NF-κB’s importance stems from its dual identity. In healthy tissue, it is an indispensable guardian. The pathway exists in five family members—NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and c-Rel—that pair into homo- and heterodimers. Under resting conditions, these dimers are held inactive in the cytoplasm by inhibitory IκB proteins, chiefly IκBα. When the cell encounters pro-inflammatory cytokines such as TNF-α or IL-1β, or pathogen-associated molecular patterns recognized by toll-like receptors, the canonical pathway springs into action. Receptor engagement recruits adaptor proteins like TRADD and MyD88, which activate the IκB kinase (IKK) complex, composed of IKKα, IKKβ, and the regulatory subunit NEMO. IKK phosphorylates two conserved serine residues on IκBα, tagging it for ubiquitination and proteasomal destruction. Freed from its inhibitor, the p65/p50 heterodimer translocates to the nucleus, binds κB DNA sequences through its Rel homology domain, and switches on genes governing inflammation, immunity, cell survival, and proliferation. A parallel non-canonical route, driven by NF-κB-inducing kinase and IKKα, processes the precursor p100 into p52, forming p52/RelB dimers that regulate B cell maturation and lymphoid organogenesis. Both arms are essential, but both can be hijacked.

The trouble begins when this exquisitely regulated system never switches off. Persistent NF-κB activation is now recognized as a defining feature of chronic low-grade inflammation, the smoldering substrate on which cancers, cardiovascular disease, metabolic syndrome, and neurodegenerative conditions take root. In tumorigenesis, constitutive NF-κB signaling acts as a multipurpose engine of malignancy. It suppresses apoptosis by upregulating anti-death proteins such as Bcl-2, Bcl-xL, survivin, and the inhibitor-of-apoptosis proteins, allowing damaged cells to evade programmed cell death. It fuels angiogenesis through vascular endothelial growth factor and interleukin-8, arming growing tumors with the vasculature they need to expand. It catalyzes metastasis by inducing the epithelial-to-mesenchymal transition, upregulating transcription factors like Snail and Twist while silencing E-cadherin, and by stimulating matrix metalloproteinases that degrade the extracellular matrix. Perhaps most frustrating for oncologists, NF-κB also underwrites chemoresistance, boosting drug efflux pumps such as MDR1 and BCRP and accelerating DNA repair programs involving XRCC1 and RAD51 that let cancer cells shrug off chemotherapy-induced damage.

The review’s authors catalogue this pathology across organ systems in striking detail. In breast cancer, elevated nuclear NF-κB1 expression marks a high-risk subset of estrogen receptor-positive tumors, and knockdown of NF-κB1 in inflammatory breast cancer cells impairs the motility that underlies their notorious metastatic phenotype. In gastric cancer, the bacterium Helicobacter pylori emerges as a master manipulator: its virulence factors, including the lipopolysaccharide metabolite ADP-heptose, activate NF-κB through the cytosolic receptor ALPK1 and its partner TIFA, recruiting the TRAF6–TAK1–IKK cascade and sustaining the inflammatory milieu from which malignancy arises. Genetic polymorphisms in NFKB1, NFKBIA, IKBKB, TNIP1, and MYD88 all correlate with gastric cancer risk or survival, and in mice, loss of NF-κB1 produces invasive intestinal-type gastric tumors in a STAT-1-dependent manner. In prostate cancer, NF-κB upregulates androgen receptor splice variants and amplifies cytokine loops involving IL-6, IL-8, and TNF-α that drive castration-resistant disease, while in colorectal cancer, p50 homodimers skew macrophage polarization toward a pro-tumorigenic state and cooperate with the anti-apoptotic protein BAG-1 at the promoters of EGFR and COX-2. Non-small cell lung cancer shows uniformly elevated NF-κB subunit expression, and nuclear—not cytoplasmic—RelA localization predicts worse five-year survival. Even glioblastoma multiforme, the most lethal brain tumor, depends on NF-κB, with genetic silencing of the pathway or its target Timp1 slowing progression in experimental models.

Against this formidable molecular machinery, the review positions an equally detailed arsenal drawn from the plant kingdom. The unifying logic is elegant: rather than attacking NF-κB with blunt synthetic inhibitors—which have repeatedly failed in clinical trials because of off-target toxicity stemming from the pathway’s many legitimate functions—phytochemicals exploit multiple low-intensity intervention points across the cascade. Curcumin, the diarylheptanoid from turmeric, suppresses IKK activity and prevents IκBα phosphorylation, trapping NF-κB in the cytoplasm and reducing the transcription of pro-inflammatory and pro-survival genes. Resveratrol, the stilbene from grapes and red wine, targets NEMO and IKK to block the ubiquitin-dependent steps that the pathway requires, while also diminishing NF-κB’s DNA-binding capacity. Epigallocatechin gallate, the principal catechin of green tea, prevents lipopolysaccharide-induced IκBα degradation and blocks the nuclear migration of RelA, engaging ROS-sensitive signaling routes that frequently converge on NF-κB activation.

