Natural deep eutectic solvents occupy a curious place in chemistry. They arise when certain natural compounds, typically a hydrogen bond donor and a hydrogen bond acceptor such as an amino acid, a sugar, an organic acid or choline chloride, are mixed in specific ratios. The resulting mixture behaves in a striking way: instead of crystallizing as its individual components would, it melts or remains liquid at temperatures far lower than either ingredient alone, forming a stable eutectic liquid. The concept gained prominence in 2011, when researchers proposed in Plant Physiology that such mixtures might be the missing link in understanding cellular metabolism, since cells are crowded with exactly these kinds of small molecules. By 2013, Dai and colleagues had framed NADES as a new potential medium for green technology, and the field has expanded steadily since.

What makes NADES attractive to pharmaceutical scientists is the combination of properties they bring to the table. They are largely non-toxic, biodegradable and inexpensive to produce, often from food-grade or metabolite-grade starting materials. They can be synthesized sustainably by several methods, and their characteristics can be tuned, for example by adjusting water content, which alters viscosity and other physicochemical parameters. Studies have shown that adding water tailors NADES properties to facilitate applications, and that these solvents even modulate the thermal behavior of water, which has led to their exploration as non-toxic cryoprotective agents. Crucially for drug delivery, NADES excel at dissolving poorly water-soluble molecules, a chronic bottleneck, since a large fraction of active pharmaceutical ingredients and phytochemicals exhibit solubility so low that oral absorption becomes unreliable.

The review’s central argument is that pairing NADES with nanocarriers multiplies these advantages. Conventional drug delivery systems face a familiar litany of shortcomings: lack of targeted delivery, fluctuation in drug release, possible side effects, frequent dosing requirements, environmental hazards and high costs. Nanocarrier-based delivery already offers substantial rewards over conventional systems, but the carriers themselves often rely on solvents and excipients that raise toxicity or environmental concerns. The authors highlight, for instance, pro-inflammatory concerns that have been raised with lipid nanoparticles, the platform behind mRNA vaccines, and safety questions surrounding these systems for nucleic acid delivery. NADES-integrated nanocarriers, by contrast, promise low toxicity, biodegradability, cost-effectiveness and tunability, while enhancing the therapeutic efficacy of bioactive drugs.

The technical landscape covered in the review is broad. Solid lipid nanoparticles and nanostructured lipid carriers, established platforms for improving bioavailability and enabling targeted therapy, have been combined with NADES to encapsulate compounds such as curcumin, a notoriously insoluble but biologically active polyphenol. One 2024 study reported enhanced curcumin delivery and stability through NADES-based niosomes, vesicular carriers assembled from non-ionic surfactants. Another line of work integrated natural deep eutectic solvents into nanostructured lipid carriers with an explicitly industrial outlook, and a 2025 study used green nanostructured lipid carriers and NADES to solubilize extracts from Brazilian Cerrado byproducts, boosting antioxidant potential and simultaneously valorizing agricultural waste. Thermosensitive niosomes have even been designed from eutectic mixtures of natural fatty acids, adding stimulus-responsive behavior to the toolkit.

Polymeric systems feature prominently as well. Researchers have synthesized biodegradable poly(2-hydroxyethyl methacrylate) using NADES for sustainable cancer drug delivery, and fabricated green poly(vinyl alcohol) nanofibers with NADES for fast-dissolving drug delivery. Doxorubicin, a mainstay chemotherapy agent, has been loaded onto functional graphene nanocarriers using ternary deep eutectic solvent systems. A targeted solid-liquid polymer carrier supported by NADES has been explored for breast cancer therapy. Beyond polymers, the review describes NADES-based surfactant-free microemulsions that solubilize and extract curcumin from turmeric, and eutectogels, gel networks formed within deep eutectic solvents, that have been engineered for colon-targeted delivery of mesalazine, an anti-inflammatory drug used in inflammatory bowel disease. Smart supramolecular eutectogels have been designed for pH- and thermo-responsive transdermal delivery of anticancer curcumin, illustrating how the platform can incorporate environmental triggers.

The application domains extend well beyond cancer. In wound care, a curcumin emulgel enriched with a camphor-menthol-based deep eutectic solvent demonstrated wound healing efficacy, and NADES-based chitosan hydrogels have been developed for enhanced photoimmunomodulation treatment of various wounds. Nano-electrospun membranes combining NADES with Platostoma palustre polysaccharides and polyvinyl alcohol showed transdermal properties and bioactivity. In dermatology, a deep eutectic solvent-assisted kaempferol hydrogel emerged as a promising therapeutic approach for psoriasis-like skin inflammation. Ocular medicine has joined in too: green-sourced polyphenols delivered through a sustainable NADES-based approach have been proposed for dry eye disease treatment. Cosmeceutical applications include the green extraction of Rosa canina and Prunus spinosa by NADES followed by encapsulation in chitosan nanoparticles, and deep eutectic solvent nanoparticles have been used to enhance intradermal delivery of hyaluronic acid for anti-aging and moisturizing effects.

