Phytochemical-based nanomedicine as a promising therapeutic strategy for erectile dysfunction

Abstract

Erectile dysfunction (ED) is a common condition among aging men, often associated with metabolic disorders, diabetes mellitus, hypertension, oligozoospermia, cardiovascular disease, sedentary lifestyles, chronic infections, and inflammation. A major therapeutic challenge is the inefficient delivery of drugs to penile smooth muscle tissue. Moreover, synthetic pharmacological treatments frequently cause adverse effects, including off-target interactions and risks to vital organs, especially the heart. As a result, there is growing interest in phytochemicals derived from medicinal plants, which offer natural, cost-effective, and less toxic alternatives. Numerous preclinical and clinical studies have shown that phytochemicals support muscle function through antioxidant and anti-inflammatory properties, modulation of the phosphodiesterase type 5 (PDE5) pathway, and hormone regulation. This review highlights the potential of combining phytochemicals with nanotechnology to develop safer and more effective treatments for penile tissue disorders. We also examine nanomedicine delivery systems such as liposomes, nanoemulsions, and dendrimers that enhance the bioavailability, targeted delivery, and controlled release of these compounds. Overall, this review underscores the promise of phytochemical-based nanomedicine in improving therapies for penile smooth muscle dysfunction.

INTRODUCTION

Sexual health plays an important role in overall well-being; it affects physical health, as well as psychological and social aspects of life.1 According to the World Health Organization, sexual health is defined as a state of well-being that includes physical, emotional, mental, and social aspects related to sexual life.2 Erectile dysfunction (ED) is a common condition, especially among older men, characterized by the inability to achieve or maintain a sufficient erection for satisfactory sexual performance. In cases of infertility, various factors, such as congenital conditions, muscular disorders, immunological issues, iatrogenic effects, or endocrine imbalances, may contribute to reduced chances of conception in the female partner.3,4 Synthetic drugs such as phosphodiesterase type 5 (PDE5) inhibitors (PDE5i; sildenafil, tadalafil, etc.) are generally used to alleviate these problems; however, they often carry drawbacks such as high costs and possible side effects, including headaches, gastrointestinal upset, flushing, nasal congestion, and priapism.5,6,7,8 Thus, there is an increasing demand for effective natural remedies.9,10 Herbal approaches are widely recognized as natural medicines that promote health and address various diseases. They serve as sources of preventive and therapeutic outcomes.11,12 These phytochemical compounds, including flavonoids, alkaloids, terpenoids, and saponins, can affect human health in various ways.13 These extracts are natural, abundant, easily obtainable, and cost-effective. Although they are traditionally regarded as safe, comprehensive pharmacovigilance and clinical data remain limited.14 Specific phytochemicals have received substantial attention for their therapeutic potential, particularly in terms of improving sexual function.15,16 The therapeutic potential of certain phytochemicals may enhance libido, improve penile smooth muscle function, regulate hormones, and reduce stress, all of which are critical components of sexual health.17,18 Phytochemicals are claimed to achieve these effects through antioxidant, anti-inflammatory, and hormonal regulatory properties. These compounds are now being re-evaluated for their potential to enhance therapeutic applications through nanotechnology. By leveraging insights into their underlying mechanisms, they can be more effectively targeted to specific organs.

Phytochemical-based nanomedicine may offer a promising future for enhancing sexual health. Several nanomedicine-based strategies have been developed to improve the bioavailability, therapeutic efficiency, and targeted controlled release of bioactive compounds, including nutraceuticals, liposomes, nanoemulsions, exosomes, and dendrimers.19,20 The integration of nanotechnology with phytochemicals ensures controlled release, precise targeted delivery, enhanced stability, and synergistic effects, all contributing to improved therapeutic efficacy with fewer side effects in ED patients.21,22 This review outlines the underlying mechanisms of ED, highlights bioactive compounds from various medicinal plants and their modes of action, and explores emerging therapeutic strategies enabled by phytochemical-based nanomedicine. It specifically discusses advanced delivery systems such as liposomes, nanoemulsions, exosomes, and dendrimers.

