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Advanced Natural Therapeutics and Delivery Strategies for Diabetic Foot Ulcers: A Mini Review
Received 2 August 2025
Accepted for publication 14 November 2025
Published 25 November 2025 Volume 2025:19 Pages 10449—10472
DOI https://doi.org/10.2147/DDDT.S557827
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Anastasios Lymperopoulos
Qi Liu,1 Xinxin Yu2
1Department of Peripheral Vascular II, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People’s Republic of China; 2Department of Peripheral Vascular, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang, 150036, People’s Republic of China
Correspondence: Xinxin Yu, Department of Peripheral Vascular, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang, 150036, People’s Republic of China, Email [email protected]
Abstract: Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus with complex pathophysiology. Conventional therapies often lead to poor healing and high recurrence. This mini-review highlights the promise of advanced natural therapeutics and delivery strategies for DFU management. We focus on bioactive natural compounds, such as ginsenosides, astragalus polysaccharides, and resveratrol, that target critical processes like hyperglycemia, vascular impairment, and oxidative stress by modulating key signaling pathways. To improve bioavailability, innovative delivery systems including nanotechnology and nitric oxide-releasing platforms have been developed, enabling sustained release and enhanced healing. Clinical evidence shows promising results, such as shortened healing time and improved ulcer closure rates, supports the translational potential of standardized natural formulations. Moving forward, priorities should focus on standardizing natural formulations, optimizing delivery, and conducting rigorous clinical trials. With continued innovation, natural therapeutics hold significant potential to improve wound healing, reduce amputations, and enhance the quality of life for DFU patients.
Keywords: diabetic foot ulcers, natural therapeutics, bioactive compounds, wound healing, nanotechnology
Introduction
Diabetic foot ulcers (DFUs) represent a critical complication of diabetes mellitus and pose a significant global healthcare challenge. Globally, over 550 million people live with diabetes, including 37 million in the United States.1 Approximately 18.6 million new DFU cases occur annually, affecting about 34% of the diabetic population. DFUs are chronic, non-healing wounds that predominantly occur on the feet, driven by a multifactorial etiology including hyperglycemia-induced peripheral neuropathy, tissue ischemia and impaired angiogenesis due to peripheral arterial disease, and dysregulated chronic inflammation with compromised immune defense.2 The impact of DFUs is profound, resulting in substantial disability-adjusted life years (DALYs) lost and healthcare costs amounting to billions of dollars annually.3 DFU management accounts for a significant portion of diabetes-related expenditures, driven by high hospitalization rates and prolonged treatments. Moreover, DFUs are a leading cause of lower limb amputations, with approximately 20% of diabetic patients with foot ulcers requiring amputation, either partial or complete.4,5 In the United States alone, over 150,000 non-traumatic lower limb amputations are performed annually, contributing to a global total of 1.6 million amputations, of which 33% involve complete limb loss.6,7 These factors collectively underscore the urgent need for innovative therapeutic strategies to alleviate the socioeconomic impact of DFUs on both patients’ quality of life and healthcare systems.
Standard management of DFUs has traditionally relied on practices such as debridement, infection control, and offloading pressure from the affected area.8 However, these conventional therapies often prove insufficient, as many patients experience slow or incomplete wound healing, which significantly compromises their recovery.9 The high recurrence rate of DFUs, which can be as high as 60%, further highlights the limitations of current standard-of-care, which frequently fails to address the underlying pathological mechanisms such as persistent inflammation, microvascular dysfunction, and cellular senescence. This therapeutic failure poses ongoing risks to patients’ health and quality of life.10 This persistent clinical challenge underscores the urgent need for innovative therapeutic approaches that can effectively target the multifaceted pathophysiological mechanisms of DFUs, particularly those related to impaired tissue regeneration and chronic inflammation.11
Given these unmet needs, there is growing interest in exploring alternative and adjunctive therapies. Recent advancements in natural therapeutics have opened new avenues for DFUs management by combining bioactive compounds with cutting-edge delivery technologies.12,13 Phytochemicals, a diverse group of naturally occurring compounds found in plants such as fruits, vegetables, grains, and other plant foods, have emerged as promising therapeutic agents due to their multi-targeted actions.14 Preclinical, clinical, and epidemiological studies suggest that phytochemicals may be effective in treating various diseases owing to their anti-inflammatory, antioxidant, and pro-angiogenic activities.15 However, challenges such as poor bioavailability, chemical instability, and limited tissue penetration have historically constrained their clinical application. To overcome these barriers, nanotechnology-driven strategies have been employed to enhance their therapeutic potential. For instance, nano-encapsulation of active ingredients enables sustained release, targeted delivery to wound sites, and improved cellular uptake.16,17 These innovations not only optimize pharmacokinetics but also amplify key healing processes such as collagen synthesis, macrophage polarization, and angiogenesis.
