Smart Nanoparticles Unleash Antifungal Drug Only Where Infection Burns

Fungal infections are quietly becoming one of medicine’s most stubborn adversaries. Fungal keratitis now ranks among the leading causes of blindness worldwide, while cutaneous mycoses afflict roughly a quarter of the global population. Yet the therapeutic arsenal remains startlingly thin: because fungi are eukaryotes, they share deep structural and metabolic similarities with human cells, leaving researchers with precious few pathogen-specific drug targets. Worse, fungal infections are entangled with runaway inflammation, meaning that even when the pathogen is killed, the host’s own immune overreaction can devastate surrounding tissue and delay healing. A new study published in Materials Today Bio by Yongnan Chen, Fuyao Chen and colleagues reports a nanoparticle platform that attacks both problems at once, pairing the most potent antifungal antibiotic in the clinic with a plant-derived anti-inflammatory polyphenol inside a single, environment-responsive carrier.

The centerpiece of the work is amphotericin B, or AmB, the polyene macrocyclic antibiotic long regarded as the gold standard for serious fungal disease. AmB’s amphiphilic, amphoteric structure gives it high affinity for ergosterol, the sterol that anchors fungal membranes. By sequestering ergosterol and permeabilizing the membrane, it collapses cellular homeostasis and kills fungi outright, with remarkably low propensity for resistance. But the same drug cannot distinguish fungal ergosterol from the cholesterol in mammalian membranes, a shortcoming that produces the notorious nephrotoxicity that has haunted AmB therapy for decades. It also lacks any inherent ability to calm inflammation or promote tissue repair once the pathogen is gone. The new platform, called ATE nanoparticles, was engineered specifically to resolve both limitations simultaneously.

The design hinges on elegant supramolecular chemistry. The researchers synthesized a trivalent phenylboronic acid derivative, termed T-PBA, by reacting N,N,N′,N′,N″-pentamethyldiethylenetriamine with 4-(bromomethyl)phenylboronic acid. Boronic acids form dynamic boronate ester bonds with ortho- and meta-positioned dihydroxyl groups, and the team exploited this to crosslink T-PBA with epigallocatechin gallate, the catechin from green tea better known as EGCG, while simultaneously encapsulating hydrophobic AmB through its own 1,3-diol groups. Nuclear magnetic resonance, an Alizarin Red S competitive displacement assay, Fourier-transform infrared spectroscopy and ultraviolet-visible spectrophotometry all confirmed the boronate ester network: a new B-O-C stretching band appeared at 1011 cm⁻¹, and AmB’s characteristic 337-nanometer absorption red-shifted to 340 nanometers with pronounced broadening, hallmarks of successful encapsulation.

The resulting particles are uniformly spherical, roughly 100 nanometers in diameter, with a net positive surface charge of about +16.3 millivolts that keeps them stably dispersed through electrostatic repulsion. X-ray diffraction showed the encapsulated AmB adopts an amorphous state, and energy-dispersive X-ray mapping revealed a homogeneous distribution of carbon, nitrogen, oxygen and boron throughout each particle. Crucially, the exposed boronic acid groups of T-PBA bind avidly to the cis-diol-rich polysaccharides, β-glucans and mannans, that carpet fungal cell walls. In confocal microscopy experiments with Rhodamine B-labeled drug and Hoechst-stained Candida albicans, ATE nanoparticles accumulated extensively on fungal surfaces, while free AmB produced almost no detectable signal. This adhesive behavior promises prolonged retention at infected lesions, a decisive advantage on the tear-flushed ocular surface.

What makes the platform genuinely intelligent is its responsiveness to the chemistry of infection. Inflamed, fungus-colonized tissue is locally acidic and rich in reactive oxygen species, and both cues destabilize the boronate ester scaffold. In dialysis release experiments, the nanoparticles leaked AmB slowly at physiological pH 7.4, but at pH 6.0, mimicking the infected microenvironment, more than 90 percent of the cargo was liberated within eight hours. Meanwhile, the EGCG component proved a formidable antioxidant in its own right: the particles scavenged 54.22 percent of ABTS radicals at 120 micrograms per milliliter and over 62.78 percent of DPPH radicals at just 32 micrograms per milliliter, offering a shield for host cells bathed in oxidative stress.