The pharmacological nuances the authors document reveal how structurally diverse compounds converge on the same pathway through distinct molecular tactics. Quercetin, a flavonoid abundant in onions and apples, inhibits NF-κB DNA-binding activity and induces dephosphorylation and upregulation of IκBα, showing half-maximal inhibitory concentrations of 20 to 35 micromolar against colon cancer cell lines, and suppresses IKKα expression in non-small cell lung cancer cells. Apigenin, from chamomile, binds IKK directly—an action the review notes outperformed conventional IKK inhibitors in prostate cancer cells, producing cell-cycle arrest—and simultaneously curtails COX-2 expression and pro-inflammatory cytokine biosynthesis. Genistein, the soy isoflavone, downregulates NF-κB production and its transcriptional activity across breast, ovarian, liver, colon, and cervical cancer models. Gingerol blocks TPA-induced phosphorylation of p65; gallic acid limits the pathway by lowering acetylation of RelA; pterostilbene, a more bioavailable analog of resveratrol from blueberries, suppresses upstream PI3K/Akt and PKC signaling that would otherwise activate both NF-κB and AP-1, preventing epithelial-to-mesenchymal transition and MMP-9-driven invasion. Salidroside from Rhodiola rosea couples IκBα-stabilizing effects with activation of the antioxidant Nrf2 pathway, while the lignan honokiol from Magnolia bark adds the rare ability to cross the blood–brain barrier. Silymarin’s flavonolignans disrupt NF-κB–DNA crosstalk, and carnosol from rosemary and sage inhibits IκBα kinase activity while also damping MAPK pathways that feed NF-κB expression.

Beyond the classical dietary polyphenols, the review extends its mechanistic map to non-dietary phytochemicals that corroborate the same principles. The naphthoquinone plumbagin induces apoptosis while inhibiting NF-κB through redox cycling and reactive oxygen species generation. The iridoid glycosides aucubin and catalpol prevent IκBα degradation and p65 nuclear translocation, with catalpol additionally blocking TGF-β1-driven epithelial-to-mesenchymal transition in lung cancer cells via Smad2/3 suppression. Sesquiterpene lactones display perhaps the most direct mechanism of all: helenalin from Arnica covalently alkylates a cysteine in the p65 Rel homology domain, physically obstructing DNA binding, while parthenolide from feverfew blocks p65 nucleocytoplasmic transport and enhances cyclophosphamide’s efficacy in lung cancer models. Terpenes limonene and α-pinene prevent the phosphorylation cascades that release NF-κB from its cytoplasmic custody, triterpenes such as lupeol, betulin, and ginsenosides stabilize IκBα and restrain IKK activity, and carotenoids like lycopene and β-carotene inhibit IκB phosphorylation in prostate and other cancer models.

Yet the authors are refreshingly candid about the gulf between laboratory promise and clinical reality. Most of these compounds display potent effects in vitro and in animal models at concentrations that human pharmacokinetics struggle to replicate. Curcumin’s poor aqueous solubility and rapid metabolism have limited its clinical translation despite decades of enthusiasm; resveratrol’s bioavailability is notoriously low; quercetin’s early-phase trials confirmed safety but produced equivocal therapeutic signals; and EGCG’s phase I trial in lung cancer radiotherapy showed tolerability but no significant impact on tumor progression. Artemisinin illustrates a different constraint: while antimalarial doses sit in the nanomolar range, the micromolar concentrations needed for anticancer effects risk neurotoxicity. The review identifies poor solubility, limited cellular penetration, off-target effects, and dose-dependent toxicity as the principal barriers separating bench from bedside.

The path forward, the authors argue, lies in delivery innovation and combination strategies. Nanotechnology—liposomal formulations, microencapsulation, and nano-emulsions—can dramatically enhance solubility, stability, and target specificity while reducing the doses required for efficacy, and nano-phytochemical formulations have already demonstrated superior performance over free compounds in multiple cancer models. Because NF-κB sits at the confluence of PI3K/Akt, MAPK, and p53 signaling, polyphenols’ capacity to modulate these intersecting networks simultaneously may prove most valuable as adjuvants that sensitize tumors to conventional chemotherapy and targeted therapy, echoing curcumin’s demonstrated ability to potentiate gemcitabine in pancreatic cancer and genistein’s sensitization of cervical cancer cells to cisplatin.