Therefore, this mini-review aims to synthesize current mechanistic evidence and translational opportunities for advanced natural therapeutics in DFUs care. The potential of these agents is explored, focusing on their ability to target critical pathological processes, including hyperglycemia, peripheral neuropathy, vascular insufficiency, persistent inflammation, wound infection, and oxidative stress. Furthermore, supplementary strategies, such as nanocarriers and nitric oxide (NO)-releasing gels, are discussed for their role in enhancing therapeutic efficacy. While clinical trials demonstrate promising translational progress, challenges related to standardization and scalability remain. By integrating mechanistic insights with therapeutic advancements, this review highlights the transformative potential of natural compounds in redefining DFU management.
Pathophysiology of Diabetic Foot Ulcers
Hyperglycemia-Induced Neuropathy
Diabetic peripheral neuropathy (DPN) is a critical factor in the pathogenesis and progression of diabetic foot complications and is strongly associated with lower limb ulcers, amputations, and disability.18 One of its core clinical consequences is severe impairment of sensory nerve function, coupled with autonomic neuropathy leading to dysfunction in sweat gland secretion.19 Neuropathy-induced sensory deficits, particularly in pain perception, significantly elevate the risk of trauma in diabetic patients. Alarmingly, this sensory impairment often leads to delayed detection of skin injuries and ulcers, which may remain unnoticed by both patients and healthcare providers for weeks or even months, resulting in inadequate and untimely intervention.20
Persistent hyperglycemia, typically defined as blood glucose levels exceeding 180 mg/dL, drives nerve damage through a complex interplay of mechanisms. Firstly, it induces metabolic dysregulation, characterized by the accumulation of fructose and sorbitol and a decline in myo-inositol levels.21 This metabolic imbalance triggers osmotic disturbances, including sodium and water retention, as well as reduced Na+, K+-ATPase activity, which directly injures neurons. Secondly, glucose overload exacerbates mitochondrial dysfunction, leading to the generation of excessive reactive oxygen species (ROS) that damage Schwann cell DNA and impair the axonal transport of neurotrophic factors.22 In an oversaturated system, acetyl-CoA converts to acylcarnitine, inducing stress in Schwann cells and dorsal root ganglion (DRG) neurons while further exacerbating mitochondrial dysfunction, ultimately resulting in axonal degeneration.23 Thirdly, hyperglycemia degrades type IV collagen within the basement membrane of nerve-nourishing blood vessels and disrupts the distribution of aquaporins on astrocyte end-feet, compromising the glio-vascular interface and exacerbating nerve ischemia.24 Collectively, these processes impair axonal conduction, signal transmission, and neurotrophic support, culminating in centripetal degeneration and distal axonal length-dependent loss.
