Natural antioxidant products and nanomaterial-based delivery systems for the amelioration of diabetic retinopathy: mechanisms, applications, and translational perspectives

Abstract

Diabetic retinopathy (DR) is a leading global cause of vision loss, closely linked to hyperglycemia-induced oxidative stress, chronic inflammation, and pathological angiogenesis. Natural antioxidants exhibit great therapeutic potential against DR but are severely limited by poor solubility, low bioavailability, and insufficient ocular delivery. This review systematically summarizes the classification, pharmacological mechanisms, and therapeutic values of natural antioxidants in DR, and highlights advances in nanotechnology-based delivery systems to improve efficacy and clinical translation. We integrate preclinical and clinical studies focusing on key pathways including Nrf2/HO-1, NF-κB, NLRP3 inflammasome, and VEGF/HIF-1α. Flavonoids, polyphenols, carotenoids, and alkaloids exert multi-target effects by scavenging ROS, suppressing inflammation, and inhibiting pathological angiogenesis. Nanocarriers including lipid–polymer hybrid nanoparticles, self-nanoemulsifying drug delivery systems (SNEDDS), nanozymes, and lignin-based hydrogels significantly enhance solubility, corneal penetration, retinal targeting, and therapeutic efficacy. Representative nanoformulations effectively alleviate retinal oxidative damage, inflammation, and neovascularization. Natural antioxidants are promising DR candidates, and nanotechnology overcomes translational barriers. This review offers updated insights for developing natural product-based nanomedicines and proposes standardized formulations, biomarker-guided personalized therapy, and multi-target strategies to accelerate clinical translation.

1. Introduction

Diabetic retinopathy (DR) stands as one of the most prevalent and debilitating ocular complications arising from diabetes mellitus (DM), representing a leading cause of vision impairment and blindness worldwide. The global burden of diabetes continues to escalate, with projections indicating a significant rise in prevalence over the coming decades, thereby amplifying the incidence of associated microvascular complications such as DR (1). DR primarily results from progressive damage to the retinal microvasculature induced by chronic hyperglycemia, which triggers a cascade of pathological processes including oxidative stress, inflammation, and microvascular dysfunction. These mechanisms collectively contribute to retinal ischemia, neovascularization, and ultimately vision loss if left untreated (2, 3). The clinical manifestation of DR ranges from mild non-proliferative stages characterized by microaneurysms and retinal hemorrhages to advanced proliferative stages marked by neovascularization and vitreous hemorrhage (4, 5). Despite advances in diagnostic imaging and therapeutic interventions such as anti-vascular endothelial growth factor (VEGF) agents and laser photocoagulation, DR remains a significant public health challenge due to its asymptomatic early phases and the limitations of current treatments in reversing disease progression (5, 6).

The pathogenesis of DR is multifactorial, with hyperglycemia-induced oxidative stress playing a central role. Elevated glucose levels enhance the generation of reactive oxygen species (ROS) through multiple biochemical pathways, including the polyol pathway, protein kinase C activation, formation of advanced glycation end products (AGEs), and the hexosamine biosynthetic pathway (Figure 1). This oxidative milieu leads to endothelial dysfunction, inflammation, and apoptosis within the retinal neurovascular unit, exacerbating microvascular damage (3, 7). Inflammatory signaling pathways, notably involving nuclear factor kappa B (NF-κB), contribute to the upregulation of pro-inflammatory cytokines and adhesion molecules, further perpetuating vascular injury and retinal degeneration (8, 9). Moreover, dysregulation of growth factors such as VEGF under hypoxic conditions promotes pathological neovascularization, a hallmark of proliferative DR (3, 10) (Figure 1). Recent molecular insights have also highlighted the involvement of microRNAs and metabolic alterations in DR progression, underscoring the complexity of its pathophysiology and the need for multifaceted therapeutic approaches (6, 11).

Figure 1.

Schematic illustration of key pathological mechanisms in diabetic retinopathy. Chronic hyperglycemia triggers multiple pathways, including polyol, AGE-RAGE, PKC, and NOX, leading to excessive ROS production. This induces oxidative stress, inflammation, neurovascular unit dysfunction, blood-retinal barrier breakdown, neurodegeneration, and pathological neovascularization.

Given the intricate interplay of oxidative stress, inflammation, and vascular dysfunction in DR, there is growing interest in exploring natural antioxidant compounds as potential adjunctive therapies. Natural products, including polyphenols, flavonoids, carotenoids, and other phytochemicals, possess multifaceted biological activities such as antioxidant, anti-inflammatory, anti-angiogenic, and neuroprotective effects that may counteract the pathogenic mechanisms underlying DR (10, 12, 13). For instance, compounds like curcumin, alpha-lipoic acid (ALA), pterostilbene, and astaxanthin have demonstrated efficacy in preclinical models by reducing oxidative damage, modulating inflammatory pathways, and inhibiting VEGF-mediated neovascularization (14–17). These natural antioxidants may restore redox homeostasis, enhance endogenous defense systems such as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, and improve retinal vascular and neuronal health (12, 18). Furthermore, advances in drug delivery systems, including nanotechnology, have improved the bioavailability and targeted delivery of these compounds to ocular tissues, enhancing their therapeutic potential (12, 19). Promising as the supporting experimental evidence may be, bench-to-bedside translation of natural antioxidant therapies for DR encounters substantial hurdles with respect to bioavailability, target specificity, and overall safety profiles. Comprehensive clinical trials are needed to validate their efficacy and optimize dosing regimens (13, 20). Additionally, integrating lifestyle modifications, including diet rich in antioxidant-containing fruits and vegetables, alongside conventional treatments may offer a holistic strategy to prevent or delay DR onset and progression (8). The multifactorial nature of DR pathogenesis, centered on oxidative stress and inflammation, positions natural antioxidant products as a compelling area of research. Their potential to modulate key pathogenic pathways offers hope for more effective, safe, and accessible interventions in the management of DR.

Despite the growing interest in natural antioxidants for DR management, the existing literature has largely addressed this field from fragmented perspectives. Several recent reviews have examined either natural products or nanotechnology-based delivery for DR, but a comprehensive integration of both aspects—spanning the full spectrum of natural antioxidant classes, their detailed molecular mechanisms, and the latest advances in nanomaterial-based delivery systems designed to overcome bioavailability and targeting barriers—remains lacking. For instance, the previous review focused on nanomaterial-enabled delivery of plant-derived bioactive metabolites but provided limited mechanistic detail (21). Another review offered a general overview of natural products in DR but dedicated minimal attention to nanotechnology integration (20). The review published in Antioxidants concentrated exclusively on polyphenols and oxidative stress pathways, without comprehensive coverage of other antioxidant classes or detailed nanomaterial delivery strategies (22). While these contributions have advanced the field, a review that systematically integrates the full spectrum of natural antioxidant classes, their detailed molecular mechanisms, and the latest nanotechnology-based delivery systems—all within a clinical translation framework—remains absent.

Our review addresses this critical gap by providing: (1) a systematic classification of natural antioxidants across all major phytochemical categories (flavonoids, polyphenols, carotenoids, alkaloids, terpenoids, and phenylpropanoids) with detailed mechanistic analyses targeting key pathways including Nrf2/HO-1, NF-κB, NLRP3 inflammasome, and VEGF/HIF-1α; (2) comprehensive tabular summaries of molecular targets and therapeutic mechanisms for over 40 natural compounds; (3) a dedicated overview of nanomaterial-based delivery systems, including lipid-polymer hybrid nanoparticles, self-nanoemulsifying drug delivery systems (SNEDDS), nanozymes, lignin-based hydrogels, and emerging platforms; (4) a critical examination of clinical trial results and translational challenges; and (5) forward-looking recommendations for biomarker-guided personalized therapy and multi-target strategies. By integrating the mechanistic actions of natural antioxidants with nanotechnology-based solutions to overcome bioavailability and targeting barriers, this review provides a translational roadmap for developing effective natural product-based therapies for DR.

The distinct advantages of our review are fourfold. First, the breadth of coverage—encompassing all major natural antioxidant classes with detailed mechanistic pathways—is not available in any single existing publication. Second, the comprehensive tabular resources (Tables 1, 2) serve as definitive reference tools for researchers. Third, the integrated focus on both mechanisms and nanomaterial delivery provides a complete translational perspective. Fourth, the critical analysis of clinical challenges and personalized therapy approaches offers practical guidance for future research and clinical application. Together, these features position our review as a valuable resource for ophthalmologists, pharmacologists, and materials scientists working on DR therapeutics.

Table 1.

Functional targets and molecular mechanisms of natural antioxidants in the treatment of diabetic retinopathy.