What makes this synthesis genuinely newsworthy is its reframing of a familiar message. The advice to eat fruits, vegetables, tea, and spices is hardly revolutionary, but grounding it in a precise, multi-point mechanistic map of NF-κB regulation transforms dietary polyphenols from vague antioxidants into a coherent pharmacological concept. Inflammation-driven cancer is a problem of a transcription factor that will not rest, and the review makes a compelling case that the plant world supplies molecules calibrated, over millions of years of co-evolution, to modulate exactly the checkpoints—IKK phosphorylation, IκBα degradation, p65 translocation, DNA binding, and RelA acetylation—whose dysregulation defines the disease. The challenge now is to convert that molecular insight into formulations and trials robust enough for the clinic.

Among the forefront of such advancements, lipid-based delivery vehicles, particularly liposomes, offer a compelling platform. Liposomes are nanoscale spherical vesicles composed primarily of phospholipids and cholesterol, capable of encapsulating both hydrophilic and hydrophobic molecules. Their classification into emulsion-type and solid lipid nanoparticles (SLNs) enables customization for specific pharmacological needs. While emulsion-type liposomes exhibit superior biocompatibility due to their fluidic lipid membranes, SLNs possess enhanced stability for polyphenol encapsulation but suffer from relatively reduced compatibility because of their rigid structure.

Robust encapsulation via liposomes translates into several pharmacokinetic advantages: increased aqueous solubility, protection against premature degradation, controlled release kinetics, and targeted tissue delivery. Such characteristics substantially amplify the bioavailability and therapeutic efficacy of dietary polyphenols. Experimental studies validate these assertions: quercetin-loaded SLNs demonstrated superior biocompatibility and controlled-release properties, while liposomal curcumin exhibited up to six-fold greater potency than free curcumin in cellular assays. Furthermore, liposome-encapsulated anthocyanins were shown to profoundly reduce reactive oxygen species (ROS) in radiation-induced pulmonary injury, highlighting the clinical relevance of tailored liposomal formulations.

Enhancing the inherent limitations of liposomal systems, such as sensitivity to environmental factors (temperature, pH, ionic strength) and suboptimal encapsulation efficiency, has been accomplished through surface modifications. The application of biopolymers like chitosan to coat liposomal surfaces significantly augments stability within gastric and intestinal environments, optimizing release profiles and bioavailability. Innovations include chitosan derivatives, such as succinic anhydride-based coatings, that maintain liposome integrity while imparting enhanced mucoadhesive properties, thereby increasing gastrointestinal retention and absorption. Complementary strategies such as hyaluronic acid functionalization of solid lipid nanoparticles further extend the platform’s versatility by introducing targeted anti-inflammatory effects in radiation contexts.

While liposomes are relatively well-characterized, inorganic nanoparticles emerge as a versatile and stable alternative for polyphenol delivery. These nanoparticles, encompassing metal, metal oxide, and metal sulfide classifications, present favorable physicochemical properties, including high thermal and chemical stability, tunable size, and surface modifiability, making them resilient carriers under variable biological conditions. Metal nanoparticles like gold, silver, and copper leverage unique photothermal and fluorescent properties to enable sophisticated tracking and targeted therapy in radiation-induced disease models. Notably, silver and gold nanoparticles coated with polyphenols have shown potent suppression of pro-inflammatory mediators such as nitric oxide and tumor necrosis factor-alpha, suggesting a dual-function modality combining direct therapeutic effects of polyphenols and intrinsic nanoparticle activities.

Metal oxide nanoparticles, including titanium dioxide, iron oxide, and zinc oxide, further expand the delivery repertoire with magnetic and catalytic functionalities. Mesoporous core-shell silica nanoparticles functionalized with quercetin exemplify the intersection of nanotechnology and natural product therapeutics, yielding enhanced antioxidant capacity and superior mitigation of radiation-induced oxidative stress compared to conventional formulations. Metal sulfide nanoparticles possess inherent enzyme-mimetic activities, such as peroxidase-like functions, which synergistically potentiate the antioxidant efficacy of encapsulated polyphenols, opening new avenues for combinatorial therapy against radiation-induced inflammation.

The adaptability of inorganic nanoparticles extends beyond stability, offering controlled release mechanisms through material engineering. By modulating nanoparticle porosity, surface chemistry, and core-shell architecture, researchers can finely tune payload release kinetics, enhancing localized drug concentration and minimizing systemic exposure. For example, quercetin-loaded silica nanoparticles demonstrated prolonged release profiles significantly improving therapeutic outcomes in neurodegenerative disease models involving radiation therapy. However, challenges remain regarding biocompatibility and long-term stability of inorganic nanoparticle systems, fueling ongoing research into surface functionalization techniques such as polyethylene glycol conjugation and shape optimization to mitigate protein adsorption and cytotoxicity.