Ischemic-Vascular Pathology
Diabetes induces widespread ischemic vascular pathology by damaging both macro- and microvascular systems, posing a severe threat to peripheral nerves and wound healing. Chronic hyperglycemia is the central driver of these vascular complications.25 At the macrovascular level, it accelerates atherosclerosis through mechanisms involving hyperglycemia, insulin resistance, excess free fatty acids, and advanced glycation end products (AGEs).26 These factors collectively suppress endothelial nitric oxide synthase (eNOS) activity, increase ROS production, and activate pro-inflammatory transcription factors such as NF-κB and aquaporin 1.27 This inflammatory cascade promotes leukocyte adhesion, migration, and lipid uptake by macrophages, leading to foam cell formation and atherosclerotic plaque development. Atherosclerosis, affecting large arteries, is a primary cause of cardiovascular disease, stroke, and peripheral arterial disease (PAD). PAD, in turn, impairs distal limb perfusion, contributing to approximately 50% of DFUs, while delaying wound healing and increasing infection risks.28
At the microvascular level, diabetes triggers characteristic microangiopathy, involving small arteries and capillaries, which underpins nephropathy, retinopathy, and DPN. Endothelial injury initiates microvascular dysfunction, causing hemodynamic abnormalities, impaired oxygen delivery, and fluid filtration imbalance.29 Damage to the vasa nervorum, the microvessels supplying nerves, is particularly critical, reducing blood flow to neural tissues.30 This manifests as impaired intraneural hemodynamics, loss of autoregulation, and structural abnormalities such as basement membrane thickening, endothelial cell swelling, and reduced tight junction proteins. These changes lead to vessel narrowing, increased resistance, and chronic ischemia, contributing to DPN pathogenesis.31
Thus, diabetic vascular pathology creates a vicious cycle of macrovascular occlusion and microvascular dysfunction, exacerbated by vasoconstriction and hypercoagulability. This not only elevates ulcer risk but also impedes wound healing by depriving tissues of oxygen and nutrients, ultimately leading to non-healing ulcers and catastrophic outcomes like amputations.32
Inflammation-Infection Vicious Cycle
In diabetic patients, skin barrier disruption facilitates bacterial invasion, initiating a complex interplay between infection and a maladaptive host inflammatory response that is central to the pathophysiology of DFUs.33 Unhealed ulcers provide an ideal environment for polymicrobial infections. Gram-positive bacteria (eg, Staphylococcus aureus, Streptococcus species) often dominate superficial wounds, while Gram-negative bacteria colonize deeper abscesses. Mixed infections, involving bacteria (eg, coagulase-negative staphylococci, enterococci, anaerobes) and fungi (eg, Candida albicans, Candida parapsilosis), complicate treatment, impair healing, and increase the risk of chronic wounds and scarring.34
Chronic inflammation is a central barrier to DFU healing.35 Even before skin breakdown, endogenous damage in diabetic feet is linked to abnormal inflammatory cytokine levels. Persistent inflammation disrupts the epidermal microenvironment, impairs cellular repair, exacerbates hyperglycemia, and increases insulin resistance.36 Hyperglycemia itself compromises immune function, reducing monocyte counts, disrupting T-cell subsets, and impairing phagocytic activity in neutrophils and macrophages, while promoting excessive inflammatory cytokine release.37 During wound healing, macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes is critical for resolving inflammation.38 However, in DFUs, macrophage dysfunction and impaired polarization perpetuate a pro-inflammatory state, delaying repair.
Immune cell dysfunction exacerbates the inflammation-infection cycle. Diabetic wounds exhibit impaired neutrophil chemotaxis, phagocytosis, degranulation, and ROS production, further compromised by hyperglycemia-induced upregulation of protein arginine deiminase 4 and inhibition of neutrophil extracellular trap formation. This weakens antimicrobial defense and promotes tissue damage through excessive cytokine and protease release.39,40 This dysfunction is compounded by a protease imbalance caused by activated macrophages and neutrophils, which secrete proteases such as MMPs that degrade extracellular matrix proteins, including collagen, elastin, and fibronectin. The resulting fragments recruit inflammatory cells, sustain inflammation, and activate additional MMPs, creating a destructive feedback loop.41 Additionally, diabetic wounds suffer from immune dysregulation, characterized by disrupted collaboration between immune cells, such as macrophages, neutrophils, and lymphocytes, and repair cells, including keratinocytes, fibroblasts, and endothelial cells, which collectively undermines the healing process.42,43
Thus, DFUs are trapped in a self-perpetuating inflammation-infection cycle: hyperglycemia and initial injury trigger chronic inflammation and immune suppression, increasing infection susceptibility. Persistent infections, in turn, activate dysfunctional immune cells that release destructive mediators, further impeding healing and maintaining a non-healing wound environment. Breaking this cycle is therefore a primary therapeutic objective in DFU management. Figure 1.
 |
Figure 1 Pathophysiology of Diabetic Foot Ulcers. |
Current Treatment Strategies for Diabetic Foot Ulcers
The treatment strategies for DFUs require a comprehensive approach that directly addresses the complex pathophysiology, outlined in Pathophysiology of Diabetic Foot Ulcers, including hyperglycemia-induced neuropathy, ischemic-vascular pathology, and the inflammation-infection vicious cycle.