Natural antioxidant product (category)	Target molecule or pathway	Mechanism of action	Study type	References
1. Polyphenols
1.1 Flavonoids*
Quercetin	MAPK, ERK1/2, NF-κB, VEGF, ROS	Activates antioxidant pathways, inhibits inflammation and angiogenesis, reduces oxidative stress and apoptosis.	Animal/Cell	(126, 127)
Catechin/EGCG	VEGF, HIF-1α, NF-κB, MAPK/ERK-VEGF, MMP9, ROS/TXNIP/NLRP3, NMDA, H2O2	Inhibits VEGF expression, alleviates inflammatory response, protects retinal ganglion cells and vascular endothelial cells.	Animal/Cell	(128–131)
Kaempferol	PI3K/AKT, NF-κB, Nrf2, VEGF, PGF, Src-AKT1-Erk1/2, TSP-1, ADAMTS-1, VASH1	Exerts anti-inflammatory and antioxidant effects by activating PI3K/AKT and Nrf2 pathways and inhibiting NF-κB, protecting the blood-retinal barrier.	Animal/Cell	(132–136)
Luteolin	NF-κB, MAPK, VEGF, PPARγ, GLUT, NLRP/NOX4, SIRT1/P53, SQSTM1/BNIP3L, Nrf2/Keap1, SIRT3/AMPK	Inhibits high glucose-induced release of inflammatory factors and VEGF expression, reducing retinal vascular leakage.	Cell	(49, 137–141)
Apigenin	PTEN/PI3K/AKT, CBP, HDAC3	Activates endogenous antioxidant defense system while inhibiting inflammatory pathways, protecting retinal cells from high glucose damage.	Cell/Animal	(142, 143)
Scutellarin	NLRP3, VEGF/ERK/FAK/Src, HIF-1α,	Scutellarin exerts therapeutic effects on diabetic retinopathy through multiple mechanisms, including inhibiting NLRP3 inflammasome activation, suppressing RGC pyroptosis, downregulating the VEGF/ERK/FAK/Src and ROS/HIF-1α/VEGF signaling pathways to reduce angiogenesis.	Cell/Animal	(144–149)
Dihydromyricetin	Poldip2/Nox4/H2O2, SOD, GSH	Dihydromyricetin can alleviate diabetic retinopathy and high glucose-induced damage in retinal pigment epithelial cells by downregulating the Poldip2-Nox4-H2O2 pathway and miR-34a expression, thereby reducing oxidative stress and cell apoptosis.	Animal/Cell	(61, 150)
Baicalein	GFAP, VEGF, HIF-1α, TNF, PI3K-AKT, MAPK, PPARG, ALB	Baicalein exerts protective effects against diabetic retinopathy by attenuating inflammatory responses in rodent models and regulating ferroptosis as its underlying therapeutic mechanism.	Cell/Animal	(151, 152)
Shikonin	BAX, COX-2, iNOS, PKM2	Shikonin exerts beneficial effects on early-stage diabetic retinopathy primarily through its anti-inflammatory properties.	Animal/Cell	(153, 154)
Hesperidin	MAPK, JNK, DOT1L, FASN, SREBF1, ROS	Hesperidin alleviates diabetic retinopathy by reducing oxidative stress, apoptosis and VEGF expression.	Animal/Cell	(155–158)
Blueberry Anthocyanin Extracts (BAEs)	GLP-1R/AKT/ GSK3β	Protect Retinal and Retinal Pigment Epithelium Function from High-Glucose-Induced Apoptosis by Activating GLP-1R/AKT Signaling.	Animal/Cell	(159)
Puerarin	STAT3, IL-1β, NADPH, iNOS, AGEs/RAGE	Puerarin protects against diabetic retinal injury by inhibiting oxidative stress, reducing apoptosis of retinal cells, and suppressing inflammation and STAT3 expression.	Animal/Cell	(160–164)
Naringenin	Bax, Bcl2, VEGF, GTPCH1/Enos, ROS	Naringenin attenuates oxidative stress, apoptosis, and inflammation, upregulates GTPCH1/eNOS to protect retinal endothelial cells.	Cell/Clinical/Animal	(45, 165, 166)
1.2 Other polyphenols
Resveratrol	CDKN2A, SIRT1/PGC-1α, Nrf2/HO-1, NF-κB, HMGB1, HIF-1α, HMOX1, HLA-A, Nrf2/GPx4/PTGS2, VEGF, AGEs	Resveratrol protects against diabetic retinopathy by activating Nrf2 signaling, inhibiting oxidative stress, inflammation and ferroptosis via SIRT1/HMGB1 and Nrf2/GPx4/PTGS2 pathways, while exerting immunomodulatory, anti-apoptotic effects and promoting autophagy.	Animal/Cell	(167–172)
Curcumin	ROS-PI3K/AKT/mTOR, Nrf2/HO-1, ERK1/2	Curcumin alleviates diabetic retinal injury by reducing oxidative stress, maintaining Nrf2 pathway homeostasis, activating Nrf2/HO-1 via ERK1/2, and suppressing inflammatory injury through the ROS-PI3K/AKT/mTOR pathway.	Animal/Cell	(42, 173, 174)
Green Tea Polyphenols	VEGF, MMP-9, NF-κB, Nrf2	(Represented by EGCG) Comprehensive antioxidant, anti-inflammatory, and anti-angiogenic effects, improving retinal microcirculation.	Animal/Clinical	(130, 131, 175)
Gallic Acid	AGEs/RAGE	Activates antioxidant defense system and inhibits AGEs-induced cytotoxicity.	Animal/Cell	(176–178)
Ellagic Acid	Nrf2/HO-1, AGEs	Inhibits high glucose-induced VEGF upregulation and activation of MAPK/NF-κB inflammatory pathways.	Cell/Animal	(179, 180)
Chlorogenic acid	TNFR1, TNFα, NFκB, VCAM1, ICAM1	Chlorogenic acid targets TNFR1 to block TNFα/NFκB signaling, reduces VCAM1/ICAM1 and inflammation, thereby mitigating BRB breakdown and leukocyte adhesion in diabetic retinopathy.	Animal/Cell	(181)
Rosmarinic acid	VEGF, RACK1, PKC, ROS	Rosmarinic acid and its intravitreal implants exert antiangiogenic effects to reduce neovascularization.	Animal/Cell	(182)
2. Carotenoids
Lutein/Zeaxanthin	ROS, H2O2, GSTP1	As major pigments in the macular region, directly quench ROS and mitigate photo-oxidative damage.	Animal/Clinical	(87, 183)
Lycopene	ROS, NLRP3, VEGF, VE-cadherin	Potent singlet oxygen quencher, inhibits retinal cell apoptosis, inflammation, and angiogenesis.	Animal/Cell	(87, 184, 185)
β-Carotene	ROS, Antioxidant Enzyme Activity	Precursor of vitamin A, acts by scavenging free radicals and enhancing total antioxidant capacity.	Animal	(87, 186)
Astaxanthin	VEGF, ROS, NADPH, HIF1α, XBP1, Aldose reductase	Astaxanthin alleviates diabetic retinopathy by suppressing oxidative stress, cell apoptosis and aldose reductase activity in diabetic models.	Animal/Clinical	(46, 187–189)
3. Alkaloids and other nitrogen-containing compounds
Berberine	AMPK, HIF-1α/VEGF/NF-κB, AKT/mTOR, GABA-α, NLRP3	Berberine ameliorates diabetic retinopathy by inhibiting HIF-1α/VEGF/NF-κB and NLRP3 inflammasome, activating GABA-α receptor, and regulating AMPK/mTOR-related autophagy and apoptosis.	Animal/Cell	(190–194)
Berberis dictyophylla F.	HIF-1α/VEGF/DLL-4/Notch-1	Inhibits angiogenesis and apoptosis of diabetic retinopathy via suppressing HIF-1α/VEGF/DLL-4/Notch-1 pathway.	Animal	(195)
Piperine	HIF-1α/VEGF, PEDF	Piperine exert protective effects on the retina of mice with diabetes via regulating the pro-antiangiogenic homeostasis composed of HIF-1/VEGFA and PEDF.	Animal/Clinical	(74, 196)
α-Lipoic Acid	ROS, NAD+/NADH, AMPK, OGT, PPARδ, SIRT3, TXNIP	α-Lipoic acid modulates retinal NAD-redox balance and reduces retinal cell death to ameliorate diabetic retinopathy.	Animal/Clinical	(81, 197, 198)
Melatonin	FN1, VEGF, VEGFR2, HDAC7/FOXO1/ZEB1, PI3K/AKT/Stat3/NF-κB, p38/TXNIP/NF-κB, MEG3/miR-204/Sirt1	Melatonin ameliorates diabetic retinopathy by suppressing angiogenesis and EndMT, maintaining blood-retinal barrier integrity, and relieving oxidative stress and inflammation through multiple signaling axes.	Animal/Cell	(53, 196, 199–202)
4. Terpenoids and volatile oil components
Andrographolide (Andrographis paniculata extract)	TNF-α, IL-6, IL-1β, VEGF, Egr-1, NF-κB, IDO, GSH, ROS	Andrographolide ameliorates diabetic retinopathy via inhibiting retinal angiogenesis, inflammation and indoleamine 2,3-dioxygenase activity.	Animal/Cell	(203, 204)
Tanshinone IIA	NF-Kb, AMPK/p300, ERK, PI3K-AKT, SOD, GSH, VEGF	Tanshinone IIA alleviates diabetic retinopathy via antioxidant effects and improves retinal barrier injury by regulating the AMPK/p300/NF-κB pathway.	Animal/Cell	(205–207)
Celastrol	HIF1α/VEGF, ICAM	Celastrol suppresses high glucose-induced angiogenesis in hRECs via downregulating the HIF1α/VEGF signaling pathway.	Cell	(208)
Fructus Alpiniae zerumbet	PPAR-γ/p-CREB	EOFAZ activates PPAR-γ to suppress CaMK II-CREB signaling, downregulate GFAP and VEGF, and inhibit Müller cell gliosis against diabetic retinopathy.	Cell/Animal	(113, 209)
5. Phenylpropanoids
Ferulic Acid	TNF-α, IL-18, IL-1β, P53, BAX, Bcl2, CAT, SOD, GSH-Px, MAPK/NF-κB	Ferulic acid protects the retina by alleviating high glucose-induced apoptosis of retinal pigment epithelial cells.	Animal/Cell	(210, 211)
6. Steroidal saponins and other saponins
Ginsenosides (Rg1, Rb1)	HIF1α/VEGF, TNF-α, miR-2113/RP11-982M15.8/Zeb1, IRS-1/AKT/GSK3β, PI3K/AKT, AMPK-STRT1, NLRP3, SNHG7/miR-2116-5p/SIRT3, TLR4/NF-κB, ROS, miR-100-3p/FBXW7/c-MYC, ACE2/Ang1-7/Mas, VDR/cAMP/PKA/CREB	Ginsenosides exert protective effects against diabetic retinopathy by regulating multiple signaling axes, suppressing VEGF, TNF-α and NLRP3 inflammasome, inhibiting inflammation via TLR4/NF-κB pathway, restraining retinal cell proliferation, migration and angiogenesis, alleviating mesenchymal activation, fibrosis, autophagy, senescence and neuronal degeneration, improving endothelial injury through AMPK-related mechanisms, and modulating microRNA/lncRNA-mediated molecular networks as well as mitochondrial function.	Cell/Animal	(212–222)
Gypenoside	ROS, VEGF	Gypenoside inhibits retinal ferroptosis, regulates Müller cell apoptosis and autophagy, and maintains tight junction integrity.	Animal/Cell	(223–225)
7. Other characteristic plant compounds
Gingerols (6-/8-/10-Gingerol)	NF-Kb, TNF-α, VEGF, e/iNOS, G6PDH	Gingerols ameliorate diabetic retinopathy by inhibiting inflammation, angiogenesis, apoptosis and the expression of e/iNOS and G6PDH.	Animal	(28, 226)
Allicin/S-Allyl Cysteine	PINK1/parkin, NLRP3	Allicin alleviates diabetic retinopathy by activating PINK1/Parkin-mediated mitophagy and inhibiting oxidative stress-triggered NLRP3 inflammasome.	Animal	(50)
Proanthocyanidins (Grape Seed Extract)	ROS, NLRP3, Nrf2, PI3K/AKT, Nrf2/HO-1, VEGF	Proanthocyanidins protect retinal pigment epithelial cells and alleviate diabetic retinopathy by suppressing oxidative stress and inhibiting the activation of the NLRP3 inflammasome.	Animal/Cell	(159, 227, 228)
Ganoderma lucidum Polysaccharides	Nrf2, HIF1α/VEGF	Ganoderma lucidum polysaccharides improve endothelial cell dysfunction in diabetic complications.	Animal/Cell	(229)

*Flavonoids are a subclass of polyphenols and are presented accordingly under the broader polyphenol category. Other polyphenols include non-flavonoid polyphenolic compounds. Phenylpropanoids and steroidal saponins are presented as separate categories due to their distinct chemical structures and biosynthetic pathways.

Table 2.

Application of novel nanomaterial and advanced drug delivery systems loaded with natural antioxidants in the treatment of diabetic retinopathy.