MECHANISMS OF PENILE SMOOTH MUSCLE TISSUE IN ERECTILE PHYSIOLOGY

The process of achieving penile erection involves a complex interplay of psychological, hormonal, neurological, vascular, and cavernosal factors.23 Any disruption or imbalance in these factors can lead to ED. Figure 1 proposes possible mechanisms for the development of ED. ED is not solely a localized penile smooth muscle disorder but rather a complex condition influenced by a broad spectrum of anatomical, physiological, psychological, and medical factors (Figure 1).24 Anatomically, penile smooth muscle structural abnormalities such as fibrosis, Peyronie’s disease, and venous leakage can impair erectile function. Physiologically, disruptions in the neurovascular pathways, nitric oxide (NO) signaling, calcium homeostasis, and hormone regulation, particularly testosterone, are critical contributors to penile smooth muscle tissue physiology.25 Clinically, ED often presents as a comorbidity of systemic illnesses such as diabetes mellitus, hypertension, metabolic syndrome, cardiovascular disease, and chronic kidney or liver disorders (Figure 1). These conditions exacerbate endothelial dysfunction and oxidative stress, which directly impact penile hemodynamics and smooth muscle relaxation.24,26,27,28 In addition, ED is frequently associated with medication side effects, including antihypertensives, antidepressants, and chemotherapeutic agents. Psychosocial elements, such as stress, anxiety, depression, interpersonal relationship challenges, and lifestyle habits including smoking, alcohol consumption, and physical inactivity, also play a substantial role in the onset and progression of ED.29,30,31

Figure 1.

Multifactorial contributors to erectile dysfunction. Schematic overview of key domains that can precipitate or exacerbate erectile dysfunction. NO: nitric oxide; NADPH: nicotinamide adenine dinucleotide phosphate.

Although ED has a multifactorial etiology, it has also been linked to reactive oxygen species (ROS) or free radicals. It has been proposed that dysfunction and structural alterations are related to the accumulation of inhibitors of endogenous nitric oxide synthase (NOS) in the penile smooth muscle of the corpus cavernosum.25 Such accumulation can lead to oxidative stress due to the production of dysfunctional antioxidant enzymes and an excess of free radicals or ROS (for example, superoxide anion radicals [O₂⁻], hydrogen peroxide [H₂O₂], and hydroxyl radicals [OH⁻]).32 Furthermore, studies have shown that nonphagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the main source of ROS in vascular endothelial cells (Figure 2).32,33,34

Figure 2.

ED is mediated by the primary mechanisms illustrated. Oxidative stress caused by excess ROS leads to a disruption of calcium homeostasis, resulting in smooth muscle contraction. Additionally, disturbances in homeostatic balance, such as testosterone deficiency, play a significant role. These physiological imbalances impair NO signaling, reduce penile blood flow, and ultimately compromise smooth muscle function within the penile tissue. ED: erectile dysfunction; ROS: reactive oxygen species; NO: nitric oxide; Ca²⁺: calcium ions. This figure was created using BioRender (HST No. 779568310RT0001).

In NO-rich tissues, oxygen-free radicals tend to combine with NO to form peroxynitrite (ONOO⁻), a highly cytotoxic compound resulting from the reaction between O₂⁻ and NO radicals.33 ED is generally associated with reduced NO bioavailability; it may appear contradictory to suggest that peroxynitrite, a reaction product of NO and superoxide (O₂⁻), plays a significant role in oxidative tissue damage in ED.34 While NO levels are indeed diminished in ED due to endothelial dysfunction, localized and transient NO production can still occur, particularly from neuronal nitric oxide synthase (nNOS) and partially functional endothelial NOS (eNOS).35 Simultaneously, ROS are elevated in ED due to eNOS uncoupling, NADPH oxidase overactivity, and mitochondrial dysfunction.36 Even at low NO concentrations, it can react with superoxide to form ONOO⁻. Thus, peroxynitrite formation is not solely dependent on high NO levels, but rather on disproportionately high levels of ROS and the altered ratio of NO/ ROS in ED.37 Moreover, ONOO⁻ can amplify oxidative damage by forming secondary radicals such as hydroxyl radicals and nitrogen dioxide. In addition, ONOO⁻ is a potent oxidant that nitrates proteins, damages vascular and smooth muscle cells, and inhibits eNOS activity, contributing to endothelial dysfunction.38 Importantly, ONOO⁻ can oxidize tetrahydrobiopterin (BH₄), further promoting eNOS uncoupling and exacerbating ROS production, thus establishing a self-reinforcing cycle of oxidative stress and NO depletion.39,40 In contrast, while NO levels are higher in healthy individuals, the accompanying low ROS levels and efficient antioxidant systems (e.g., superoxide dismutase and glutathione peroxidase) effectively prevent significant ONOO⁻ accumulation, preserving endothelial and smooth muscle function.37,41 This contributes to ED in men.42,43

