and Bacillus licheniformis.

The green route offers more than environmental credentials. Phytochemicals such as flavonoids, phenolics, alkaloids, and terpenoids remain adsorbed on the nanoparticle surface, adding antioxidant and antimicrobial activity of their own while reducing cytotoxicity to host cells. The review found that green-synthesized ZnO NPs met all but one of the traits required for biocompatibility, and several studies reported favorable therapeutic windows, excellent hemocompatibility with minimal hemolysis, and low toxicity toward mammalian cells at concentrations that effectively kill Candida. Doping strategies add another layer of tunability: calcium-doped ZnO nanoparticles showed strong activity against multidrug-resistant C. auris, while gadolinium and lanthanum doping have been shown to modify antimicrobial properties and defect states such as oxygen vacancies, potentially allowing researchers to optimize the balance between fungal killing and host safety.

Perhaps the most clinically exciting finding concerns synergy with existing drugs. Green-synthesized ZnO NPs significantly enhanced the activity of fluconazole against multiple Candida species, with especially strong effects against C. glabrata and C. parapsilosis, and moderate synergy against C. albicans and C. tropicalis. Amphotericin B conjugated onto ZnO nanoparticles outperformed unconjugated particles, suggesting the nanoparticles could double as drug delivery vehicles, and ZnO-based nanocomposites incorporating vancomycin, silver, or chitosan also showed enhanced antifungal activity. The mechanistic logic is compelling: by disrupting membrane integrity, the nanoparticles increase intracellular drug penetration, while their own oxidative stress and antibiofilm effects complement the drugs’ actions. In principle, such combinations could lower effective drug doses, reduce dose-dependent toxicity, and delay the emergence of resistance in multidrug-resistant and biofilm-associated infections.

The authors are careful, however, not to oversell the current state of evidence. Most of the 33 studies focused on synthesis, characterization, and susceptibility testing, while in-depth molecular investigations were rare; comprehensive transcriptomic, proteomic, and metabolomic analyses of how Candida responds to nanoparticle exposure are almost entirely lacking. Cytotoxicity data frequently came from immortalized or cancer-derived cell lines such as HepG2 rather than primary human cells, which may distort safety estimates in either direction. Not a single clinical trial has evaluated ZnO NPs for candidiasis, few studies progressed to animal models, and none comprehensively assessed the environmental fate or ecotoxicological impact of the nanoparticles after biomedical use. Heterogeneity in particle size, surface chemistry, synthesis methods, and testing protocols further complicates direct comparison between studies.

Those caveats frame the road ahead. The review calls for standardized synthesis and characterization protocols covering zeta potential, colloidal stability, hydrodynamic size, and dissolution kinetics; toxicity testing in normal human cell lines and repeated-dose animal studies; pharmacokinetic and biodistribution assessments; systematic evaluation of combinations across all major antifungal classes; and, ultimately, well-designed clinical trials. If those steps succeed, zinc oxide nanoparticles could move from the laboratory bench to catheter coatings, wound dressings, denture liners, implant surfaces, and systemic combination therapies—applications where their multimodal mechanism, green manufacturability, and synergy with existing drugs could make a decisive difference in an era when the fungi are winning ever more often.

Subject of Research: Antifungal activity and mechanisms of zinc oxide nanoparticles against drug-resistant Candida species

Article Title: Zinc oxide nanoparticles against Candida: mechanistic pathways, synergistic potentials, and biocompatibility challenges in the era of antimicrobial resistance

Article References: Sahu, B. K., Mohanta, T. K., Sahu, M. C., & Panda, S. K. (2026). Zinc oxide nanoparticles against Candida: mechanistic pathways, synergistic potentials, and biocompatibility challenges in the era of antimicrobial resistance. Frontiers in Antibiotics, 5, Article 1933663. https://doi.org/10.3389/frabi.2026.1933663

Image Credits: AI Generated

DOI: 10.3389/frabi.2026.1933663

Keywords: zinc oxide nanoparticles, Candida, antifungal resistance, green synthesis, biofilm inhibition, reactive oxygen species, Candida auris, fluconazole synergy, nanotechnology, biocompatibility, candidiasis, virulence genes