Parallel to inorganic platforms, organic nanoparticle delivery systems exhibit sophisticated capabilities in improving polyphenol bioavailability and functional stability. Organic nanoparticles, synthesized through methods like self-assembly, solvent evaporation, and oil-in-water emulsification, allow precise control over physicochemical properties including particle size, surface charge, and drug loading efficiency. These systems are biocompatible, capable of targeted delivery, and often biodegradable, presenting an appealing alternative for sustained release of dietary polyphenols.

Empirical studies corroborate the efficacy of organic nanoparticles in enhancing polyphenol pharmacodynamics. Curcumin encapsulation has notably modulated gut microbiota composition, reduced oxidative stress, and abated inflammation in animal models of radiation enteritis. Similarly, organic nanoparticle formulations stabilize tea polyphenols, preserving antioxidant activity in aqueous and biological environments. Lignin-based nanoparticles have illustrated enhanced biological activity, further broadening the functional spectrum of organic delivery vehicles. Modifications using polymer matrices like polylactic-co-glycolic acid (PLGA) prolong release and improve systemic bioavailability, positioning these carriers as promising candidates for mitigating radiation-induced injury.

Despite their promise, organic nanoparticle systems face hurdles such as complexity in manufacturing, variability in batch-to-batch consistency, and challenges in scaling production with reproducible quality control. The multi-parameter optimization required for stable formulations necessitates ongoing methodical investigation to translate bench findings into viable clinical therapies. Nonetheless, the modular nature of organic nanoparticles allows for continual refinement compatible with emerging biomedical demands.

In addition to nanoparticle-based carriers, hydrogels and microneedle arrays represent innovative drug delivery modalities tailored specifically for skin and superficial tissue applications frequently affected by radiation therapy. Hydrogels, composed of hydrophilic polymer networks able to retain substantial water content, create biocompatible matrices that facilitate sustained polyphenol release in situ. When integrated with extracellular matrix components, these hydrogels support tissue repair, cellular adhesion, and accelerated wound healing. Compared with oral or systemic administration, hydrogel-based delivery directly targets localized radiation-induced inflammation with reduced systemic side effects.

Microneedle systems utilize minimally invasive, micron-scale projections to breach the stratum corneum, delivering polyphenol payloads into deeper dermal layers without significant pain or infection risk. These platforms ensure precise dosing, rapid onset of action, and improved patient compliance, particularly for chronic radiation dermatitis or osteitis. Combined with nanoparticles or hydrogel matrices, microneedles represent a frontier in transdermal delivery for polyphenol-based radioprotective therapies. Emerging studies demonstrate their potential in enhancing drug bioavailability and therapeutic efficacy, yet further clinical validation remains necessary.

The synergistic integration of these delivery systems defines a transformative approach to overcoming long-standing barriers in polyphenol pharmacology. Encapsulation not only shields polyphenols from premature degradation and rapid clearance but also enables site-specific targeting, reducing collateral damage and enhancing therapeutic indices in radiation-injured tissues. This paradigm shift paves the way for broadening the scope of polyphenol application from preventive dietary supplements to sophisticated pharmaceutical interventions in oncology and beyond.

Nevertheless, the journey from experimental innovation to clinical translation demands meticulous attention to safety, formulation stability, and manufacturing scalability. Regulatory pathways must adapt to encompass nanomaterial complexities, and interdisciplinary collaborations are crucial for optimizing physicochemical properties in harmony with biological environments. Continued research into polymer coatings, surface functionalization, and responsive release mechanisms will be essential to fully harness the therapeutic potential of polyphenol delivery systems.

In conclusion, the evolving landscape of dietary polyphenol delivery is charting an exciting course toward effective radioprotection strategies. By leveraging liposomal vesicles, inorganic and organic nanoparticles, hydrogels, and microneedle systems, researchers are developing multifaceted platforms that surmount inherent chemical challenges and biological barriers. These advancements not only improve polyphenol bioavailability and targeting but also illuminate new possibilities for combating radiation-induced inflammation and tissue damage. With sustained innovation and rigorous validation, the promise of dietary polyphenols in clinical radioprotection may soon be realized as a mainstream therapeutic modality.

Subject of Research:
Dietary polyphenol delivery systems for enhancing radioprotection and mitigating radiation-induced inflammation.

Article Title:
Advancements in delivery systems for dietary polyphenols in enhancing radioprotection effects: challenges and opportunities.

Article References:
Lu, Y., Wang, K. & Hu, L. Advancements in delivery systems for dietary polyphenols in enhancing radioprotection effects: challenges and opportunities. npj Sci Food 9, 51 (2025). https://doi.org/10.1038/s41538-025-00419-6

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