Moreover, the molecular mechanisms underlying ED mainly involve the uncontrolled influx of calcium ions (Ca²⁺), which are regulated by neuroendocrine signaling pathways.44 In addition, hormone-based mechanisms also modulate penile function. Norepinephrine can trigger the activation of phospholipase C enzymes, which promote the hydrolysis of phosphatidylinositol-4,5-bisphosphate to produce inositol-1,4,5-trisphosphate. This molecule subsequently promotes the release of Ca²⁺ from the endoplasmic reticulum into the cytosol of penile muscle cells. The surge in intracellular Ca²⁺ facilitates calmodulin signaling pathways, which activate myosin light chain kinase, leading to smooth muscle contraction and contributing to penile muscle flaccidity.45,46 The noradrenaline signaling pathway may also inhibit adenylyl cyclase and reduce cyclic adenosine monophosphate (cAMP) levels. This hormone enhances the sensitivity of myosin light chain to Ca²⁺ via the Ras homolog gene family (RHO)-associated protein kinase pathway, amplifying smooth muscle contraction.44,47 This pathway is negatively regulated by testosterone, which modulates these contractions and, when deficient, may predispose individuals to ED. Additionally, endothelin and prostaglandins released from endothelial cells elevate intracellular Ca²⁺ levels, further promoting smooth muscle contraction. Constriction of penile smooth muscle restricts arterial blood flow, whereas venous drainage via the inferior vena cava is increased, maintaining penile muscle relaxation.46,48,49 This complex chain of molecular events emphasizes the critical balance between contraction and relaxation factors that regulate penile erection; when this balance is disturbed, ED can occur.

CURRENT DRUG DELIVERY FOR ED

Throughout history, numerous aphrodisiacs and traditional therapies have been employed across various cultures to address ED and enhance sexual performance.50 Numerous substances of animal and plant origin and minerals have been used in folk medicine to energize, vitalize, and improve sexual function and physical performance in men.24 However, only a limited number of these have been pharmacologically validated. For example, Panax ginseng has been shown to enhance NO synthesis and facilitate vasodilation, consequently improving penile blood flow in Traditional Chinese Medicine.15,51,52 Ayurvedic medicines such as Safed Musli (Chlorophytum borivilianum) and Tribulus terrestris are recognized for their potential benefits in elevating testosterone levels, increasing libido, and enhancing sperm quality.17,18 Traditional African remedies, such as Mondia whitei and Eurycoma longifolia (Tongkat ali), have been employed to augment male virility and improve sperm parameters.53,54,55 Additionally, saffron (Crocus sativus) has demonstrated aphrodisiac activity in experimental models, although clinical outcomes in humans remain inconclusive. Maca (Lepidium meyenii), native to the Andes, is traditionally utilized to enhance sexual desire and stamina, with studies indicating that its effects are independent of hormonal changes.15,56 Other historical aphrodisiacs include cantharidin (Spanish fly), which is known for stimulating arousal but is associated with significant toxicity, as well as ambrein derived from the whale Ambra grisea, which exerts hormonal and stimulant effects.54 Furthermore, certain foods, such as oysters, chocolate, and honey, are widely regarded as aphrodisiacs in popular culture, although substantial scientific evidence validating these claims remains limited. Despite the prevalence of these traditional remedies in various cultures and their comparatively fewer side effects relative to pharmaceuticals, the efficacy and safety of these remedies vary significantly.

Modern pharmacotherapy for ED includes a range of drug and their delivery systems, each with specific pharmacokinetics, mechanisms of action, and side effect profiles (Supplementary Table 1). PDE5i such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) are considered first-line pharmacotherapy for ED.57 Sildenafil was developed by Pfizer Inc. (New York, NY, USA), tadalafil by Eli Lilly (Indianapolis, IN, USA) in collaboration with ICOS (Bothell, WA, USA), vardenafil by Bayer AG (Leverkusen, Germany), and avanafil by Vivus Inc. (Campbell, CA, USA), now marketed by Metuchen Pharmaceuticals (Woodbridge, NJ, USA). These agents enhance the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway, leading to relaxation of smooth muscle in the corpus cavernosum and increased penile blood flow (Supplementary Table 1). Their advantages include oral administration and high efficacy across a broad patient population. However, they are associated with adverse effects such as headaches, facial flushing, dyspepsia, and visual disturbances.58 Although PDE5i agents (such as sildenafil, tadalafil, and vardenafil) are effective for many, they do not provide satisfactory results in a significant proportion of patients. Clinical studies have shown that 30%–40% of men, particularly those with diabetes mellitus, post-prostatectomy status, spinal cord injuries, or severe endothelial dysfunction, do not respond to PDE5i.58,59,60

Supplementary Table 1.

A comparative table for the efficacy and limitations of multiple drugs for the treatment of erectile dysfunction