The mechanisms underlying these systems are as varied as the formulations. NADES can act as solubilizing media within the carrier, as structural components of the carrier itself, or as permeation enhancers that interact with biological membranes. Research into how NADES interact with artificial and natural membranes supports their role in facilitating transport across the skin and mucosal barriers. Choline chloride-malic acid NADES containing hydrophobic drugs has been studied for solubility and permeability behavior in digestive tract models, informing oral delivery design. Methotrexate solubilization and transdermal delivery have been enhanced in microemulsions with NADES screened by computational COSMO-RS methods, showing how molecular simulation can guide solvent selection. Pharmacokinetic evidence is accumulating as well: rutin dissolved in a proline-glycine NADES showed improved bioavailability after oral administration in rats, and deep eutectic solvents altered the pharmacokinetics of salvianolic acid B in rats, with acute toxicity testing performed alongside. Notably, NADES have also been shown to protect RNA from thermal degradation, and a ready-to-use lipid nanoparticle technology for nucleic acid delivery based on deep eutectic solvents has been developed, hinting at relevance for gene therapy and mRNA medicine.

Safety data, while still maturing, are encouraging. Cytotoxicity profiling of choline chloride-based NADES has been carried out, and toxicity studies of a betaine-glycerol NADES in rats have been published. A noncytotoxic, hemocompatible ion gel was prepared by self-polymerization of 2-hydroxyethyl methacrylate in a green deep eutectic solvent, and hydrogel formulations containing lidocaine have incorporated NADES to advantage. Buccal xanthan gum-hyaluronic acid eutectogels with dual anti-inflammatory and antimicrobial properties have been reported, relevant given the well-documented organ damage and gastrointestinal risks associated with long-term nonsteroidal anti-inflammatory drug use. Alginate hydrogels incorporating essential oils loaded in chitosan nanoparticles extend the platform to biomedical applications such as antimicrobial wound management.

The review is candid about the obstacles standing between laboratory promise and clinical reality. Viscosity, limited recyclability and safety data, long-term stability and scalability remain key issues for large-scale industrial application. High viscosity complicates handling, mixing and manufacturing; the recyclability of these solvents at industrial scale is not yet established; and comprehensive long-term safety and stability profiles are still being assembled. Regulatory pathways for such novel combination products also require clarification, a theme echoed in broader discussions of nanopharmaceutical quality-by-design frameworks and post-marketing surveillance. The authors frame their work as identifying these challenges, research gaps and opportunities for translating NADES-based nanocarrier technologies from laboratory scale to clinical and industrial application, and as a theoretical foundation for broader use in pharmaceutical and biomedical fields. If those gaps close, the vision is compelling: drug carriers built from the same molecular vocabulary that cells themselves use, delivering difficult medicines more safely, more sustainably and more effectively.

Subject of Research: Natural deep eutectic solvent-based nanocarriers for sustainable drug delivery

Article Title: Engineering green nanocarriers using natural deep eutectic solvents: a sustainable platform for modern drug delivery

Article References: Patil, N. B., & Gopinath, S. C. B. (2026). Engineering green nanocarriers using natural deep eutectic solvents: a sustainable platform for modern drug delivery. Journal of Nanoparticle Research, 28(9), Article 233. https://doi.org/10.1007/s11051-026-06749-0

Image Credits: AI Generated

DOI: 10.1007/s11051-026-06749-0

Keywords: natural deep eutectic solvents, NADES, nanocarriers, drug delivery, green chemistry, lipid nanoparticles, niosomes, eutectogels, curcumin, biomedicine, pharmaceuticals, sustainability

The industrial problem they target is both old and enormous. Oxidation is one of the principal mechanisms of food deterioration, degrading nutritional quality, altering flavor, aroma and color, and shortening shelf life, particularly in lipid-rich products. To fight it, manufacturers have long relied on synthetic antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and tert-butylhydroquinone (TBHQ). Yet mounting evidence of potential health risks, combined with a consumer shift toward natural ingredients and transparent ‘clean label’ products, has intensified the search for plant-based alternatives that can do the same job without the baggage of synthetic chemistry.

Phenolic compounds are the leading candidates in that search. This broad class of plant secondary metabolites includes flavonoids, phenolic acids and tannins, and their antioxidant power arises from a set of complementary chemical mechanisms: they scavenge free radicals, chelate transition metal ions that catalyze oxidation, and interrupt the chain reactions by which lipid peroxides propagate. When these mechanisms operate in a food matrix, lipid oxidation is delayed and shelf life is extended. The challenge is that plants produce these compounds as defensive responses to environmental stress, so their abundance depends heavily on where and how a species grows, and extracting them efficiently without damaging them has been an enduring technical obstacle.