Management of Hyperglycemia-Induced Neuropathy
Strict glycemic control is the cornerstone of DPN management, with pancreatic transplantation showing significant efficacy in normalizing blood glucose and improving motor and sensory neuropathy.44 For pharmacological treatment, pregabalin, tapentadol, and duloxetine are FDA-approved for alleviating DPN-related pain.45 Additionally, antioxidants such as alpha-lipoic acid (ALA) have shown potential in delaying or reversing peripheral nerve damage.46 Stem cell therapy and low-dose IL-6 biotherapy are also under exploration, offering new directions for DPN treatment by promoting angiogenesis and neuroprotection.47,48
Intervention for Ischemic-Vascular Pathology
Ischemic vascular pathology is a major barrier to DFU healing. Revascularization techniques, such as bypass surgery and endovascular angioplasty, are primary methods for restoring blood flow.49,50 While atherectomy can remove atherosclerotic plaques, its efficacy has not been proven superior to angioplasty.51 Postoperative multidisciplinary care, including the management of hypertension and hypercholesterolemia, is crucial for successful outcomes. Hyperbaric oxygen therapy (HBOT) enhances tissue oxygenation by increasing plasma oxygen levels, significantly boosting physically dissolved oxygen.52 According to Fick’s law, elevated oxygen partial pressure enhances the driving force and diffusion distance of oxygen, accelerating ulcer healing. Furthermore, HBOT activates the hypoxia-inducible factor (HIF-1α) signaling pathway, promoting the expression of vascular endothelial growth factor (VEGF) and improving local blood supply, thereby providing the oxygen and nutrients necessary for tissue repair.53,54
Control of the Inflammation-Infection Vicious Cycle
Given the critical role of the inflammation-infection cycle described in the previous section, its control is paramount in DFU management. Infection control is a critical component. The choice of empirical antibiotic therapy should be selected based on the likely pathogens and the severity of the infection.55 Mild infections may be treated with dicloxacillin or cephalexin, moderate infections with vancomycin combined with ampicillin/sulbactam, and severe infections with broad-spectrum antibiotics such as piperacillin/tazobactam or carbapenems. HBOT enhances the antibacterial effects of antibiotics by promoting bacterial aerobic metabolism and increasing drug uptake.56 Additionally, HBOT induces the production of oxygen free radicals, directly damaging bacterial membrane proteins and DNA structures, inhibiting the generation of inflammatory factors, and promoting the resolution of inflammation at the infection site.57
Debridement is a crucial component of infection management, as it removes bacterial biofilms and necrotic tissue from the wound, creating favorable conditions for healing.58 Wound debridement and cleansing are typically performed using isotonic saline solution and are essential adjuncts to antibiotic therapy. Wound dressings, such as hydrogels,59 alginate dressings,60 hydrocolloids,61 foam adhesives,62 and hydrofibers,63 protect the wound from infection and environmental exposure while maintaining optimal moisture levels to promote new tissue formation and autolytic debridement.
Advanced Natural Therapeutics for Diabetic Foot Ulcers
Key Bioactive Compounds and Mechanisms
Advanced natural therapeutics address the core pathophysiological mechanisms of DFUs through multifaceted approaches. Of particular relevance is their potential to disrupt the persistent inflammation-infection cycle that profoundly impedes healing.