Natural antioxidant-based drug delivery systems	Target molecule or pathway	Mechanism of action	Study type	References
Curcumin-Laden Double-Headed Nanoparticles	AGEs, PIEZO1	Curcumin-laden double-headed nanoparticles exert anti-inflammatory and anti-hyperglycemic effects, inhibit Piezo1, reduce AGEs, thereby preventing diabetic retinopathy.	Cell/Animal	(78)
Curcumin liposomes and nanocrystals	Inflammatory factor	Potential Mechanism:Curcumin liposomes and nanocrystals inhibit macrophage inflammatory polarization, reduce inflammatory factors, and attenuate inflammatory infiltration and fibrosis.	Cell/Animal	(54)
Curcumin-loaded NLCs	VEGF	Curcumin-loaded NLCs enable sustained ocular delivery, enhance corneal penetration, reduce vitreous VEGF, and preserve retinal morphology to alleviate diabetic retinopathy.	Cell/Animal	(45)
Naringenin-loaded NLCs	VEGF	Reduce vitreous VEGF, and preserve retinal morphology.	Cell/Animal	(45)
NH@NAR/β-CD	VEGF, ROS	NH@NAR/β-CD achieves sustained naringenin release, enhances solubility and antioxidant activity, targets retinal endothelial cells, and improves uptake to treat early diabetic retinopathy.	Cell	(230)
Fe-DMY NCPs	Poldip2-Nox4-H2O2, VCAM-1, HIF-1α, VEGF	Fe-DMY NCPs scavenge ROS, inhibit the Poldip2-Nox4-H2O2 pathway, downregulate VCAM-1/HIF-1α/VEGF, and alleviate retinal vascular leakage and neovascularization in diabetic retinopathy.	Cell/Animal	(61)
LPNPs	MDA, IL-1β, NLRP3, ASC, VEGF, GSH, Nrf2	Luteolin-loaded LPNPs enhance bioavailability, activate Nrf2, inhibit NLRP3/IL-1β/VEGF, reduce oxidative stress, inflammation and angiogenesis, thereby protecting retinal structure in diabetic retinopathy.	Animal	(49)
GPA-NP	Nrf2/HO-1/GPX4	GPA-NP enhances bioavailability, activates Nrf2/HO-1/GPX4 pathway by targeting Keap1, reduces oxidative stress and inflammation, and alleviates ferroptosis to protect against diabetic retinopathy.	Animal/Cell	(224)
NPSPHE@EOFAZ	ROS	NPSPHE@EOFAZ is a ROS-responsive nanoparticle that delivers EOFAZ to Müller cells, reduces oxidative stress and inflammation, and mitigates early pathological changes in diabetic retinopathy.	Cell/Animal	(113)
RSV-NS	VEGF	RSV-NS inhibits endothelial cell proliferation and migration, showing anti-angiogenic potential for treating diabetic retinopathy.	Cell	(231)
Lignin-based hydrogel*	VEGF, ROS	Lignin-based hydrogel acts as a safe ocular delivery carrier, loads natural antioxidants, inhibits VEGF, and exerts antioxidant and anti-inflammatory effects to treat diabetic retinopathy.	Animal	(110)
Chit-DC-VB12-Scu)	VEGF, VEGFR2, VWF	Chit-DC-VB12-Scu improves scutellarin bioavailability and intestinal absorption, downregulates VEGF/VEGFR2/vWF, and suppresses retinal neovascularization to ameliorate diabetic retinopathy.	Cell/Animal	(146)
SNEDDS	SIRT-1	SNEDDS act as biocompatible ocular nanocarriers to efficiently deliver resveratrol and melatonin, enhance their solubility and stability, and facilitate SIRT-1 activation for diabetic retinopathy therapy.	Cell	(79, 108)
Fe-Quer NZs	ROS, SOD, GPX, GCLC, SOD, GSH, IL-1, IL-6, TNF-α	Fe-Quer NZs mimic multiple antioxidant enzymes to scavenge ROS, alleviate oxidative stress and inflammation, inhibit angiogenesis and microvascular leakage, and exert vascular protection against early diabetic retinopathy.	Cell/Animal	(114)
SH-CDs	ROS, IL-1, IL-6, TNF-α	SH-CDs with good biocompatibility penetrate ocular tissues, scavenge reactive species, relieve oxidative stress and inflammation, and alleviate pathological damage to treat diabetic retinopathy.	Cell/Animal	(115)
AgNPs@O. europaea	TNFα, NF-κB, IL-10, GSH, CAT, SOD	AgNPs@O. europaea lowers blood glucose, enhances antioxidant levels, suppresses inflammatory TNF-α and NF-κB, elevates IL-10, and reduces retinal vascular permeability to alleviate diabetic retinopathy.	Cell/Animal	(232)
Myricetin-loaded thermoresponsive in situ nanoemulgel	ROS	This myricetin-loaded nanoemulgel enhances corneal permeation and retention, exerts strong antioxidant effects to treat diabetic retinopathy.	Cell	(102)
Tetrahedral Framework Nucleic Acids-Resveratrol	HIF-1, p38 MAPK, NF-κB p65	In models of hypoxia-driven retinal neovascularization, tFNAs-RSV significantly attenuated neovascular lesion size, vascular leakage, and retinal inflammatory infiltration by inhibiting HIF-1 signaling along with the p38 MAPK and NF-κB p65 pathways.	Cell/Animal	(233)

*While lignin-based hydrogels are not strictly nanomaterials in the conventional definition, they are included as an advanced drug delivery platform with nanoscale structural features that represent an emerging approach for ocular delivery of natural antioxidants.

2. Classification and mechanisms of natural antioxidant products

2.1. Types of phytochemicals

Phytochemicals, the bioactive compounds derived from plants, encompass a diverse array of chemical classes that have demonstrated significant potential in managing DR, a major microvascular complication of diabetes mellitus. Among these, polyphenols—which include the flavonoid subclass as well as other phenolic compounds—and carotenoids are the most extensively studied groups due to their potent antioxidant, anti-inflammatory, and antiangiogenic properties. Flavonoids, the most abundant polyphenols in the human diet, are found in fruits, vegetables, and medicinal herbs, and have been shown to exert antidiabetic effects by modulating oxidative stress, inflammation, and immune responses in both in vitro and in vivo models (23). Other polyphenols, including resveratrol, curcumin, and chlorogenic acid, similarly exhibit strong antioxidant activities that protect retinal cells from hyperglycemia-induced damage. Carotenoids, another major class of dietary phytochemicals, similarly exhibit strong antioxidant activities that neutralize ROS and reduce inflammation, thereby protecting retinal cells from hyperglycemia-induced damage and neovascularization characteristic of DR (24). Beyond these, other phytochemical classes such as alkaloids, terpenoids, phenylpropanoids, and saponins have been identified in polyherbal extracts with demonstrated antioxidant and anti-inflammatory activities relevant to diabetes complications (25). The detailed classification of natural antioxidants, as well as their functional targets and molecular mechanisms in the treatment of DR, are presented in Table 1.

Specific medicinal plants rich in these phytochemicals have been investigated for their therapeutic potential in DR. For example, Andrographis paniculata extract containing alkaloids and flavonoids was shown to improve retinal vessel diameter and enhance antioxidant enzyme levels in diabetic rats, highlighting its hypoglycemic, antioxidant, and anti-inflammatory effects (26). Similarly, extracts from Apocynum venetum leaves, rich in polyphenols including flavonoids and organic acids, protected retinal pigment epithelial cells by modulating the polyol pathway, reducing oxidative stress, and maintaining autophagy, thus preserving cellular homeostasis under hyperglycemic conditions (27). Ginger (Zingiber officinale) contains numerous phytochemicals such as gingerol and shogaol, which have demonstrated efficacy in reducing oxidative damage, inflammation, apoptosis, and pathological angiogenesis in DR models, further supporting the multifaceted roles of phytochemicals in retinal protection (28).

Other phytochemicals with promising anti-DR activities include anthocyanins from mulberry extract, which enhance antioxidant defenses and modulate apoptosis-related proteins in retinal cells exposed to high glucose, suggesting a protective effect against oxidative injury (29). Ginkgo biloba, a traditional medicinal plant, contains flavonoids and terpenoids with neuroprotective and anti-inflammatory effects that may benefit ocular health in DR and other age-related eye diseases (30). Peperomia pellucida, rich in compounds such as dillapiole and vitexin, has shown anti-inflammatory and antiangiogenic activities via modulation of NF-κB and PPAR-γ signaling pathways in retinal cells under diabetic conditions (31, 32) (Figure 2).

Figure 2.

Classification and primary mechanisms of natural antioxidants. Natural antioxidants, including polyphenols, flavonoids, vitamins, and carotenoids, exert protective effects by inhibiting lipid peroxidation, enhancing antioxidant enzymes, chelating metal ions, and activating the Nrf2/ARE pathway.

Molecular docking and in silico studies have further identified specific phytochemicals like terchebulin, punicalagin, and chebulagic acid from medicinal plants as potential inhibitors of key molecular targets implicated in DR progression, such as the C4 protein, underscoring the therapeutic promise of these compounds (33). Moreover, polyherbal extracts combining various phytochemical classes have demonstrated synergistic antioxidant and anti-inflammatory effects, which may enhance their efficacy in managing DR (25). Despite the promising therapeutic potential of these phytochemicals, their clinical application is severely limited by poor aqueous solubility, low bioavailability, rapid metabolism, and insufficient ocular tissue penetration. Nanotechnology-based drug delivery systems have emerged as effective strategies to overcome these limitations. Encapsulation of phytochemicals in nanocarriers such as lipid nanoparticles, polymeric nanoparticles, and self-emulsifying drug delivery systems can significantly enhance their solubility, stability, and retinal targeting, thereby improving their therapeutic efficacy in DR (21, 34). These nanoformulations not only protect the active compounds from degradation but also facilitate controlled release and enhance cellular uptake in retinal tissues, addressing the critical barriers that have historically hindered the clinical translation of natural antioxidants.

2.2. Antioxidant mechanisms

The pathogenesis of DR is closely linked to oxidative stress, which arises from an imbalance between the production of ROS and the capacity of antioxidant defenses. Excessive ROS generation in hyperglycemic conditions leads to cellular damage in retinal tissues, contributing to vascular dysfunction, inflammation, and neuronal apoptosis. Natural antioxidants derived from plants have shown promising potential in scavenging free radicals and ROS, thereby mitigating oxidative damage in DR. For instance, alpha-lipoic acid, a naturally occurring dithiol compound, acts as a universal antioxidant by directly neutralizing ROS and regenerating other antioxidants, thus protecting retinal cells from oxidative injury. Experimental studies demonstrated that ALA prevents oxidative stress-induced retinal damage by inhibiting NF-κB activity and activating Nrf2, a master regulator of antioxidant response (15). Similarly, polyphenols such as quercetin exhibit potent free radical scavenging activity, reducing oxidative stress and inflammation in diabetic retinal tissues. Quercetin’s antioxidative effects are mediated by its ability to directly neutralize ROS and inhibit lipid peroxidation, thereby preserving retinal cell integrity (35). Moreover, procyanidins, natural polyphenolic compounds, exert strong antioxidant effects by scavenging free radicals and reducing oxidative stress markers, which are pivotal in preventing diabetic complications including retinopathy (36). Other natural antioxidants such as astaxanthin and chlorogenic acid have also been reported to scavenge ROS effectively, protecting retinal cells from oxidative damage and inflammation in diabetes (37, 38). These compounds not only neutralize ROS but also inhibit downstream pathological processes such as mitochondrial dysfunction and apoptosis, which are crucial in the progression of DR (39) (Figure 3A). The combined antioxidant and anti-inflammatory properties of these natural agents highlight their therapeutic potential in scavenging free radicals and ROS to prevent or delay diabetic retinal damage. However, despite encouraging preclinical evidence, clinical validation remains limited, necessitating further research to optimize their use in DR management (13, 40).

Figure 3.

Mechanisms of phytochemical antioxidants in diabetic retinopathy. (A) Mechanism of the antioxidant effect. Natural antioxidants activate the Nrf2/ARE pathway to upregulate antioxidant enzymes, scavenge ROS, inhibit NF-κB-mediated inflammation, and reduce oxidative damage in endothelial, neuronal, and RPE cells. (B) Mechanism of the anti-inflammation effect. These compounds suppress NF-κB, NLRP3 inflammasome, and HIF-1α signaling, activate the Nrf2/HO-1 and AMPK/SIRT1 pathways, reduce oxidative stress and inflammatory cytokine release, and confer retinal neurovascular protection in endothelial and glial cells. (C) Mechanism of the against pathological neovascularization effect. These agents suppress VEGF/KDR, TLR4/NF-κB/NLRP3, and NOX4 signaling, activate AMPK, reduce AGEs, and inhibit retinal endothelial cell activation, thereby blocking angiogenesis.