Category	Examples	Mechanism of action	Efficacy/human evidence	Limitations	Reference
PDE5 inhibitors	Sildenafil, Tadalafil, Vardenafil	Enhances NO-cGMP pathway, increases blood flow	60%–70% (higher with sexual stimulation), Extensive RCTs confirm efficacy vs Placebo-controlled	Requires intact NO pathway; Side effects (headache and flushing)	1 2 3 4
Intracavernosal injections	Alprostadil, papaverine, phentolamine	Direct smooth muscle relaxation via vasodilators	70%–90% initially; Placebo-controlled	Invasive; Pain, fibrosis	5 6 7
Intraurethral PGE1	Alprostadil, prostaglandins	Absorption of vasodilator through urethral mucosa	45%–65%; Human evidence	Less effective than injections; urethral pain	8 9
Melanocortin receptor agonists (PT-141)	PT-141, Melanotan II	Activates melanocortin receptors	34%–68% in non-responders; Multiple placebo-controlled human trials	Nausea, long latency, limited long-term data	10 11 12
Traditional herbs	Safed Musli, Tribulus terrestris, Ashwagandha	Improves testosterone and antioxidant effects	Moderate improvement in ED; Tribulus have RCTs; others lack placebo control	Lack of standardization, regulatory approval, variable quality	13 14 15
Phytochemicals	Ginseng, Maca, Tongkat ali	Boosts libido, no synthesis, or antioxidant effects	Moderate; Varies with formulation and dose; Ginseng and Maca supported by RCTs; Others lack	Inconsistent clinical evidence; Not FDA-regulated	16 17 18 19
Topical agents	Alprostadil cream, minoxidil, and nitroglycerin-based gels	Local vasodilation via dermal absorption	Moderate; Less effective than oral/injectable; Several clinical trials with placebo controls	Variable absorption, risk of irritation	20 21 22
NO-releasing	NCX 911, L-arginine	Dual action: PDE5 inhibition, no donation	More effective in low-NO conditions; Limited placebo-controlled human studies	Short half-life, risk of systemic hypotension; limited data	23 24 25
Neurotoxin drugs	Botulinum Neurotoxin A	Inhibits neurotransmission in overactive pathways	56%–78% in ED, limited – preliminary trials; More needed	Not suitable for normal use, risk of neurotoxicity	26 27 28 29
CNS-targeted agents	Apomorphine, dopamine agonists	Stimulates central dopamine receptors	Mild to moderate; Improves libido and erection quality; No placebo-controlled human trials	Short half-life, side effects (nausea and yawning), and limited efficacy	30 31 32 33
Nanoherbal medicine	Nano-ginseng, Nano-maca	Improved bioavailability and targeted delivery of phytochemicals	Enhanced efficacy in preclinical models; No placebo-controlled human trials	Limited clinical data; Formulation stability issues	34 35 36 37
Peptide-based therapeutics	Bremelanotide setmelanotide	CNS stimulation for libido and erection initiation	Moderate, improves sexual desire and function; FDA-approved based on RCTs (Bremelanotide)	Adverse effects (nausea, flushing); Limited duration	38
Combination therapy	PDE5i + PT-141	Combines peripheral and central mechanisms	Synergistic approach to improving erectile function; Limited placebo-controlled studies exist	Needs optimization of dose and timing	39 40 41 42 43

RCTs: randomized controlled trials; CNS: central nervous system, PDE5: phosphodiesterase type 5; ED: erectile dysfunction; FDA: food and drug administration, NO: nitric oxide; cGMP: cyclic guanosine monophosphate

Furthermore, the side effect profile of PDE5i, although generally mild, can be bothersome or medically contraindicated for certain populations. Commonly reported adverse events include headaches (12%–16%), facial flushing (10%–12%), dyspepsia (7%–9%), nasal congestion, visual disturbances (e.g., cyanopsia or blurred vision), myalgia, and back pain.61,62 Importantly, PDE5i are contraindicated in patients using nitrates or certain antihypertensives due to the risk of severe hypotension.62,63 Sildenafil, the first PDE5i reaching the market, is associated with side effects such as headache, flushing, dyspepsia, rhinitis, and visual disturbances, including altered color perception due to cross-reactivity with PDE6.7,8,63 It has a relatively short half-life of 3–5 h and an onset time of approximately 30 min. Tadalafil is distinguished by its longer half-life of up to 36 h, allowing for a prolonged duration of effect and once-daily dosing. While it is generally well tolerated, it may cause headache, dyspepsia, and back pain, of which the latter is likely related to PDE11 inhibition.8 Vardenafil has a pharmacokinetic profile similar to sildenafil, with a rapid onset (approximately 25 min) and a half-life of approximately 4 h. It shares common side effects such as headache, flushing, dyspepsia, and rhinitis but notably lacks the visual disturbances seen with sildenafil.64,65 Avanafil, the most recently the U.S. Food and Drug Administration (FDA)-approved PDE5i, exhibits a rapid onset of action (10–15 min) and has shown a lower incidence of hypotensive episodes when coadministered with nitrates in healthy volunteers compared to a control placebo. This suggests a potential advantage in select populations; however, further studies are needed to confirm its safety in patients with cardiovascular disease.10,66,67,68

PDE5i-based drugs carry a risk of severe hypotension and cardiac failure, particularly when coadministered with nitrate-containing medications (nitroglycerin, isosorbide mononitrate, etc.) due to synergistic vasodilatory effects.58,69 While generally well-tolerated, PDE5i can lead to serious adverse events under these conditions.70

