Polyphenols have long attracted interest for wound therapy because they combine several beneficial properties in a single molecule. Chlorogenic acid (CGA), found in coffee and many fruits, exhibits antioxidative, anti-inflammatory, and antibacterial activities. Quercetin (QCT), a flavonoid with broad pharmacological effects, modulates oxidative stress, inflammatory responses, and cellular signalling pathways. Both compounds act as antimicrobials with limited potential for resistance development, a crucial advantage in an era when conventional antibiotics are losing efficacy. Yet both face a fundamental delivery problem: poor water solubility, low stability, or limited dermal bioavailability restrict their clinical use. CGA is chemically unstable and prone to degradation, while QCT is so poorly soluble that it struggles to exert biological activity at all.

Liposomes offer a compelling solution. Composed of phosphatidylcholine from soybean, these vesicles resemble biological membranes, providing high biocompatibility, low cytotoxicity, and non-irritant properties suitable for application to damaged or inflamed skin. Hydrophilic compounds can be carried in the aqueous core, while lipophilic ones partition into the lipid bilayer. The Tromsø team, led by Lisa Myrseth Hemmingsen and Nataša Škalko-Basnet, used the thin-film hydration method to prepare both CGA-loaded liposomes (CGA-LP) and QCT-loaded liposomes (QCT-LP), then tailored vesicle size through membrane extrusion for CGA-LP and probe sonication for QCT-LP, depending on each compound’s physicochemical properties.

All formulations landed within the target range of 200–300 nanometres, a size considered favourable for dermal therapy because it enhances retention within wound tissue and supports penetration into bacterial biofilms. Entrapment efficiency varied dramatically between the two compounds, reflecting their opposing chemistries. CGA-LP showed a low entrapment efficiency of about 23 percent, commonly observed for small hydrophilic molecules held in the aqueous core. QCT-LP, in contrast, achieved an entrapment efficiency of roughly 98 percent, consistent with the lipophilic nature of QCT and its incorporation into the lipid bilayer. Notably, the loaded formulations remained more stable over four weeks of storage than their empty counterparts, possibly because polyphenols interact with phospholipid headgroups through hydrogen bonding and polar interactions, increasing membrane cohesion and limiting vesicle fusion or aggregation.

In vitro release studies using Franz diffusion cells maintained at 32 degrees Celsius, simulating skin surface temperature, revealed the sustained-release behaviour that makes liposomes attractive for chronic wounds. Free CGA permeated rapidly, with about 60 percent crossing the membrane within 24 hours, whereas CGA-LP released only about 30 percent over the same period. QCT-LP released about 50 percent over 24 hours, while free QCT in methanol showed lower permeation of roughly 13 percent. The slower release from liposomes is attributable to diffusion of the payload through the lipid bilayer, providing more consistent exposure, a sought property for chronic wound therapy where prolonged therapeutic concentrations are needed. Sustained release might also maintain concentrations at the infection site for extended periods, potentially enhancing antimicrobial activity while minimizing off-target effects and reducing the frequency of dressing changes.

Antioxidant activity was assessed using two complementary radical scavenging assays, DPPH and ABTS·+, with vitamins C and E serving as reference antioxidants. CGA exhibited concentration-dependent scavenging between 5 and 25 micromolar, reaching a plateau at higher concentrations, and showed higher activity than vitamin C at 10 micromolar, confirming radical scavenging potential comparable to the reference vitamins. QCT displayed high DPPH activity across the tested range, likely favoured by the lipophilic nature of the DPPH radical, but only about 20 percent scavenging in the ABTS·+ assay regardless of concentration, a comparatively low response that may reflect the assay’s compatibility with hydrophilic antioxidants and possible interactions between QCT and formulation components.

Biocompatibility studies on murine macrophages, cells that play a central role in wound healing, revealed no cytotoxicity for either liposomal formulation. Almost all formulations maintained cell viability above 80 percent, the generally regarded non-toxic threshold, at lipid concentrations up to 50 micrograms per millilitre. In a striking contrast, free QCT at equivalent concentrations exhibited cytotoxic effects, underscoring how liposomal entrapment can transform a problematic compound into a tolerable one. The anionic and neutral liposome compositions, similar to cell membranes, generally exhibit low cytotoxicity, reinforcing the suitability of these systems for topical use.

Antimicrobial evaluation against S. aureus MSSA 476 produced nuanced results. In the conventional broth microdilution assay, only QCT-LP showed measurable inhibitory activity, with a minimum inhibitory concentration of 61.25 micrograms per millilitre. Free QCT could only be tested up to 10 micrograms per millilitre due to limited solubility, at which it achieved just 25.5 percent inhibition. CGA and CGA-LP showed no measurable MIC within the tested range. However, when the researchers turned to isothermal microcalorimetry, a technique that monitors bacterial metabolic activity in real time through heat flow measurements, a different picture emerged. CGA-LP induced a greater reduction in total metabolic rate than free CGA, with more pronounced suppression at lower concentrations of 30 to 120 micrograms per millilitre, suggesting that entrapment might enhance the interaction or uptake of CGA by bacterial cells at sub-inhibitory concentrations. Interestingly, the empty liposomes alone also decreased measurable metabolic activity, implying that components of the liposomal carrier exert subtle metabolic pressure on S. aureus independently of the active compound.

The discrepancy between the two antimicrobial assays likely reflects their different readouts: metabolic activity can persist even when bacterial growth is inhibited, and decreases in metabolic activity do not always correspond directly to reductions in viable bacteria. The microcalorimetry findings point toward the added value of real-time metabolic monitoring in revealing nuanced effects that endpoint MIC measurements cannot capture, potentially influencing bacterial physiology and response to treatment in ways that conventional testing overlooks.

The Tromsø team concludes that liposomal entrapment of CGA and QCT was successful, enabling sustained release and modulating the delivery and biological performance of both polyphenols. QCT-LP demonstrated measurable antibacterial activity in a conventional assay, while CGA-LP altered bacterial metabolism via microcalorimetry. Both formulations showed suitable biocompatibility with murine macrophages, supporting their topical potential. The researchers caution, however, that direct evaluation of wound-healing efficacy in biologically relevant wound models remains necessary to confirm therapeutic relevance. Additional studies in relevant in vitro and in vivo wound models will be required to establish effects on oxidative stress, inflammation, and wound healing processes. Still, the findings suggest that liposomal delivery could address two of the most stubborn challenges in chronic wound care, oxidative stress and bacterial infection, with natural compounds that bacteria are unlikely to develop resistance against.

Subject of Research: Liposomal delivery of polyphenols for chronic wound therapy

Article Title: Harnessing liposomal delivery to boost polyphenols’ potential in chronic wound therapy

Article References: Hemmingsen, L. M., Kristensen, M., Dang, C. T. L., Salamonsen, M., Fredheim, E. G. A., & Škalko-Basnet, N. (2026). Harnessing liposomal delivery to boost polyphenols’ potential in chronic wound therapy. Frontiers in Drug Delivery, 6, Article 1839747. https://doi.org/10.3389/fddev.2026.1839747

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1839747

Keywords: liposomes, polyphenols, chronic wounds, chlorogenic acid, quercetin, antimicrobial resistance, drug delivery, wound healing, Harnessing, liposomal, delivery, boost