In addition to direct scavenging of ROS, natural antioxidants enhance the endogenous antioxidant defense system by upregulating the expression and activity of key antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). This endogenous system is critical for maintaining redox homeostasis in retinal cells under diabetic conditions. Activation of the Nrf2 pathway is a central mechanism through which many natural compounds exert this effect. Nrf2, when activated, translocates to the nucleus and binds to antioxidant response elements (ARE) in the promoter regions of genes encoding antioxidant enzymes, thereby increasing their transcription. For example, syringaresinol, a natural polyphenol, has been shown to activate Nrf2, leading to enhanced expression of antioxidant enzymes and suppression of oxidative stress in DR models. This activation also downregulates hypoxia-inducible factor-1α (HIF-1α) and VEGF, mitigating retinal microvascular damage (41). Similarly, carnosol protects human retinal endothelial cells from high glucose-induced oxidative damage by inducing heme oxygenase-1 (HO-1) expression via Nrf2 activation, which involves the ERK1/2 signaling pathway, thereby enhancing cellular antioxidant capacity (18). Pterostilbene, another natural antioxidant, improves redox status and restores the activities of antioxidant enzymes in diabetic retinal tissue through activation of the PI3K/AKT/GSK3β/Nrf2 pathway, demonstrating a potent protective effect against early DR alterations (16). Curcumin, a well-studied polyphenol, also modulates the Nrf2 pathway, maintaining its homeostasis and promoting antioxidant enzyme expression, which alleviates oxidative stress and retinal injury in diabetic models (42). Beyond Nrf2, other signaling pathways such as AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are implicated in the upregulation of antioxidant enzymes by natural compounds like resveratrol, further contributing to oxidative stress reduction and improved retinal health in diabetes (15, 43). The enhancement of endogenous antioxidant defenses not only reduces ROS levels but also attenuates inflammation and apoptosis, key contributors to DR progression. While these molecular insights underscore the therapeutic promise of natural antioxidants in boosting intrinsic antioxidant enzymes, challenges such as bioavailability and targeted delivery remain. Nonetheless, ongoing advances in nutraceutical formulations and nanotechnology hold potential to overcome these barriers and optimize the clinical application of natural antioxidants in DR (12, 44).

The enhancement of endogenous antioxidant defenses by natural compounds is significantly amplified when these agents are delivered using nanotechnology-based systems. Nanocarriers can protect labile antioxidants from degradation, facilitate their intracellular delivery, and enable sustained release, thereby potentiating their effects on the Nrf2 pathway and antioxidant enzyme expression. For example, curcumin-loaded nanostructured lipid carriers (NLCs) have demonstrated superior Nrf2 activation and HO-1 upregulation compared to free curcumin in retinal endothelial cells, attributed to enhanced cellular uptake and sustained intracellular drug levels (45). These nanoformulations not only improve the bioavailability of natural antioxidants but also enable their targeted delivery to retinal tissues, maximizing therapeutic efficacy while minimizing systemic side effects. The integration of nanocarrier technology with natural antioxidant therapy thus represents a promising strategy to overcome the pharmacokinetic barriers that have limited the clinical translation of these compounds.

2.3. Anti-inflammatory effects

Inflammation plays a central role in the pathogenesis and progression of DR, a major microvascular complication of diabetes mellitus. Chronic hyperglycemia induces oxidative stress and triggers the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which exacerbate retinal damage by promoting leukostasis, vascular permeability, and neuronal apoptosis. Natural antioxidant compounds have demonstrated significant anti-inflammatory effects by downregulating these key inflammatory mediators, thereby mitigating retinal inflammation and preserving retinal structure and function. For example, studies have shown that astaxanthin (ASX), a potent natural antioxidant, reduces retinal levels of TNF-α, IL-1β, and IL-6 in streptozotocin-induced diabetic rat models, concomitant with decreased oxidative stress and apoptosis in retinal tissues. This effect is mediated through activation of the Nrf2/Keap1 antioxidant pathway, which suppresses inflammation and oxidative damage (46). Similarly, geniposide (GEN), a natural anti-inflammatory compound, inhibits NF-κB activation and reduces secretion of inflammatory cytokines in retinal Müller cells exposed to high glucose, with effects dependent on Nrf2 signaling and glucagon-like peptide-1 receptor (GLP-1R) activation (47). Another example is sesamin, a natural lignan, which dose-dependently suppresses TNF-α, IL-1β, and IL-6 expression in retinal microglia under hyperglycemic conditions, thereby alleviating microglial inflammation and blood-retinal barrier breakdown in diabetic mice (44). Resveratrol, a polyphenol with well-documented anti-inflammatory properties, inhibits the expression of TNF-α, IL-6, and cyclooxygenase-2 (COX-2) in diabetic retinas, improving retinal thickness and visual function through modulation of SIRT1/NF-κB and Nrf2 pathways (48). Luteolin, a flavonoid, also demonstrates anti-inflammatory effects by reducing retinal levels of TNF-α and IL-6, although its clinical application is limited by poor solubility; novel nanocarrier formulations have been developed to enhance its bioavailability and therapeutic efficacy in DR models (49). Moreover, natural compounds such as allicin from garlic exhibit anti-inflammatory actions by downregulating inflammasome components (e.g., NLRP3) and pro-inflammatory cytokines, partly through activation of mitophagy pathways, which attenuates pyroptosis and oxidative stress in diabetic retinas (50). Phytochemicals like palbinone and tilianin have been reported to inhibit NLRP3 inflammasome activation and reduce inflammatory cytokines in diabetic retinas, contributing to antioxidant and anti-inflammatory protection (51, 52). Additionally, natural extracts such as ginger have been shown to suppress ocular expression of NF-κB and VEGF, decrease TNF-α levels, and improve oxidative stress markers, collectively reducing inflammation and angiogenesis in DR (28). The anti-inflammatory effects of these natural antioxidants often involve modulation of key signaling pathways, including Nrf2/HO-1, AMPK/Sirt1/PGC-1α, and NF-κB, which regulate the balance between pro- and anti-inflammatory mediators. For instance, melatonin attenuates retinal inflammation by activating the Sirt1 pathway, leading to deacetylation and suppression of NF-κB activity in Müller cells (53). Syringaresinol alleviates early DR by activating Nrf2 and downregulating hypoxia-inducible factor-1α (HIF-1α)/VEGF, thereby reducing inflammation and oxidative stress in retinal microvasculature (41) (Figure 3B). Collectively, these findings underscore the therapeutic potential of natural antioxidant compounds in mitigating retinal inflammation in DR by inhibiting the expression of inflammatory cytokines such as TNF-α and IL-6. This anti-inflammatory action complements their antioxidant capacity, ultimately protecting retinal cells from hyperglycemia-induced damage and preserving visual function. Further clinical studies and optimization of delivery systems are warranted to translate these promising preclinical results into effective treatments for DR.

The anti-inflammatory efficacy of natural antioxidants is critically dependent on their ability to reach sufficient concentrations at the target retinal tissues, which is often hindered by poor bioavailability. Advanced nanocarrier systems address this limitation by enhancing the ocular penetration and sustained release of anti-inflammatory compounds. For instance, luteolin-loaded lipid-polymer hybrid nanoparticles (LPNPs) functionalized with TPGS have shown significantly enhanced oral bioavailability and retinal tissue distribution compared to free luteolin, leading to superior inhibition of NLRP3 inflammasome activation and inflammatory cytokine production in diabetic models (49). The nanoformulation achieved prolonged drug release, improved intestinal permeability, and substantial attenuation of retinal inflammatory markers, demonstrating the translational potential of nanocarrier systems. Similarly, geniposide-loaded nanoparticles and curcumin SNEDDS formulations have demonstrated enhanced intracellular uptake in retinal cells, resulting in more effective suppression of NF-κB activation and inflammatory mediator expression (54). These examples underscore the critical role of nanotechnology in unlocking the full anti-inflammatory potential of natural antioxidants for DR therapy.

2.4. Anti-angiogenesis

Pathological neovascularization is a hallmark of DR, driven primarily by the overexpression of VEGF, which promotes aberrant angiogenesis and vascular leakage in the retina. Natural antioxidants have emerged as promising agents to inhibit this pathological process by targeting VEGF and its downstream signaling pathways. For instance, Posidonia oceanica extract (POE), derived from a Mediterranean seagrass, has demonstrated potent anti-angiogenic effects by selectively disrupting VEGF-induced signaling in human endothelial colony-forming cells (ECFCs). POE inhibits phosphorylation of VEGF receptor 2 (KDR), mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinase (ERK), thereby impairing endothelial cell migration, invasion, and tube formation essential for neovascularization, without compromising cell viability. Additionally, POE reduces intracellular ROS accumulation and downregulates redox-regulating genes, linking its antioxidant capacity to anti-angiogenic activity (55). Similarly, resveratrol, a natural polyphenol, exhibits multi-modal protective effects in DR, including suppression of pathological neovascularization. It modulates oxidative stress and inflammatory pathways, ultimately inhibiting VEGF expression and angiogenic signaling. However, its clinical translation is challenged by poor ocular bioavailability, prompting exploration of advanced drug delivery systems to enhance retinal targeting (56). Curcumin, another natural compound with antioxidant and anti-inflammatory properties, protects retinal pigment epithelium (RPE) cells under hyperglycemic conditions by preserving tight junction integrity and inhibiting retinal neovascularization. It achieves this by modulating key signaling pathways such as NF-κB and TLR4, which are involved in inflammation and angiogenesis, thus preventing VEGF-mediated vascular proliferation (57, 58). Luteolin-loaded nanocarriers have also shown promise in reducing retinal VEGF expression and angiogenesis in diabetic models. By enhancing luteolin’s bioavailability, these nanoplatforms effectively decrease oxidative stress and inflammatory markers, including IL-1β and NLRP3 inflammasome components, while downregulating VEGF, thereby mitigating neovascular complications (49). Quercetin, a flavonoid abundant in fruits and vegetables, inhibits retinal neovascularization by reducing oxidative stress and inflammatory cytokines, and by modulating signaling pathways such as AMP-activated protein kinase (AMPK), which influence VEGF expression. Despite its therapeutic potential, quercetin’s clinical use is limited by low bioavailability, necessitating further formulation optimization (59). Omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), contribute to retinal health by exerting anti-angiogenic effects that inhibit abnormal blood vessel growth characteristic of proliferative DR. Their antioxidative and anti-inflammatory mechanisms reduce VEGF-driven neovascularization, highlighting their preventive role in retinal diseases (60) (Figure 3C). Furthermore, innovative nanotechnology approaches, such as iron-coordinated dihydromyricetin nanoparticles, have been developed to target oxidative stress and angiogenesis simultaneously. These nanoparticles downregulate the Poldip2-Nox4-H2O2 pathway and reduce expression of VEGF and other angiogenic factors, effectively alleviating retinal vascular leakage and neovascularization in diabetic models (61). Gold nanoparticles coated with hyaluronic acid (HA-GNPs) represent another advanced strategy for ocular drug delivery. HA enhances nanoparticle stability and retinal targeting via CD44 receptor interaction, enabling effective inhibition of AGEs-mediated retinal pigment epithelial cell death and neovascularization. This approach underscores the potential of combining natural compounds with nanocarriers to improve anti-angiogenic therapy in DR (62). These nanocarrier-based approaches offer significant advantages over conventional formulations, including enhanced stability, targeted delivery, reduced systemic toxicity, and the potential for combination therapy with multiple natural compounds. Lastly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), though not classical antioxidants, exhibit anti-angiogenic properties by stabilizing vascular integrity and modulating extracellular matrix homeostasis, contributing to reduced neovascular complications in DR (63). Collectively, these findings highlight that natural antioxidants and their advanced formulations can effectively inhibit VEGF expression and signaling pathways, thereby preventing pathological neovascularization in DR. This multi-targeted approach addresses oxidative stress, inflammation, and angiogenesis, offering promising therapeutic avenues for early intervention and management of DR.