Intracavernosal injection therapy uses various drug molecules, such as alprostadil (Caverject, Edex), papaverine, and phentolamine, to repair and restore the function of penile smooth muscle.71 This method induces erection through vasodilation and smooth muscle relaxation, independent of sexual stimulation. This method is particularly beneficial for patients who are unresponsive to oral therapies, such as those with diabetes, spinal cord injuries, or post-prostatectomy complications. A combination of papaverine, phentolamine, and prostaglandin E1 created a potent vasoactive drug for ED effective for six months.72,73 Used in 116 patients, small doses achieved successful diagnostic and therapeutic outcomes. Alprostadil can be used alone or in combination with other agents as part of a “bimix” (papaverine + phentolamine) or “trimix” (alprostadil + papaverine + phentolamine) formulation. While this approach demonstrates high efficacy, with success rates up to 90% using the trimix, it carries limitations such as invasiveness and localized discomfort.73,74 This 10-year study followed 38 diabetic men with severe ED using self-injection of vasoactive drugs in type I and type II patients for sustained erectile function.75

Although intracavernosal injection therapy demonstrates high efficacy and rapid onset of action, it is limited by its invasive nature and the potential for pain at the injection site. Alternatively, drug administration via the urethra promotes erection by facilitating local absorption into the penile smooth muscle tissue.76 This method is associated with side effects compared to injections, including urethral discomfort, burning sensations, minor bleeding, and systemic hypotension.77,78 ED drugs such as alprostadil cream (Vitaros), developed by Apricus Biosciences, Inc. (San Diego, CA, USA), offer a non-invasive alternative in which the drug is applied to penile skin.79 This local absorption may enhance vasodilation in the penile muscular tissue.80 However, topical therapy can cause local irritation and is generally less effective than systemic or intracavernosal therapies.77,81 Along with NCX 911 is a novel nitric oxide-releasing PDE5i that combines PDE5 inhibition with direct NO donation. It has shown promising preclinical results in enhancing erectile function, even under conditions of impaired NO signaling.82 L-Arginine, a semiessential amino acid, serves as a precursor for NO synthesis, improving blood flow and erectile function, particularly in mild-to-moderate vasculogenic ED.83,84 While NCX 911 remains experimental, L-Arginine is widely available, generally safe, and offers a non-invasive treatment option for select patients.82,84 Botulinum neurotoxin A (BoNT-A) is emerging as a therapy for ED, especially in cases unresponsive to standard treatments. Studies by El-Shaer et al.85 and Ghanem et al.86 demonstrated that intracavernosal BoNT-A injections can significantly improve erectile function. Giuliano et al.87 reported a 77.5% success rate with repeated injections, maintaining an acceptable safety profile. Additionally, a systematic review by Abou Zahr et al.88 reviewed the role of BoNT-A, highlighting its positive effects on erectile hardness and patient satisfaction.

Combination therapy involving a PDE5i and PT-141 (bremelanotide) merges peripheral vasodilation with central melanocortin receptor activation, enhancing both erectile response and sexual desire.89 Clinical studies have demonstrated that coadministration of sildenafil (25 mg) with PT-141 (7.5 mg) significantly increases the duration of erectile activity compared to sildenafil alone, without introducing new adverse effects.89,90 This synergistic effect is particularly beneficial for patients who do not respond adequately to PDE5i monotherapy. To address the limitations of monotherapy, a phase 2 clinical trial is currently underway to evaluate a coformulated single-injection therapy combining bremelanotide with a PDE5i for the treatment of erectile dysfunction in patients unresponsive to PDE5i treatment.89,90,91 While these findings are promising, further research is needed to optimize dosing strategies and timing to maximize efficacy and minimize side effects.

PHYTOCHEMICALS FOR ED TREATMENTS

Current medications are unable to fully resolve ED and often cause serious adverse health effects. This situation underscores the need for alternative approaches to treating sexual health issues.92 Various phytochemicals, including phenolics, carotenoids, terpenoids, alkaloids, and organosulfur compounds, have been suggested for their potential benefits in the treatment of ED.11,93 Phytochemicals possess therapeutic properties that involve modulating and regulating signaling pathways related to human health.93,94 An understanding of the role phytochemicals might play in ED could pave the way for alternative treatment strategies. ED is also associated with oxidative stress and inflammation, which can damage the endothelial cells lining blood vessels (Figure 3). The accumulation of free radicals may lead to negative effects such as lipid peroxidation, protein oxidation, DNA damage, decreased availability of endothelial and neuronal NO, and increased levels of pro-inflammatory cytokines, growth factors, and tissue-specific receptors.95,96 The use of antioxidants has been suggested to protect these functions from oxidative damage.97 These antioxidants may be enzymatic (such as catalase and superoxide dismutase) or non-enzymatic (such as organic acids, α-tocopherol, ascorbic acid, and carotenoids). They help prevent the initiation and propagation of oxidative damage.