Immunomodulatory and Anti-Inflammatory Mechanisms
Inflammation and infection control are addressed through the modulation of innate immune responses, directly targeting pathways involved in the vicious cycle. Bletilla striata polysaccharide (BSP) inhibits NLRP3 inflammasome activation, targeting a key driver of chronic inflammation in DFUs.64 Puerarin suppresses NF-κB and MAPK signaling pathways and promotes macrophage polarization towards the reparative M2 phenotype.65 Astragalus polysaccharide shifts macrophage polarization via β-catenin/NF-κB and Nrf2/HO-1 pathways, significantly reducing pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12.66,67 Resveratrol exhibits broad anti-inflammatory effects, inhibits the AGE-RAGE pathway and promotes healing via PI3K/Akt signaling.68,69
In summary, the immunomodulatory actions of these natural compounds are pivotal for breaking the inflammation-infection cycle in DFUs. By targeting key inflammatory signaling hubs and promoting a pro-resolving macrophage phenotype, they help resolve chronic inflammation, reduce tissue damage, and create a microenvironment conducive to healing. This represents a fundamental shift from merely suppressing infection to actively reprogramming the dysfunctional immune response.
Glucose-Lowering and Neuropathy-Targeting Mechanisms
Beyond inflammation control, these therapeutics also target other key pathological axes, primarily hyperglycemia reduction and neuropathy improvement. Gomisin A enhances insulin sensitivity and accelerates wound healing by suppressing the neuroinflammatory TLR4/p38 MAPK/IL6 pathway.70 Similarly, the ethanolic extract of Euphorbia hirta demonstrates dual efficacy by reducing hyperglycemia and oxidative stress markers such as malondialdehyde and NO while promoting wound closure.71
Collectively, targeting hyperglycemia and associated neuropathic pathways addresses the root cause of DFU development. By improving glycemic control and directly protecting nerves from glucotoxic insults, these compounds can prevent initial ulceration and improve sensory function, thereby reducing the risk of unnoticed trauma, a critical factor in DFU pathogenesis.
Pro-Angiogenic Mechanisms
For alleviation of vascular lesions and impaired angiogenesis, several compounds exhibit potent activity. Ginsenoside Rg1, which promotes endothelial cell function and neovascularization, acts through PI3K/Akt/eNOS signaling and modulates microRNAs including miR-489-3p/Sirt1 and miR-23a/IRF-1.72–74 Ramulus Mori alkaloids (SZ-A) protect endothelial cells from oxidative damage and stimulate angiogenesis via the NRF2/HO-1/eNOS axis.75 β-sitosterol activates MAPK/mTOR/VEGF pathways, enhancing microvascular perfusion,76 while Astragalus aqueous extract upregulates HIF-1α and VEGF expression, directly counteracting tissue ischemia.77
The core significance of these pro-angiogenic agents lies in their ability to reverse tissue ischemia, a major barrier to healing in DFUs. By activating critical pathways that drive the formation of new blood vessels and enhancing endothelial cell survival, they improve the delivery of oxygen and nutrients to the wound bed, which is essential for supporting the cellular activities required for tissue repair.
Antioxidant Mechanisms
Moreover, oxidative stress mitigation represents another critical therapeutic axis. Resveratrol alleviates hyperglycemia-induced ferroptosis in endothelial cells by regulating Nrf2 activity and key markers such as GPX4, SLC7A11, and ACSL4.78 Dracorhodin activates the Nrf2 pathway while inhibiting ferroptosis, reducing ROS and promoting repair.79 Narirutin reprograms cellular metabolism via the AMPK/Mfn2 pathway, reducing oxidative damage and inflammation.80
The antioxidant mechanisms, particularly those involving the Nrf2 pathway, are crucial for mitigating oxidative damage that perpetuates cellular dysfunction and death in the diabetic wound environment.