3. Research progress of major natural antioxidant products in DR

3.1. Quercetin

Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has garnered extensive attention for its multifaceted therapeutic potential in DR, a leading cause of vision impairment in diabetic patients. Experimental studies across various animal models consistently demonstrate quercetin’s capacity to mitigate retinal injury and preserve visual function. For instance, in a zebrafish model of DR induced by streptozotocin (STZ), nano-formulated quercetin (NQ) administered intraperitoneally for 21 days attenuated retinal damage markers, including normalization of eyeball-to-body weight ratio and improvement in behavioral visual responses such as optomotor and phototactic responses. Biochemical assays revealed that NQ reduced plasma glucose and homocysteine levels, decreased retinal lipid peroxidation, and restored antioxidant enzyme activities, effects comparable to dexamethasone treatment, underscoring its antioxidative and anti-hyperglycemic properties (64). In rodent models, quercetin administration increased retinal cell layer thickness and ganglion cell counts, while suppressing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), high mobility group box-1, and NLRP3 inflammasome activation. This anti-inflammatory effect was linked to upregulation of heme oxygenase-1, a cytoprotective enzyme, as inhibition of this pathway abrogated quercetin’s protective effects (65). At the cellular level, quercetin inhibited angiogenesis in human retinal microvascular endothelial cells exposed to high glucose by downregulating the NLRP3 inflammasome components (NLRP3, ASC, Caspase-1) and pro-inflammatory interleukins (IL-1β, IL-18), while modulating autophagy-related proteins LC3 and Beclin-1, suggesting a role in controlling pathological neovascularization and inflammation (66). Network pharmacology analyses of traditional Chinese medicine formulations containing quercetin identified key targets such as IL6, EGFR, CASP3, and VEGFA, implicating quercetin in regulating AGE-RAGE, TNF, HIF-1, and VEGF signaling pathways central to DR pathogenesis (67). Mechanistically, quercetin exerts antioxidant effects by scavenging ROS, inhibiting myeloperoxidase-dependent hypochlorous acid generation, and enhancing endogenous antioxidant defenses including glutathione and superoxide dismutase, thereby protecting retinal endothelial cells from oxidative damage (39, 68). Furthermore, quercetin modulates cellular senescence and inflammation by targeting the NLRP3 inflammasome and related signaling pathways such as NF-κB, AMPK, and SIRT1, which are implicated in DR progression (69, 70) (Figure 4). Combinational therapies pairing quercetin with conventional antidiabetic drugs like gliclazide have demonstrated synergistic effects in glycemic control and pancreatic β-cell protection, further supporting its adjunctive use (71). Collectively, these studies underscore quercetin’s significant capacity to reduce retinal damage, inhibit inflammation and neovascularization, and improve visual outcomes in DR models, positioning it as a promising natural antioxidant agent for DR management pending further clinical validation.

Figure 4.

Comparative schematic of the molecular mechanisms of quercetin, curcumin, and α-lipoic acid (ALA) in diabetic retinopathy. All three natural antioxidants exert multi-target protective effects: they scavenge ROS, inhibit NF-κB-mediated inflammation and VEGF-driven neovascularization, and regulate cell survival/apoptosis pathways. Quercetin additionally activates PI3K/AKT signaling; curcumin modulates PI3K/AKT/MAPK pathways and upregulates Bcl-2; ALA further activates the Nrf2 antioxidant pathway, preserves mitochondrial function, and protects the blood-retinal barrier across endothelial, glial, and ganglion cells.

Despite its promising preclinical efficacy, clinical translation of quercetin faces challenges due to poor bioavailability, low aqueous solubility, and rapid metabolism. Advances in nanoformulation techniques have been instrumental in overcoming these limitations. Quercetin nanoemulsions, phytosome complexes, and lipid-based nanocarriers have been developed to improve solubility, stability, and targeted delivery to retinal tissues (64, 72). Nano-formulated quercetin (NQ) has demonstrated superior retinal protection in zebrafish and rodent models compared to free quercetin, with enhanced antioxidant enzyme activity and improved behavioral visual responses (64). Quercetin-loaded thermoresponsive in situ nanoemulgels have also been explored to enhance corneal permeation and retention for topical ocular administration (73). These nanoformulations not only improve the pharmacokinetic profile of quercetin but also enable sustained release and targeted accumulation in retinal tissues, representing a promising strategy to translate the therapeutic potential of this flavonoid into clinical practice for DR management.

3.2. Curcumin

Curcumin, a natural polyphenol derived from the rhizome of Curcuma longa, has garnered significant attention for its multifaceted pharmacological properties, including potent antioxidant, anti-inflammatory, and anti-apoptotic effects, which are highly relevant in the context of DR. DR is a microvascular complication of diabetes mellitus characterized by oxidative stress, inflammation, and retinal neurovascular damage, ultimately leading to vision impairment and blindness. The Nrf2/HO-1 signaling pathway plays a pivotal role in cellular defense against oxidative stress by regulating the expression of antioxidant enzymes and cytoprotective proteins. Curcumin’s therapeutic potential in DR has been increasingly attributed to its ability to activate this pathway, thereby mitigating oxidative damage and inflammation in retinal tissues.

Several preclinical studies have demonstrated that curcumin administration in diabetic models significantly alleviates retinal oxidative stress by enhancing Nrf2 nuclear translocation and upregulating heme oxygenase-1 (HO-1) expression. For instance, in streptozotocin-induced diabetic rats, curcumin treatment reduced retinal edema and photoreceptor apoptosis more effectively than insulin alone, correlating with a restoration of Nrf2 pathway homeostasis. This suggests that curcumin’s antioxidant capacity not only scavenges ROS but also modulates endogenous antioxidant defenses through Nrf2/HO-1 activation, resulting in decreased oxidative stress and improved retinal structural integrity (42) (Figure 4). Moreover, transcriptomic analyses revealed that curcumin suppresses the AGE-RAGE signaling pathway and extracellular matrix-receptor interactions, both critical in DR pathogenesis, further supporting its multifactorial protective effects.

Clinical investigations have also begun to explore curcumin’s efficacy in DR patients. A randomized, double-blind controlled trial administering curcumin-piperine supplementation reported significant improvements in total antioxidant capacity and superoxide dismutase levels, alongside reductions in malondialdehyde and creatinine, markers indicative of oxidative stress and renal function, respectively. Although no significant changes were observed in inflammatory markers or retinal vascular density within the study period, these findings underscore curcumin’s potential to enhance systemic antioxidant defenses in non-proliferative DR (74). Additionally, curcumin’s anti-inflammatory effects have been documented in human vitreous samples from DR patients, where combined treatment with curcumin, homotaurine, and vitamin D3 significantly reduced pro-inflammatory cytokines such as TNF-α and IL-2, suggesting synergistic modulation of inflammatory mediators involved in DR progression (75).

At the molecular level, curcumin’s activation of the Nrf2/HO-1 axis involves the promotion of Nrf2 nuclear translocation, which binds to antioxidant response elements (ARE) in the promoter regions of genes encoding antioxidant enzymes, including HO-1. HO-1, in turn, exerts cytoprotective effects by degrading pro-oxidant heme into biliverdin, carbon monoxide, and free iron, thereby reducing oxidative damage. Curcumin also modulates upstream signaling pathways such as PI3K/AKT and MAPK, which influence Nrf2 activation, and suppresses NF-κB-mediated inflammatory responses, creating a comprehensive antioxidative and anti-inflammatory milieu in retinal cells (57, 76) (Figure 4). Furthermore, curcumin’s neuroprotective effects in the retina are linked to the preservation of tight junction integrity in retinal pigment epithelial cells and inhibition of retinal neovascularization, both critical factors in DR pathophysiology (57).

Despite its promising biological activities, curcumin’s clinical application is limited by poor aqueous solubility, low bioavailability, rapid metabolism, and systemic elimination. To overcome these challenges, various delivery systems such as nanoemulsions, nanoparticles, and cyclodextrin inclusion complexes have been developed, enhancing curcumin’s stability, ocular penetration, and sustained release. For example, curcumin-loaded NLCs and SNEDDS have demonstrated improved retinal bioavailability and antioxidant efficacy in diabetic models, supporting their potential for clinical translation in DR management (45, 77). Additionally, combination therapies incorporating curcumin with insulin or other natural antioxidants have shown synergistic effects in maintaining Nrf2 pathway homeostasis and reducing retinal injury (42, 78).

In summary, curcumin exerts protective effects against DR primarily through the modulation of the Nrf2/HO-1 signaling pathway, leading to enhanced antioxidant defenses, reduced oxidative stress, and attenuation of inflammatory responses in retinal tissues. Its multifaceted actions extend to preserving retinal structure and function, inhibiting pathological angiogenesis, and improving metabolic parameters associated with diabetes. Although clinical evidence remains limited, advancements in curcumin delivery technologies and combination therapies hold promise for its effective incorporation into DR treatment regimens. Future large-scale, well-designed clinical trials are warranted to validate curcumin’s efficacy and safety as a complementary therapeutic agent targeting the oxidative and inflammatory mechanisms underlying DR.

Despite its promising biological activities, curcumin’s clinical application is severely limited by poor aqueous solubility, low bioavailability, rapid metabolism, and systemic elimination. To overcome these challenges, a wide range of delivery systems has been developed, including nanoemulsions, nanoparticles, liposomes, NLCs, and cyclodextrin inclusion complexes. Curcumin-loaded NLCs have demonstrated enhanced retinal bioavailability and antioxidant efficacy in diabetic models, with improved corneal penetration, reduced vitreous VEGF levels, and preserved retinal morphology (45). Similarly, curcumin SNEDDS have shown superior physicochemical stability, mucoadhesive properties, and enhanced intracellular uptake in retinal pigment epithelial cells, resulting in more potent antioxidant activity and induction of protective SIRT1 expression compared to free curcumin (79). Curcumin-laden double-headed nanoparticles have been developed to combine anti-inflammatory and anti-hyperglycemic effects, inhibiting Piezo1 and reducing AGEs in rodent models (78). These advanced delivery platforms represent a significant advancement in overcoming the translational barriers associated with curcumin, supporting its potential for clinical application in DR management.

3.3. α-Lipoic acid

α-Lipoic acid (ALA) is a naturally occurring dithiol compound that functions as a vital cofactor for mitochondrial enzyme complexes, playing a central role in cellular energy metabolism. Due to its unique chemical structure, ALA exhibits potent antioxidant properties and is often referred to as a “universal antioxidant” because it can directly scavenge ROS and regenerate other antioxidants such as vitamins C and E, coenzyme Q10, and glutathione. This broad antioxidant capacity makes ALA particularly attractive for addressing oxidative stress, a key pathological mechanism underlying diabetic complications including DR (15, 80). Oxidative stress in diabetes arises primarily from chronic hyperglycemia-induced overproduction of ROS, activation of the polyol pathway, and formation of AGEs, all of which contribute to retinal microvascular damage, inflammation, and neuronal dysfunction (Figure 4).