Figure 3.

Therapeutic interventions involving phytochemicals such as ginsenosides, flavos, and icariin are believed to counteract these effects. These processes include increasing NO production, reducing oxidative stress, and restoring hormonal balance. Nanotechnology-based delivery systems such as liposomes, nanoemulsions, and dendrimers help encapsulate these phytochemicals. They enhance stability, bioavailability, and targeted delivery to penile smooth muscle tissues. This encapsulation ensures the controlled release of phytochemicals, supporting sustained therapeutic efficacy and improved treatment outcomes for ED. ED: erectile dysfunction; ROS: reactive oxygen species; NO: nitric oxide. This figure was created using BioRender (HST No. 779568310RT0001).

Additionally, antioxidants can influence the levels and activity of neurotransmitters such as dopamine and serotonin, which play critical roles in sexual desire, especially in patients with hypoactive sexual desire disorder.98,99,100 Various types of plants, such as Angelica sinensis, Ferula hermonis, Humulus lupulus, Ginkgo biloba, Cimicifuga racemosa, Lepidium meyenii, Tribulus terrestris, Vitex agnus-castus, and Trifolium pratense, have been reported to help improve symptoms of hypoactive sexual desire disorder. Moreover, hormonal imbalances are known to significantly affect sexual health, contributing to conditions such as reduced libido and penile smooth muscle dysfunction. The bioactive compounds in these plants may modulate hormone levels indirectly by influencing enzyme activity (e.g., aromatase and 5α-reductase), interacting with hormone receptors, or exerting adaptogenic effects.101 Terpenoids and certain alkaloids have been shown to influence hormone levels in ways that support healthy sexual function. In the treatment of ED, bioactive compounds such as flavonoids can enhance the production of NO, a key mediator of vasodilation. NO plays a crucial role in increasing blood flow to penile muscle tissues, which is essential for the achievement and maintenance of erections.

Various bioactive compounds, such as ginsenosides, macamides, macaenes, protodioscin, withanolides, ginkgolides, bilobalide, apigenin, acacetin, pinocembrin, shatavarins, myristicin, and elemicin, are known to enhance antioxidant activity, modulate hormonal pathways or receptor sensitivity, and increase NO levels (Supplementary Table 2). Herbs such as Panax ginseng, Lepidium meyenii (maca), and Tribulus terrestris have been evaluated in randomized, placebo-controlled clinical trials for their effects on sexual function. Ginseng has shown improvement in erectile function and libido in multiple studies, some of which included placebo-controlled mice.102,103 Safety was generally acceptable, with mild gastrointestinal effects being the most common. Extraction of ginseng phytochemicals yields various tetracyclic triterpenoid saponins (ginsenosides) from the roots of Panax ginseng and Panax quinquefolium. Ginsenosides are well-documented adaptogens that enhance physical performance (including sexual activity), promote strength, reduce stress, and delay the aging process.104 Daily treatment with Asian ginseng (25–100 mg kg⁻¹) or ginsenoside Rg1 (2.5–10 mg kg⁻¹) has shown beneficial effects on sexual health. There is evidence of dose-related increases in mounting, intromission, and penile licking behaviors in mice.102,103 The anti-fatigue effect of oyster peptide and ginseng extracts synergistically decreases the accumulation of metabolites such as lactic acid and blood urea nitrogen, reduces oxidative damage, and conserves liver glycogen stores.52 PDE5 is an enzyme that facilitates hydrolysis of NO–cGMP. Inhibition of PDE5 is central to the management of penile dysfunction. Ginsenosides can support penile erection by directly inducing vasodilation and relaxation of the penile smooth muscle of corpus cavernosum. Additionally, the effects of ginseng on the corpus cavernosum appear to be mediated through the release and modulation of NO from endothelial cells and perivascular nerves.105 Maca, in a double-blind, placebo-controlled pilot trial, improved sexual desire without significant adverse effects. In a double-blind, randomized, placebo-controlled study, 12 weeks of supplementation showed improvement in sexual desire among healthy men. Safety was monitored through self-reports and biochemical tests, and no major adverse events were observed.106,107,108

Supplementary Table 2.