The antifungal performance in vitro was striking. The minimum inhibitory concentration of ATE nanoparticles against C. albicans was 0.16 micrograms per milliliter in AmB equivalents, eightfold lower than free AmB at 1.28 micrograms per milliliter. At 2 micrograms per milliliter, the particles eradicated more than 99 percent of fungi within four hours, and scanning electron microscopy revealed the most pronounced morphological collapse and surface wrinkling among all treatment groups. Control particles carrying only EGCG showed no intrinsic fungicidal activity, confirming that the killing power still flows from AmB, now delivered with far greater efficiency. The platform also dismantled biofilms, the self-produced exopolymeric fortresses that shield fungi from drugs and immune attack. Treatment reduced immature biofilm thickness from 30.98 to 9.19 micrometers, cut biomass by 77.44 percent, and suppressed 99.98 percent of fungal growth; against mature, two-day-old biofilms, the particles eradicated over 79.54 percent of biomass and 99.9 percent of viable C. albicans.

The anti-inflammatory half of the story proved equally compelling. In human corneal endothelial cells stressed with hydrogen peroxide, ATE nanoparticles cleared more than 90 percent of intracellular reactive oxygen species, outperforming formulations lacking EGCG. In lipopolysaccharide-stimulated RAW 264.7 macrophages, the particles significantly suppressed the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 while markedly upregulating the anti-inflammatory cytokine IL-10. Cytocompatibility testing underscored the safety gain: at 8 micrograms per milliliter of AmB equivalent, free AmB drove cell viability below 60 percent, whereas the nanoparticle formulation kept viability above 80 percent, effectively detoxifying the gold-standard drug.

In vivo, the team tested the particles in a murine model of C. albicans keratitis and in infected skin wounds. On the eye, fluorescently labeled nanoparticles lingered far longer than free dye, retaining roughly 12.6 percent of the applied dose at eight hours and 5.6 percent at sixteen hours. Over fifteen days of follow-up, treated mice recovered corneal transparency with a clinical grading score of 6, compared with 14 in untreated controls and 8 for AmBisome, the clinically used liposomal AmB formulation. Optical coherence tomography showed corneal thickness falling to 93.6 micrometers in the treated group versus 185.9 micrometers in controls, in vivo confocal microscopy revealed a marked reduction of fungal hyphae, and fungal plate counts confirmed the lowest residual burden of any group. Histology documented restored corneal architecture, downregulated IL-1β and IL-6, and dense, well-aligned collagen deposition indicative of genuine tissue regeneration rather than mere scarring.

The skin wound model told a parallel story. By day eight, wounds treated with ATE nanoparticles had contracted to 18.23 percent of their original area, with near-complete re-epithelialization, compared with 38.74 percent in untreated controls, and collagen fiber deposition reached approximately 2.2-fold that of controls. Biosafety assessments were thorough and reassuring: slit-lamp examination, fluorescein staining, optical coherence tomography and confocal microscopy found no corneal irritation or endothelial cell loss even after seven consecutive days of administration, while blood counts, liver enzymes and kidney markers remained within normal ranges, and major organs showed no pathological lesions. The authors caution that the work remains at the preclinical stage, but the convergence of targeted adhesion, dual-triggered drug release, immunomodulation and demonstrated superiority over an existing clinical formulation marks ATE nanoparticles as a promising template for the next generation of antifungal nanotherapeutics, one that treats the infection and the inflammatory fire it ignites as a single, inseparable problem.

Subject of Research: Amphotericin B-loaded polyphenolic nanoparticles for simultaneous antifungal eradication and immunomodulation in superficial fungal infections

Article Title: Amphotericin B-loaded polyphenolic nanoparticles for synchronous fungal eradication and immunomodulation in treating superficial fungal infections

Article References: Chen, Y., Chen, F., Wang, S., Dai, W., Jin, Q., Jia, F., & Ye, Y. (2026). Amphotericin B-loaded polyphenolic nanoparticles for synchronous fungal eradication and immunomodulation in treating superficial fungal infections. Materials Today Bio, 41, Article 103707. https://doi.org/10.1016/j.mtbio.2026.103707

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103707

Keywords: amphotericin B, nanoparticles, EGCG, fungal keratitis, Candida albicans, boronate ester, drug delivery, biofilm, anti-inflammatory, polyphenols, nanomedicine, tissue repair