Experimental studies have demonstrated that ALA can mitigate oxidative damage in retinal tissues by inhibiting pro-inflammatory signaling pathways such as NF-κB and by activating protective transcription factors like Nrf2 and AMP-activated protein kinase (AMPK) in retinal ganglion cells. These molecular effects translate into reduced retinal oxidative stress and inflammation, thereby preserving retinal structure and function (15) (Figure 4). Clinically, supplementation with ALA, often in combination with other antioxidants such as genistein and vitamins, has shown promise in pre-retinopathic diabetic patients by protecting retinal cells and attenuating inflammatory responses, suggesting a potential role in early intervention for DR (15).

Moreover, clinical trials have reported improvements in visual function parameters, including oscillatory potentials and contrast sensitivity, following ALA supplementation in diabetic patients, highlighting its beneficial effects on retinal electrophysiology and visual performance (80). A noteworthy aspect is the chronopharmacological optimization of ALA administration; studies in diabetic rat models demonstrated that timing the administration of ALA alongside other antidiabetic drugs enhanced glycemic control and retinal antioxidant profiles, resulting in histological preservation of retinal tissue comparable to non-diabetic controls (81). This suggests that ALA’s efficacy may be maximized by aligning its dosing with circadian rhythms, an important consideration for clinical translation. Despite its therapeutic potential, ALA’s clinical application is somewhat limited by its low water solubility and bioavailability. Innovative drug delivery systems, such as erodible polymeric inserts based on Eudragit films, have been developed to enhance transcorneal permeability and retention of ALA in ocular tissues, thereby improving its local bioavailability and therapeutic effect for ocular complications in diabetes (82). This advancement could facilitate more effective topical or localized delivery of ALA for DR and other ocular surface diseases.

In addition to its antioxidant effects, ALA exhibits anti-inflammatory and metal-chelating properties, which contribute to its neuroprotective effects in diabetic neuropathies and ocular surface diseases such as dry eye disease, conditions commonly comorbid with diabetes (83). By reducing oxidative damage and inflammation in the meibomian glands and corneal epithelium, ALA may improve tear film stability and ocular surface health, indirectly supporting retinal function in diabetic patients. Current clinical evidence supports its potential to improve retinal function and prevent progression of diabetic ocular complications, further large-scale, long-term randomized controlled trials are necessary to establish optimal dosing regimens, delivery methods, and confirm its efficacy and safety profile in diverse diabetic populations. Integrating ALA supplementation with conventional diabetes management may offer a promising strategy to reduce the burden of DR and preserve vision in affected patients (40, 84).

Despite its therapeutic potential, ALA’s clinical application is limited by its low water solubility, rapid clearance, and poor bioavailability, which restrict its effective retinal concentrations. Innovative drug delivery systems have been developed to address these limitations. Erodible polymeric inserts based on Eudragit films have been designed to enhance transcorneal permeability and retention of ALA in ocular tissues, thereby improving its local bioavailability and therapeutic effect for ocular complications in diabetes (82). Polymeric nanoparticles and liposomal formulations of ALA have also been explored to protect the compound from degradation, enable sustained release, and facilitate targeted delivery to retinal tissues (85). These advanced delivery systems can significantly enhance the ocular bioavailability of ALA, making it a more effective therapeutic option for DR and other diabetic complications. The development of sustained-release formulations is particularly important for ALA, as its rapid clearance necessitates frequent administration for maintaining therapeutic concentrations. Nanotechnology-based approaches offer the potential to overcome this limitation and optimize the clinical use of ALA in DR management.

4. Clinical applications and challenges

4.1. Clinical trial results

Clinical trials investigating the efficacy of natural antioxidants in DR have increasingly highlighted their potential to improve retinal blood flow and retinal function, addressing key pathological mechanisms underlying DR. Alpha-lipoic acid, a naturally occurring dithiol compound with potent antioxidant properties, has been evaluated in clinical settings involving pre-retinopathic diabetic patients. Trials combining ALA with genistein and vitamins demonstrated protective effects on retinal cells and a reduction in inflammatory responses, suggesting that ALA can mitigate oxidative stress and inflammation in the diabetic retina, thereby preserving retinal function (15). Similarly, dietary anthocyanins, a subgroup of polyphenols abundant in fruits and vegetables, have been clinically shown to improve glucose control, reduce oxidative stress, and enhance insulin sensitivity in diabetic patients, which may indirectly benefit retinal microvascular health and function (86). Despite the promising biochemical and physiological effects observed, clinical studies remain limited in number and often vary in design, dosage, and duration, which affects the consistency of outcomes.

Carotenoids such as lutein and zeaxanthin, known for their antioxidant and anti-inflammatory properties, have been assessed in clinical trials for their role in maintaining retinal integrity and function. These compounds are concentrated in the macula and are believed to protect the retina from oxidative damage induced by hyperglycemia and light exposure. Clinical evidence suggests that supplementation with macular xanthophylls can improve retinal health and delay the progression of DR, although larger-scale randomized controlled trials are needed to confirm these benefits (87, 88). Furthermore, clinical trials with flavonoids and polyphenols such as quercetin and resveratrol have indicated improvements in oxidative stress markers and retinal function parameters, supporting their therapeutic potential in DR management (35, 43).

Nutraceuticals, defined as natural functional foods with minimal side effects, have also been explored in clinical contexts for DR. While preclinical studies show their antioxidative, anti-inflammatory, neuroprotective, and vasoprotective effects, clinical trials have yielded mixed results, largely due to issues such as low bioavailability and instability of these compounds. Innovative delivery systems, including nanoparticle carriers, are being developed to overcome these limitations and enhance clinical efficacy (89, 90). Notably, fenofibrate, a lipid-lowering agent with antioxidant and anti-inflammatory properties, has shown in clinical trials to slow DR progression independently of its lipid-modifying effects, highlighting the importance of antioxidant mechanisms in retinal protection (91, 92).

Epidemiological studies further support the association between higher antioxidant exposure and reduced risk and severity of retinopathy. A higher oxidative balance score, reflecting cumulative antioxidant intake and lifestyle factors, correlates with a lower prevalence of retinopathy and decreased all-cause mortality among affected individuals, underscoring the clinical relevance of antioxidant status in DR outcomes (93). Additionally, clinical investigations into trace elements such as zinc have revealed that supplementation may improve glycemic control and reduce the incidence of diabetic complications including retinopathy, suggesting a supportive role for micronutrient antioxidants in clinical management (94).

Table 3 summarizes the key clinical studies of natural antioxidants in DR. Quercetin combined with resveratrol reduced central macular thickness by 32 μm, and improved visual acuity by 0.15 logMAR (95, 96). NHANES analysis associated flavonoid-rich diets with a 30% DR risk reduction and improved glycemic and inflammatory markers (97). Curcumin-piperine supplementation enhanced total antioxidant capacity and SOD, reduced MDA, and improved mental health and sleep quality, though inflammatory and retinal vascular changes were not significant (74, 98); complementary in vitro evidence showed curcumin combination reduced TNF-α and IL-2 in human vitreous (75). Lutein/zeaxanthin supplementation improved contrast sensitivity (p=0.02) in a 31-patient RCT (99), while a larger trial (n=208) reported DR progression in 61% of supplemented patients vs. 91% of controls, with reduced lipid peroxidation (100). α-Lipoic acid (600 mg/day, 24 months) stabilized DR progression, reduced macular edema, and maintained visual function (101). Collectively, these studies provide encouraging yet preliminary evidence.

Table 3.

Clinical studies of natural antioxidants in diabetic retinopathy.

Natural antioxidant	Study design	Population	Intervention	Duration	Key outcomes	References
Quercetin + Resveratrol	RCT (part of combination)	DR patients (n=85)	Quercetin 500 mg/day + resveratrol 250 mg/day	6 months	↓ Central macular thickness by 32 μm; ↓ HbA1c by 0.7%; ↑ Visual acuity by 0.15 logMAR	(96)
Flavonoid-rich fruit and vegetable	Analysis of NHANES 2003–2006	n=381 diabetic patient	N/A	N/A	↓ risk of developing DR by 30%;↓ C-reactive protein levels, HbA1C and glucose	(97)
Curcumin + Piperine	RCT, double-blind, placebo-controlled	Non-proliferative DR patients (n=60)	Curcumin 1000 mg + piperine 10 mg/day	12 weeks	↑ Total antioxidant capacity; ↑ SOD; ↓ MDA; ↑ Mental health; ↑ Sleep quality	(74, 98)
Curcumin + Homotaurine + Vitamin D3	In vitro (human vitreous)	DR patients (n=15)	Combined treatment	N/A	↓ TNF-α; ↓ IL-2	(75)
Lutein/Zeaxanthin	RCT, double-blind, placebo-controlled	Non-proliferative DR patients (n=31)	Lutein 10 mg/day	36 weeks	↑ Contrast sensitivity at 3 cycles/degree (p=0.02); Slight improvement in VA; Glare sensitivity: NS	(99)
Lutein/Zeaxanthin (combination in supplements)	RCT, prospective, multicenter	T2DM with NPDR ± DME (n=208)	Nutrof Omega® (lutein, zeaxanthin, omega-3)	18 months	DR progression: 61% (supplemented) vs. 91% (control); ↓ Plasma lipid peroxidation	(100)
α-Lipoic Acid (ALA)	Clinical trial	T2DM with mild-moderate NPDR (n=47)	ALA 600 mg/day	24 months	Stabilization of DR progression; ↓ New macular oedema cases; Stable vision and contrast sensation	(101)

The symbols ↓ and ↑ indicate a decrease or increase, respectively, in the corresponding parameter in the treatment group of the experiment.

Despite these encouraging findings, the clinical translation of natural antioxidants in DR is challenged by heterogeneity in study designs, small sample sizes, and limited long-term data. Many trials emphasize surrogate endpoints such as oxidative stress biomarkers or retinal imaging parameters rather than hard clinical outcomes like visual acuity or progression to proliferative DR. Therefore, well-designed, large-scale randomized controlled trials with standardized antioxidant formulations and optimized delivery methods are essential to validate efficacy, determine optimal dosing, and establish safety profiles. In conclusion, current clinical trial evidence supports the beneficial role of natural antioxidant products in improving retinal blood flow and function in DR patients, but further rigorous clinical research is needed to fully integrate these agents into standard care protocols. Multi-targeted strategies, potentially enhanced by nanotechnology-based delivery, warrant future investigation.

4.2. Challenges in application

Despite the promising antioxidant, anti-inflammatory, and antiangiogenic properties of natural compounds in DR management, significant challenges hinder their clinical translation, particularly low bioavailability and dose standardization. Many phytochemicals such as curcumin, resveratrol, quercetin, and ALA exhibit poor aqueous solubility, rapid metabolism, and limited stability, resulting in suboptimal systemic and ocular tissue concentrations after oral or topical administration. For instance, curcumin is known for its potent antioxidative and anti-inflammatory effects but suffers from poor bioavailability, necessitating the use of adjuvants like piperine or advanced delivery systems such as nanoemulsions to enhance absorption and retinal tissue penetration (14, 102). Similarly, resveratrol’s therapeutic potential is limited by its rapid metabolism and low systemic availability, prompting research into nanoparticle-based delivery to improve its ocular bioavailability (22, 103). Alpha-lipoic acid, despite its “universal antioxidant” status and demonstrated benefits in diabetic ocular complications, faces challenges due to low water solubility and rapid clearance, which restrict its effective retinal concentrations (15, 82). Moreover, the development of sustained-release formulations such as thermoresponsive nanoemulgels or liposomal carriers has been explored to overcome these limitations, showing improved corneal permeation and retention, which are critical for effective DR therapy (102, 104). However, these advanced delivery systems require rigorous clinical validation to establish optimal dosing regimens, safety profiles, and long-term efficacy. The lack of standardized dosing guidelines and variability in phytochemical content among natural extracts further complicate dose optimization, making it difficult to compare results across studies or translate preclinical findings into clinical practice (13, 20). Thus, addressing bioavailability and dose standardization is paramount for harnessing the full therapeutic potential of natural antioxidants in DR management.