This is where the Caatinga becomes strategically interesting. The biome’s plants endure high temperatures, intense solar radiation and prolonged water deficit, conditions that push them to biosynthesize phenolics as adaptive protection against oxidative stress. In other words, the very harshness that makes the Caatinga inhospitable appears to make its flora chemically rich. Barbatimão exemplifies the point. A member of the Fabaceae family, the species concentrates tannins, particularly in its bark, alongside flavonoids such as rutin and catechins and phenolic acids including gallic and caffeic acids. Its bark has a long history of empirical use in teas, tinctures and sitz baths for wounds, ulcers, gastritis and inflammatory conditions, and modern laboratory studies have shown that bark and leaf extracts exhibit pronounced free radical scavenging, lipid peroxidation inhibition and metal chelation activity.

Despite this promise, the authors argue that the technological valorization of Caatinga antioxidants has been held back by conventional methodology. Most published work relies on extraction systems built around volatile organic solvents that are poorly selective, energy-intensive and difficult to translate to food-grade applications, a mismatch with both green chemistry principles and current regulatory and consumer expectations. Conventional hydroalcoholic extraction, the standard approach in barbatimão research to date, may also leave complex phenolic fractions, such as high-molecular-weight condensed tannins, insufficiently extracted or chemically degraded during processing, meaning the full antioxidant arsenal of the plant has likely been underestimated.

The proposed solution is a pairing of two green technologies: natural deep eutectic solvents (NADES) and ultrasound-assisted extraction (UAE). NADES are tunable liquid systems formed by combining hydrogen bond acceptors, such as choline chloride, with hydrogen bond donors, including organic acids like lactic and citric acid, polyols such as glycerol, amino acids and sugars. Their effectiveness rests on extensive hydrogen-bonding networks and polarity matching, which favor the solubilization of hydroxylated aromatic structures, precisely the architecture of flavonoids, phenolic acids and condensed tannins. Choline chloride–organic acid and choline chloride–polyol combinations have already demonstrated high efficiency in pulling quercetin derivatives, gallic acid and catechins out of plant matrices.

Selectivity is the standout advantage. Because solvent composition can be rationally designed, acidic NADES systems tend to favor phenolic acids, while polyol-based systems are more effective for flavonoids and bulky tannins. This design flexibility means researchers can target specific bioactive fractions rather than accepting whatever a generic solvent happens to dissolve. The main technical limitation of NADES, their relatively high viscosity, which slows mass transfer, can be mitigated by adding water or by coupling the solvent with ultrasound. Acoustic cavitation disrupts cell walls, enhances solvent penetration into the plant tissue and accelerates mass transfer. Under optimized NADES–UAE conditions, recent studies across diverse plant materials report significant increases in total phenolic content and antioxidant activity, often exceeding conventional organic solvents while cutting extraction time and solvent consumption.

Applying this technology to barbatimão would be unprecedented, and the authors argue it could unlock underexplored phenolic fractions and clarify antioxidant mechanisms such as metal chelation and lipid oxidation inhibition that current extracts capture only partially. The food applications are equally forward-looking: many NADES constituents are non-volatile, low in toxicity and, in some cases, edible, which raises the possibility of using extracts directly or with minimal downstream processing, reducing costs and environmental impact while supporting clean-label claims. Computational tools are accelerating the design stage too, with approaches such as COSMO-RS, a Conductor-like Screening Model for Real Solvents, and machine learning enabling researchers to predict solvent–solute interactions and rationally tailor solvents to specific phenolic targets before any benchwork begins.

Significant hurdles remain before Caatinga antioxidants reach industrial shelves. Solvent viscosity, compound recovery, sensory impact on foods, and compliance with food safety regulations must all be systematically evaluated, and while NADES components are often regarded as safe, dedicated regulatory frameworks for their direct use in food systems are still under development, underscoring the need for toxicological and safety studies. The authors outline a research roadmap: rational optimization and scale-up of NADES systems with sustainability metrics such as energy efficiency, solvent recyclability and life cycle assessment; advanced chemical profiling using HPLC-DAD-MS/MS and metabolomics to identify bioactive fractions; and validation in real food matrices with kinetic and mechanistic analyses of antioxidant performance during processing and storage. Within that roadmap, S. rotundifolium serves as a proof-of-concept species, a demonstration of how one of Earth’s harshest and least-studied biomes can supply the sustainable, science-grounded ingredients that the food industry increasingly demands.

Subject of Research: Phenolic-based natural antioxidants from Caatinga plants as sustainable food additives using green extraction technologies

Article Title: Natural antioxidants from the Caatinga with insights from Stryphnodendron rotundifolium as a model for phenolic-based food additives

Article References: Ribeiro, M. A. M., Ferreira dos Santos, I. R., de Lima Pereira, J. F., Xenofonte, J. V. F., & da Costa, J. G. M. (2026). Natural antioxidants from the Caatinga with insights from Stryphnodendron rotundifolium as a model for phenolic-based food additives. Discover Green Chemistry, 1(1), Article 17. https://doi.org/10.1007/s44509-026-00019-x

Image Credits: AI Generated

DOI: 10.1007/s44509-026-00019-x

Keywords: phenolic compounds, Caatinga biome, Stryphnodendron rotundifolium, natural antioxidants, NADES, ultrasound-assisted extraction, green chemistry, food additives, tannins, clean label, Natural, antioxidants