Nanotechnology and Hydrogel-Based Delivery Systems
To overcome bioavailability limitations, nanotechnology-driven delivery systems have been developed to enhance therapeutic potential. Gallium-modified gelatin nanoparticles loaded with quercetin, which promote sustained release and TGF-β/Smad-mediated M2 macrophage polarization, accelerate repair while inhibiting scar formation.81 Curcumin nanoparticle hydrogel (Cur-NP/HG), which outperforms conventional formulations, enhances re-epithelialization and collagen deposition while reducing inflammation.82 Chitosan nanogel encapsulating Teucrium polium nanoparticles (TP-NP/CS-NG), which improves stability and bioavailability, effectively alleviates oxidative stress and promotes angiogenesis.83
A cutting-edge metal-polyphenol nanocomposite hybrid hydrogel has been developed for DFU microenvironment reprogramming.84 Composed of EGCG/Fe3+ nanoparticles loaded with salvianolic acid B and glucose oxidase within a polysaccharide hydrogel, it exhibits potent antibacterial activity, promotes M2 macrophage polarization, angiogenesis, and ROS scavenging, significantly accelerating wound healing. NO-releasing gels represent a sophisticated strategy that combines natural compounds with gaseous signaling molecules. Asiaticoside-NO gel, which enhances healing via Wnt/β-catenin signaling, increases VEGF, iNOS, eNOS, and CD34 expression while exerting antimicrobial effects.85 Asiaticoside-NO hydrogel (ACNO), which modulates critical metabolic pathways such as methyl histidine metabolism and the malate-aspartate shuttle, attenuates SRC/STAT3 activation to promote repair.86 Centella asiatica total glycosides-NO gel (CATGNOG), which provides a stable and non-toxic delivery platform, demonstrates significant clinical potential.87
Multicomponent Hydrogels synergize bioactive properties. The BSP/Berberine hydrogel, which achieves 94.9% ± 1.81% wound closure in diabetic mice by day 14, combines antibacterial, anti-inflammatory, and antioxidant actions.88
Preclinical and Clinical Evidence
Robust clinical evidence supports ON101, a standardized blend of Plectranthus amboinicus PA-F4 and Centella asiatica S1. A multicenter, randomized controlled trial demonstrated a significantly higher complete healing rate with ON101 cream (60.7%) versus absorbent dressing (35.1%) over 16 weeks, with an odds ratio of 2.84 and a 95% confidence interval of 1.66–4.84.89 Post-hoc analysis confirmed efficacy in high-risk patients, including those with Wagner grade 2 ulcers, size ≥5 cm2, duration ≥3 months, HbA1c ≥9%, and BMI ≥25.90 Teucrium polium ointment, which significantly enhances healing of non-infected DFUs, has also been validated in a randomized clinical trial.91 Table 1.
 |
Table 1 Advanced Natural Therapeutics for Diabetic Foot Ulcers |
Challenges and Future Perspectives
Comparative Analysis and Therapeutic Modalities
A critical evaluation of the different natural product classes and delivery systems reveals distinct advantage and niches for each, which is crucial for guiding future research and clinical application. Flavonoids and polyphenols, including quercetin, puerarin, resveratrol, and curcumin, are particularly notable for their potent antioxidant and anti-inflammatory activities, primarily mediated through the Nrf2 and NF-κB pathways. In contrast, polysaccharides such as Astragalus polysaccharide and BSP exhibit superior immunomodulatory effects, excellent water solubility, and biocompatibility, making them ideal for hydrogel-based dressings. Saponins, exemplified by Ginsenoside Rg1, demonstrate remarkable pro-angiogenic efficacy via pathways like PI3K/Akt/eNOS.
Regarding delivery platforms, nanocarriers, such as nanoparticles and nanogels, excel in protecting labile compounds, enabling targeted and sustained release to specific wound cells, and enhancing penetration into wound beds. Hydrogel systems provide a moist wound-healing environment, are ideally suited for topical application, and can be designed to respond to wound microenvironment cues. The emerging trend of embedding nanocarriers within hydrogels represents a promising synergy, combining the protective and targeted delivery advantages of nanotechnology with the practical application and sustained reservoir benefits of hydrogels. Table 2.
 |
Table 2 Comparison of Major Natural Product Categories and Delivery Systems for Diabetic Foot Ulcer Management |
Translational Challenges and Standardization Hurdles
Despite promising preclinical and early clinical results, significant translational challenges hinder the widespread adoption of natural therapeutics for DFUs. Standardization and quality control remain critical obstacles due to variability in plant sourcing, extraction methodologies, and active compound content.157,158 Rigorous phytochemical standardization using advanced analytical techniques such as HPLC and LC-MS, along with the establishment of pharmacopeial standards, is essential to ensure batch-to-batch consistency and meet regulatory requirements.