Another critical challenge in applying natural antioxidant therapies for DR is the considerable inter-individual variability in therapeutic response, which leads to inconsistent efficacy outcomes. This variability arises from genetic, metabolic, and physiological differences among patients, influencing absorption, metabolism, and cellular response to phytochemicals. For example, polymorphisms in antioxidant enzyme genes or variations in the Nrf2 pathway, a master regulator of cellular antioxidant defenses, can modulate the effectiveness of polyphenols and other natural compounds in mitigating oxidative stress in retinal tissues (16, 105). Furthermore, differences in gut microbiota composition affect the biotransformation and bioavailability of orally administered phytochemicals, impacting systemic and ocular levels (86). Clinical trials with antioxidants such as quercetin and ALA have reported variable outcomes, partly attributed to these individual differences, underscoring the need for personalized approaches in antioxidant therapy (15, 59). Additionally, the presence of comorbidities, concurrent medications, and the stage of DR also influence treatment response, complicating the assessment of efficacy in heterogeneous patient populations (13, 40). The complexity of DR pathogenesis, involving multifactorial oxidative, inflammatory, and angiogenic pathways, further necessitates combinational or multi-targeted therapies tailored to individual patient profiles (22, 106). Emerging strategies such as biomarker-guided therapy and advanced drug delivery systems aim to mitigate variability by enhancing targeted delivery and optimizing dosing, but these approaches remain in early stages of development (35, 107). Consequently, overcoming individual variability is essential to achieve consistent and reproducible therapeutic benefits of natural antioxidants in DR treatment.

Nanotechnology-based drug delivery systems have emerged as promising strategies to overcome the bioavailability and dose standardization challenges associated with natural antioxidants. Lipid-polymer hybrid nanoparticles, SNEDDS, NLCs, and polymeric nanoparticles have been developed to enhance the solubility, stability, and ocular penetration of phytochemicals such as curcumin, resveratrol, quercetin, and luteolin. These nanocarriers protect labile compounds from degradation, facilitate controlled release, and enable targeted delivery to retinal tissues through surface functionalization with targeting ligands. For example, TPGS-functionalized lipid-polymer hybrid nanoparticles have demonstrated enhanced oral bioavailability and retinal targeting of luteolin, resulting in superior therapeutic efficacy in diabetic models (49). Similarly, SNEDDS formulations of resveratrol and melatonin have shown improved solubility and stability, facilitating SIRT-1 activation for DR therapy (108). Thermoresponsive nanoemulgels and liposomal carriers have been developed to enhance corneal permeation and retention, which are critical for effective topical ocular delivery (109). However, these advanced delivery systems require rigorous clinical validation to establish optimal dosing regimens, safety profiles, and long-term efficacy. The development of standardized, well-characterized nanoformulations is essential to ensure consistent therapeutic outcomes and facilitate regulatory approval for clinical use.

5. Future research directions

5.1. Novel drug development

The development of novel therapeutic agents for DR increasingly focuses on improving the bioavailability and targeted delivery of natural antioxidants and anti-inflammatory compounds, which often suffer from poor solubility and limited ocular penetration. Nanotechnology-based drug delivery systems have emerged as promising strategies to overcome these limitations by enhancing drug stability, solubility, and tissue-specific accumulation. Table 2 shows the application of novel nanomaterials loaded with natural antioxidants in the treatment of DR. For instance, curcumin (CUR), a natural polyphenol with potent antioxidant and anti-inflammatory effects, shows therapeutic potential in DR; however, its clinical application is hindered by low aqueous solubility and limited retinal penetration. The formulation of CUR into SNEDDS has demonstrated improved physicochemical stability, mucoadhesive properties, and enhanced intracellular uptake in retinal pigment epithelial cells, resulting in superior antioxidant activity and induction of protective SIRT1 expression compared to free CUR (77). Similarly, the encapsulation of dihydromyricetin (DMY), a natural flavonoid antioxidant, into ultra-small nanoscale coordination polymer particles (Fe-DMY NCPs) has been shown to effectively scavenge ROS, inhibit key oxidative stress pathways such as Poldip2-Nox4-H2O2, and ameliorate vascular leakage and neovascularization in DR models, highlighting the potential of nanocarriers to improve therapeutic efficacy and bioavailability of natural compounds (61). Another innovative approach involves the use of lignin-based hydrogels derived from agricultural waste as drug carriers for natural polyphenolic antioxidants like curcumin and naringenin. These hydrogels exhibit antioxidant and anti-inflammatory properties themselves and provide controlled, non-invasive ocular delivery with demonstrated suppression of VEGF levels in vitreous fluid, addressing both oxidative stress and angiogenesis in DR (110). Lignin-based hydrogels represent an innovative and sustainable approach for ocular drug delivery, serving as both drug carriers and active therapeutic agents due to their intrinsic antioxidant and anti-inflammatory properties. While not strictly nanomaterials in the conventional sense, these hydrogels possess nanoscale structural features and provide controlled, non-invasive ocular delivery with demonstrated suppression of VEGF levels in vitreous fluid. Moreover, lipid-polymer hybrid nanoparticles functionalized with TPGS have been developed to enhance the oral bioavailability of luteolin, a flavonoid with anti-inflammatory and antioxidant activities. The optimized nanoparticles showed prolonged drug release, improved intestinal permeability, and significant attenuation of hyperglycemia-induced retinal oxidative stress, inflammation, and angiogenesis in diabetic models, underscoring the translational potential of nanocarrier systems for systemic delivery of natural therapeutics in DR (49). These advances are complemented by studies on other natural compounds such as sesamin, which inhibits high glucose-induced microglial inflammation and oxidative stress, and plumbagin, which protects retinal structure and function via activation of Nrf2 signaling and mitigation of mitochondrial-endoplasmic reticulum stress, though further formulation improvements are needed to enhance their bioavailability and retinal targeting (44, 111) (Figure 5). Collectively, these findings illustrate that integrating nanotechnology with natural antioxidant and anti-inflammatory agents offers a promising avenue to overcome pharmacokinetic barriers, achieve targeted delivery to retinal tissues, and potentiate therapeutic efficacy in DR. Future research should continue to optimize these delivery platforms, investigate their safety and pharmacodynamics in clinical settings, and explore combinatorial strategies to address the multifactorial pathogenesis of DR.

Figure 5.

Nanomaterial-based delivery systems for natural antioxidants in diabetic retinopathy therapy. These include SNEDDS, Fe-DMY coordination nanoparticles, lignin-based hydrogels, lipid-polymer hybrid nanoparticles, and other nanocarriers. They enhance ocular targeting, cellular uptake, and oral absorption, delivering curcumin, luteolin, dihydromyricetin, and other compounds to retinal cells (RPE, endothelial cells, microglia) and the vitreous compartment. Mechanistically, they reduce ROS and inflammatory cytokines, activate Nrf2/SIRT1 pathways, inhibit VEGF-mediated angiogenesis, and preserve retinal structure and function, overcoming limitations of native natural products.

The design of effective nanocarrier systems for natural antioxidant delivery to retinal tissues requires careful consideration of several key parameters, including particle size, surface charge, drug loading capacity, release kinetics, and biocompatibility. Ideal nanocarriers should be small enough (typically <200 nm) to penetrate ocular barriers while avoiding rapid clearance, possess appropriate surface properties to enhance cellular uptake and retinal targeting, and provide sustained drug release to maintain therapeutic concentrations over extended periods. Surface functionalization with targeting ligands such as hyaluronic acid (targeting CD44 receptors), RGD peptides (targeting integrins), or antibodies against specific retinal cell surface markers can further enhance the selectivity and efficacy of these delivery systems (112). Additionally, stimuli-responsive nanocarriers that release their cargo in response to specific pathological cues (e.g., elevated ROS levels in diabetic retinas) offer the potential for on-demand drug release, maximizing therapeutic efficacy while minimizing off-target effects.

Beyond the established nanocarrier systems discussed above, several emerging platforms show promise for natural antioxidant delivery in DR. ROS-responsive nanoparticles have been developed to release their cargo specifically in the oxidative microenvironment of diabetic retinas, as demonstrated by NPSPHE@EOFAZ, which delivers essential oils from Fructus Alpiniae zerumbet to Müller cells, reducing oxidative stress and inflammation in diabetic models (113). Iron-coordinated nanozymes (Fe-Quer NZs) that mimic multiple antioxidant enzymes have been designed to scavenge ROS, alleviate oxidative stress and inflammation, and inhibit angiogenesis and microvascular leakage in early DR (114). Carbon dots derived from medicinal plants (SH-CDs) with good biocompatibility can penetrate ocular tissues, scavenge reactive species, and relieve oxidative stress and inflammation (115). Lignin-based hydrogels derived from agricultural waste represent an innovative and sustainable approach, serving as both drug carriers and active therapeutic agents due to their intrinsic antioxidant and anti-inflammatory properties (110). These emerging platforms highlight the rapid evolution of nanotechnology-based solutions for natural antioxidant delivery and offer exciting possibilities for more effective DR therapy.

5.2. Mechanistic studies

The pathogenesis of DR is multifactorial, with oxidative stress playing a central role in its initiation and progression. Hyperglycemia-induced overproduction of ROS disrupts the redox homeostasis in retinal cells, leading to cellular damage, inflammation, and microvascular dysfunction. Natural antioxidant compounds derived from plants and other natural sources have emerged as promising therapeutic agents due to their multifaceted mechanisms targeting oxidative stress and associated pathological pathways in DR. These compounds exert their protective effects through modulation of key signaling cascades, transcription factors, and enzymatic antioxidant defenses, thereby attenuating retinal damage and disease progression. A critical mechanism by which natural antioxidants confer protection in DR involves the activation of the Nrf2 pathway, a master regulator of cellular antioxidant responses. Under hyperglycemic conditions, Nrf2 activity is often suppressed, leading to diminished expression of downstream antioxidant enzymes such as heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). Several phytochemicals, including carnosol and syringaresinol, have been shown to activate Nrf2 signaling, resulting in enhanced antioxidant enzyme expression and reduced oxidative stress in retinal endothelial cells and animal models of DR (18, 41). The activation of Nrf2 by these compounds involves upstream kinases such as extracellular signal-regulated kinases (ERK1/2), which mediate the nuclear translocation and transcriptional activity of Nrf2, thereby restoring redox balance and protecting retinal microvasculature.

In addition to Nrf2 activation, natural antioxidants modulate other molecular pathways implicated in DR pathogenesis. For example, ALA inhibits NF-κB activity, a pivotal transcription factor driving inflammation and vascular permeability in DR. By suppressing NF-κB, ALA reduces the expression of pro-inflammatory cytokines and matrix metalloproteinases, thereby mitigating retinal inflammation and vascular leakage (15). Similarly, activated growth factor (AGF) derived from platelets has been reported to downregulate multiple oxidative stress and inflammatory mediators, including AGEs, p38 mitogen-activated protein kinase (p38 MAPK), NF-κB, TNF-α, interleukin-1 beta (IL-1β), and VEGF, while enhancing antioxidant enzyme activity such as SOD in diabetic retinal tissue (116) (Figure 5). This comprehensive modulation of oxidative and inflammatory pathways underscores the complex network through which natural antioxidants exert their therapeutic effects.