Bioactive compounds and ethnopharmacological evidence of substances used as aphrodisiacs

Herb	Scientific name	Bioactive compound	Type of evidence	Ethnopharmacological evidence
Ginseng	Panax ginseng	Ginsenosides	Human studies with placebo control44	Studies show it can improve ED and enhance sexual desire and performance45,46,47
Maca	Lepidium meyenii	Macamides, macaenes	Human and animal studies with placebo control48,49,50	Research indicates it can improve sexual desire and alleviate sexual dysfunction51,52
Tribulus	Tribulus terrestris	Protodioscin	Animal and limited human studies with placebo control53,54,55	Evidence supports its use in enhancing sexual function and increasing libido56,57
Ashwagandha	Withania somnifera	Withanolides	Human studies with placebo control58,59	Reduces stress and improves sexual health and function60,61
Yohimbine	Pausinystalia johimbe	Yohimbine	Animal and limited human studies with absence of placebo control62,63,64	Clinical trials indicate its effectiveness in treating ED62,63
Horny goat weed	Epimedium spp.	Icariin	In vitro and in vivo (rat and mouse) with absence of Placebo control65,66,67	Improves erectile function and enhances libido65,66
Saffron	Crocus sativus	Crocin, safranal	Human studies with placebo control68,69	Studies have demonstrated its efficacy in enhancing sexual desire and erectile function70,71
Muira Puama	Ptychopetalum olacoides	Muira puama	Limited study in animal with absence of placebo control72,73	Shows improvements in libido and sexual function72,73
Ginkgo Biloba	Ginkgo biloba	Ginkgolides, bilobalide	Animal and human studies with placebo control74,75,76,77	Research indicates it can improve sexual function by enhancing blood flow75,76,77
Fenugreek	Trigonella foenum-graecum	Saponins, particularly protodioscin	Limited animal and human studies with absence of placebo control68,78,79	Enhances libido and improves sexual health68,78
Damiana	Turnera diffusa	Apigenin, acacetin, and pinocembrin	In male rate with absence of placebo control80,81	Modulates the NO level pathway39,80,81
Tongkat Ali	Eurycoma longifolia	Eurycomanone, quassinoids	In vitro and in vivo with absence of placebo control82,83	Increases testosterone levels and improves sexual performance82,83
Catuaba	Erythroxylum catuaba	Catuabine A and B	Limited study with placebo control84,85	Antioxidant, stimulates sexual arousal85
Shatavari	Asparagus racemosus	Saponins, particularly shatavarins	Animal (rat) studies with absence of placebo control86,87	Supports reproductive health and sexual vitality86,87
Kava Kava	Piper methysticum	Kavalactones	Limited study16,88	Reduces anxiety, which can improve sexual desire and function16,88
Hops	Humulus lupulus	Xanthohumol, 8-prenylnaringenin	Animal (rat) studies with absence of placebo control89,90	Improves relaxation and sperm quality89,90
Suma Root	Pfaffia paniculata	Pfaffic acid, beta-ecdysterone	Animal (mice) studies with absence of placebo control91	Increases NO and cGMP levels, while decreasing PDE591
Fo-ti (He Shou Wu)	Polygonum minus	Tetrahydroxystilbene glucoside	Limited human studies with placebo control92	Improves sexual health through antioxidant activity92,93
Nutmeg	Myristica fragrans	Myristicin, elemicin	Limited animal (rat) study with placebo control94	Increase in the sexual activity94
Clove	Syzygium aromaticum	Eugenol, caryophyllene	Limited animal and human studies with absence of placebo control95,96,97	Promotes relaxation via K+ channels independently of the NO signaling pathway95,96,97
Moringa	Moringa oleifera	Quercetin, kaempferol	Animal study with absence of placebo control98,99	Research suggests it can improve sexual function and increase libido98,99
Hibiscus	Hibiscus sabdariffa	Anthocyanins	Animal study with absence of placebo control100,101	Studies support its role in enhancing blood flow and sexual function100,101
Passionflower	Passiflora incarnata	Flavonoids, alkaloids	Animal study with absence of placebo control102,103	Studies suggest it can reduce anxiety and enhance sexual desire102,103
Ginger	Zingiber officinale	Gingerol, shogaol	Animal and human studies104,105	Research supports its role in enhancing blood flow and sexual function106,107,108
Pumpkin seed	Cucurbita pepo	Zinc, phytosterols	Animal study with absence of placebo control109	Increase in NO levels and reduction in MDA levels109
Licorice root	Glycyrrhiza glabra	Glycyrrhizin	Limited human studies with placebo control110	Research suggests it can reduce stress and improve sexual desire18
Cinnamon	Cinnamomum verum	Cinnamaldehyde, cinnamic acid	Animal study with absence of placebo control111,112	Studies support its role in enhancing blood flow and sexual function111,112
Garlic	Allium sativum	Allicin, saponins	Limited animal and human studies with placebo control113,114	Research indicates it can improve blood flow and enhance libido115
Eleuthero (siberian ginseng)	Eleutherococcus senticosus	Eleutherosides	Limited animal study with absence of placebo control116	Research supports its use in enhancing stamina, vitality, and libido117
Cistanche	Cistanche tubulosa	Echinacoside, acteoside	Limited animal study with absence of placebo control118	Up-regulating synthesis of testosterone via the CYP450-3β-HSD pathway118
Maca	Lepidium meyenii	Glucosinolates, macamides	Animal and human studies with placebo control119,120	Research indicates it can improve libido and increase sperm count and motility119,120
Blue lotus	Nymphaea caerulea	Nuciferine, aporphine	In vitro study with absence of placebo control121	Shows the potential to enhance libido and promote relaxation122
Schisandra	Schisandra chinensis	Schisandrin, gomisin	Limited animal study with absence of placebo control123	Supports penile erection, boosts energy, and enhances endurance123
Butea superba	Butea superba	Flavonoids, sterols	Animal study with absence of placebo control124,125	Studies indicate it can improve erectile function and enhance libido124,125
Velvet bean	Mucuna pruriens	L-DOPA, mucunain	Animal (rat) study with absence of placebo control17,126	Plays a role in nNOS upregulation; enhances libido, sperm count, and motility17,127