Challenges in bioavailability and delivery optimization persist. While advanced systems such as nanoparticles and NO-gels show promise, achieving effective drug concentrations in deep, ischemic ulcer beds requires further engineering. It is also important to note that the current body of literature, including this review, leans towards reporting positive preclinical outcomes. A more balanced perspective for the field requires increased publication and discussion of negative, inconclusive, or contradictory findings to fully assess therapeutic potential and avoid publication bias. Key priorities include improving the physicochemical properties and reproducibility of nanomaterials for clinical applications, as well as addressing uncertainties regarding their biodistribution, degradation, and long-term biological effects.16 Additionally, more in vivo studies in large animal models are needed, as current research predominantly relies on rodent models that imperfectly replicate human DFU pathophysiology. Developing simpler, more controllable, and reproducible delivery systems is essential to facilitate translation. Furthermore, more specific and convenient administration methods should be explored to enhance efficacy and clinical practicality.
Clinical trial design complexity arises from DFU heterogeneity.159 Future trials must implement rigorous stratification based on ulcer characteristics and patient factors to identify responsive subgroups, as demonstrated by ON101’s efficacy in high-risk patients. Safety and long-term outcomes require meticulous assessment, including comprehensive toxicology profiles, potential drug-herb interactions, and monitoring for long-term complications.
Future Research Priorities
Future research priorities should focus on several critical areas to advance the field of natural therapeutics for DFUs. First, the development of advanced delivery systems is essential, particularly next-generation platforms that incorporate antimicrobials or debriding enzymes alongside natural active compounds to achieve synergistic therapeutic effects. Second, combination therapy optimization should be systematically evaluated, integrating natural therapeutics with standard care and advanced modalities to maximize treatment outcomes. Third, biomarker-driven personalization is crucial, as identifying predictive biomarkers will enable the matching of patients with the most effective natural therapeutics based on their unique profiles. Fourth, research should prioritize treatment-refractory ulcers, focusing on efficacy studies in patients with hard-to-heal DFUs who do not respond to conventional therapies. Fifth, the integration of “omics” technologies, such as transcriptomics, proteomics, and metabolomics, will help elucidate comprehensive mechanisms of action and uncover synergistic phytochemical combinations. Finally, generating real-world evidence through the establishment of registries is vital to monitor the long-term effectiveness, safety, and cost-effectiveness of these therapies in diverse clinical settings. Addressing these priorities will significantly enhance the translation of natural therapeutics into clinical practice and improve outcomes for patients with DFUs. Table 3.
 |
Table 3 Research Gaps, Potential Solutions, and Priority Areas for Future Investigation |
Conclusion
In contrast to conventional approaches that primarily address symptoms or advanced standard-of-care therapies targeting single pathways, advanced natural therapeutics present a promising multi-targeted strategy for the complex pathophysiology of DFUs. This review synthesizes evidence on bioactive compounds that modulate key healing processes, with advanced delivery systems overcoming bioavailability limitations. Preclinical and early clinical trials with standardized formulations show considerable promise. However, the current clinical evidence remains limited, primarily consisting of a few promising but small-scale studies. This underscores the critical need for larger, well-designed randomized controlled trials to robustly establish efficacy, optimal dosing, and long-term safety.
Translating this potential into practice, however, faces challenges in phytochemical standardization, delivery optimization, and the design of robust clinical trials for heterogeneity of DFU populations. Bridging there evidence gaps is essential to seize the translational opportunities, which include developing synergistic combinations and biomarker-driven personalization.
Looking ahead, the successful integration of these therapies has the potential to significantly influence future clinical guidelines, promoting personalized wound care strategies. Broader adoption could yield substantial public health benefits, including reduced healthcare costs, improved patient outcomes, and a lower burden of diabetes-related complications. Realizing this impact necessitates continued research and collaborative innovation.
Acknowledgments
Figure was created in https://BioRender.com.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
There is no funding to report.
Disclosure
There is no conflict of interests.
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