Lipid peroxidation is another critical pathological event in DR, driven by the high content of polyunsaturated fatty acids in the retina. Natural polyphenols like pterostilbene have demonstrated efficacy in reducing lipid peroxidation markers in diabetic models, restoring redox status, and normalizing antioxidant enzyme activities. These effects are linked to the activation of the phosphoinositide 3-kinase (PI3K)/AKT/glycogen synthase kinase 3 beta (GSK3β)/Nrf2 signaling axis, highlighting a sophisticated intracellular mechanism that protects retinal cells from oxidative damage (16, 117, 118). The reduction of lipid peroxidation not only prevents structural retinal damage but also decreases the formation of oxidative stress-derived biomarkers, which may serve as indicators of DR progression and therapeutic response.

Emerging evidence also points to the involvement of long noncoding RNAs (lncRNAs) in regulating antioxidant defense in DR. For instance, MALAT1, a lncRNA upregulated by high glucose, promotes Keap1 expression, which sequesters Nrf2 in the cytoplasm, thereby impairing antioxidant gene transcription. Silencing MALAT1 restores Nrf2 nuclear translocation and enhances antioxidant defenses, suggesting that targeting lncRNAs may represent a novel mechanism to potentiate the efficacy of natural antioxidants in DR (119). Furthermore, the anti-angiogenic effects of natural antioxidants contribute significantly to their therapeutic potential. Compounds such as curcumin and axitinib inhibit VEGF expression and signaling, thereby preventing pathological neovascularization characteristic of proliferative DR. This anti-angiogenic activity often intersects with antioxidant and anti-inflammatory pathways, creating a synergistic effect that stabilizes retinal vasculature and preserves vision (14, 106, 120). For example, syringaresinol suppresses hypoxia-inducible factor-1 alpha (HIF-1α)/VEGF signaling via Nrf2 activation, reducing retinal vascular permeability and endothelial apoptosis (41) (Figure 5).

At the cellular level, natural antioxidants also prevent apoptosis of retinal cells by reducing oxidative stress-induced mitochondrial dysfunction and modulating apoptotic signaling pathways. Tocotrienol-rich fractions have been shown to decrease retinal cell apoptosis and preserve retinal morphology and visual function in diabetic rats by enhancing antioxidant enzyme activities and reducing lipid peroxidation (121). Similarly, the antioxidant tetrapeptide Epitalon inhibits hyperglycemia-induced epithelial-mesenchymal transition (EMT) and fibrosis in retinal pigment epithelial cells, promoting wound healing and retinal repair (122).

Nanotechnology-based delivery systems have been explored to enhance the bioavailability and targeted delivery of natural antioxidants to retinal tissues. For instance, ROS-responsive nanoparticles loaded with essential oils from Fructus Alpiniae zerumbet effectively reduce oxidative stress and inflammation in diabetic retinas, demonstrating improved therapeutic outcomes in preclinical models (113). Such advanced delivery platforms may overcome limitations related to poor bioavailability and specificity of natural compounds.

In summary, natural antioxidant products act through a complex network of mechanisms in DR, including activation of the Nrf2 antioxidant pathway, inhibition of NF-κB-mediated inflammation, suppression of lipid peroxidation, modulation of lncRNA-mediated gene regulation, anti-angiogenic effects via VEGF/HIF-1α pathways, and prevention of retinal cell apoptosis. These multifaceted actions collectively contribute to the preservation of retinal structure and function in DR. Continued elucidation of these mechanisms and their interplay will facilitate the development of optimized antioxidant-based therapies and guide clinical translation for effective management of DR. However, challenges such as bioavailability, specificity, and long-term safety remain and warrant further investigation through rigorous preclinical and clinical studies (15, 18, 41, 106, 113, 116, 117, 119–121).

5.3. Clinical application promotion

The clinical application of natural antioxidant products in DR management remains an evolving field, with growing preclinical evidence supporting their potential benefits but limited robust clinical validation. Strengthening randomized controlled trials (RCTs) is essential to substantiate the efficacy and safety of these agents in DR patients. Natural compounds such as carotenoids (e.g., lutein, zeaxanthin), polyphenols (e.g., resveratrol, curcumin), and other phytochemicals have demonstrated antioxidative, anti-inflammatory, anti-angiogenic, and neuroprotective effects in various in vitro and animal models of DR, suggesting their promise as adjunctive therapies to conventional treatments. For instance, lutein has been shown to reduce oxidative stress and inflammation in retinal tissues, with some clinical trials indicating improvements in visual function and retinal health, although larger, well-designed RCTs are needed to confirm these findings and optimize dosing regimens (88, 123). Similarly, resveratrol exhibits multiple protective mechanisms, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, and inhibition of pathological neovascularization. However, its clinical translation is hampered by poor bioavailability and rapid metabolism, necessitating trials that incorporate novel delivery systems such as nanoformulations to enhance ocular bioavailability and therapeutic efficacy (56). Curcumin, another potent natural antioxidant, has shown promise in preclinical DR models through its anti-inflammatory and antioxidative mechanisms, but clinical trials are limited by its low solubility and bioavailability. Advances in drug delivery platforms, including nanoparticles and cyclodextrin complexes, have improved curcumin’s ocular retention and permeability, warranting further clinical investigation to establish safety and efficacy in DR patients (58, 124). Alpha-lipoic acid, with its mitochondrial cofactor role and antioxidant properties, has demonstrated protective effects against oxidative stress and inflammation in diabetic ocular tissues. Preliminary clinical studies suggest that ALA combined with vitamins and genistein may protect retinal cells and reduce inflammation in pre-retinopathic diabetic patients, but larger RCTs are required to validate these outcomes and define therapeutic protocols (15). Other natural compounds such as crocin and anthocyanins have shown beneficial effects on retinal health through antioxidative and anti-inflammatory pathways, with some clinical evidence indicating improved visual outcomes; nonetheless, comprehensive RCTs with adequate sample sizes and long-term follow-up remain scarce (86, 125). The challenges in clinical translation include suboptimal specificity, low bioavailability, potential toxicity, and variability in natural product formulations. To overcome these barriers, future RCTs should adopt rigorous designs with standardized extracts, optimized dosing, and appropriate delivery systems to enhance bioavailability and target retinal tissues effectively. Additionally, integrating biomarkers of oxidative stress, inflammation, and retinal function into trial endpoints can provide mechanistic insights and facilitate personalized therapy approaches. The use of nanocarriers and sustained-release formulations holds promise to improve therapeutic outcomes and patient compliance. Furthermore, combination therapies incorporating natural antioxidants with existing treatments such as anti-VEGF agents may offer synergistic benefits and should be explored in clinical trials. In conclusion, while preclinical data strongly support the potential of natural antioxidant products in DR management, robust RCTs are imperative to confirm their clinical efficacy and safety, optimize therapeutic regimens, and ultimately translate these promising compounds into standard care for DR (13, 20, 56, 89).

6. Conclusion

The exploration of natural antioxidant agents in the treatment of DR represents a promising frontier in addressing the complex pathophysiology of this vision-threatening complication of diabetes. From an expert perspective, the accumulated preclinical and emerging clinical evidence underscores the potential of these compounds to mitigate oxidative stress and inflammatory pathways—two pivotal mechanisms driving retinal damage in DR. The multifaceted antioxidant properties of natural agents not only counteract ROS but also modulate cellular signaling cascades involved in inflammation, apoptosis, and vascular dysfunction, thereby offering a holistic approach to retinal protection.

Balancing the diverse research perspectives, it is clear that while in vitro and animal model studies consistently demonstrate beneficial effects of natural antioxidants, translation to human clinical outcomes remains an area requiring rigorous investigation. Variability in study designs, heterogeneity of natural compounds, dosage regimens, and patient populations contribute to the current challenges in establishing definitive clinical efficacy and safety profiles. Moreover, some studies highlight potential limitations such as bioavailability issues and the need for standardized formulations, which are critical factors influencing therapeutic success. From a clinical standpoint, the integration of natural antioxidants into DR management protocols could complement existing treatments, potentially reducing reliance on invasive procedures and pharmacologic agents with adverse effect profiles. However, this integration must be predicated on robust clinical trials that validate efficacy, optimize dosing strategies, and monitor long-term safety. Additionally, understanding the interplay between natural antioxidants and conventional therapies will be essential to avoid adverse interactions and maximize patient outcomes.

A critical advancement that has significantly enhanced the translational potential of natural antioxidants is the integration of nanotechnology-based delivery systems. Nanocarriers effectively address the fundamental limitations of phytochemicals—poor aqueous solubility, low bioavailability, rapid metabolism, and insufficient ocular tissue penetration—that have historically hindered their clinical application. By enhancing solubility, protecting compounds from degradation, facilitating targeted delivery to retinal tissues, and enabling sustained release, nanoformulations amplify the therapeutic efficacy of natural antioxidants and overcome the translational barriers that have limited their clinical utility. The development of smart nanocarriers with stimuli-responsive release, surface functionalization for active targeting, and multifunctional capabilities (e.g., combining antioxidant, anti-inflammatory, and anti-angiogenic effects) represents the next frontier in this field. As nanomedicine platforms continue to evolve and clinical validation studies accumulate, the combination of natural antioxidants with advanced delivery systems holds substantial promise for transforming DR management.

Looking forward, a multidisciplinary approach combining ophthalmology, pharmacology, and nutrition science is vital to advance this field. Future research should prioritize well-designed randomized controlled trials with standardized endpoints, alongside mechanistic studies to elucidate precise molecular targets. Furthermore, personalized medicine approaches considering genetic, metabolic, and lifestyle factors may enhance the therapeutic applicability of natural antioxidants in DR.

In summary, natural antioxidant products hold considerable promise as adjunctive or alternative therapies for DR, particularly through their capacity to attenuate oxidative stress and inflammation. Nonetheless, the transition from experimental promise to clinical reality hinges on comprehensive clinical validation and strategic integration into patient care. As the evidence base strengthens, these agents may well become integral components of a multifaceted strategy to preserve vision and improve quality of life for individuals affected by DR.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the National Natural Science Foundation of China (No. 82571248, 82371080), the Natural Science Foundation of Anhui Province (No. 2508085QH303), the China Postdoctoral Science Foundation (No. 2026M792080), the Natural Science Funds for Distinguished Young Scholar of Anhui Province (No. 2308085J29), and the Clinical and Translational Research Project of Anhui Province (No. 202527c10020041, 202527c10020042 and 202527c10020077).

Author contributions

YT: Conceptualization, Visualization, Writing – original draft, Formal analysis, Data curation. BZ: Formal analysis, Writing – review & editing, Methodology, Data curation, Software. FZ: Resources, Formal analysis, Validation, Methodology, Writing – review & editing. WD: Resources, Visualization, Writing – review & editing. SL: Validation, Writing – review & editing, Formal analysis. XG: Resources, Writing – review & editing, Visualization. WT: Supervision, Validation, Conceptualization, Writing – review & editing. JG: Project administration, Conceptualization, Writing – review & editing, Supervision. ZJ: Project administration, Supervision, Funding acquisition, Writing – review & editing, Conceptualization.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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