ED: erectile dysfunction; nNOS: neuronal nitric oxide synthase; NO: nitric oxide; MDA: malondialdehyde; cGMP: cyclic guanosine monophosphate; PDE5: phosphodiesterase 5

The antioxidant effect of Lepidium meyenii was assessed using six preclinical studies. Extracts of maca, including macamides, macaenes, and glucosinolates, were able to scavenge free radicals; their reductive capacity was directly proportional to dosage.109,110 This scavenging ultimately leads to attenuation of oxidative stress, as evidenced by a decrease in malondialdehyde and increases in the levels of glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase under conditions of gonadal toxicity.56,111 Tribulus terrestris extract demonstrated concentration-dependent relaxation of rabbit corpus cavernosum in vitro, mediated through the NO pathway and endothelium. Oral administration for one month significantly increased intracavernous pressure and cyclic AMP levels in rats, suggesting improved erectile function.112 These findings indicate that Tribulus terrestris may enhance penile erection through smooth muscle relaxation and activation of the NO/cGMP and cAMP pathways.112,113 A known adaptogen, Withania somnifera, was tested in several trials for its ability to alleviate stress-related sexual dysfunction; some trials were placebo-controlled. Safety was generally good, with occasional reports of gastrointestinal discomfort and drowsiness. Withania somnifera has also been shown to improve hormonal profiles and increase antioxidant enzyme levels, along with antioxidant vitamins A, C, and E in seminal plasma.114,115 Recent evidence suggests that yohimbine, derived from Pausinystalia johimbe, is a promising natural supplement for ED. Although some research attributes its effects to placebo or increased peripheral vascular congestion, other studies have shown that it effectively treats organic impotence.107,116,117

Epimedium spp., commonly known as Epimedium species or horny goat weed, has been traditionally used in Chinese medicine for treating ED.118 It contains the active compound icariin (ICA). A study examined the effects of ICA on penile hemodynamics and tissue in a rat model of cavernous nerve injury, as well as its in vitro effects on cultured pelvic ganglia. Rats received daily ICA or placebo treatment for four weeks, with an additional single ICA dose administered before functional testing. Results showed that low-dose ICA significantly improved intracavernous pressure ratios and increased the expression of nNOS and calponin in penile smooth muscle tissue. ICA also promoted neurite outgrowth in pelvic ganglia cultures, indicating both neurotrophic effects and PDE5 inhibitory activity.118 Concerning Crocus sativus (saffron), it has demonstrated promising results: a human clinical trial showed significant improvements in erectile function, including rigidity and tumescence, after only 10 days of administering 200 mg of saffron daily supplementation. Outcomes measured using the IIEF and nocturnal penile tumescence tests indicated notable improvements over placebo conditions.119,120 Ginkgo biloba extract has been shown to enhance blood flow, increase NO production, and relax smooth muscle, all of which may benefit sexual response. However, there is evidence that Ginkgo biloba extract, rich in flavonoids and terpenoids, improves blood viscosity and endothelial function.121,122 In a study of 50 patients with arterial erectile impotence treated with 240 mg daily for nine months, spontaneous erections and improved penile blood flow were observed after six months in the control placebo group. Among patients unresponsive to high-dose intracavernous drugs, Ginkgo biloba has the potential to enhance erectile function through vascular improvement.123 Trigonella foenum-graecum contains flavonoids and steroidal saponins that effectively modulate the PDE5 enzyme, enhancing its aphrodisiac potency through synergistic effects.124,125,126

Turnera diffusa improves sexual performance through NO pathway activation and provides anxiolytic benefits, enhancing its potential for improving sexual health.127 Mucuna pruriens treatment demonstrated multifactorial therapeutic activity in supporting penile erection, validating its traditional use for sexual health enhancement.128,129 Schisandra chinensis has been evaluated for its effects on sexual function, particularly through studies examining its impact on the corpus cavernosum muscle of rabbit penile tissue. The phytochemicals (lignans) have shown potential to influence smooth muscle activity. Findings from placebo-controlled studies suggest that these lignans may synergistically enhance the efficacy of sildenafil in human patients, leading to greater improvements in erectile function compared to sildenafil alone. This indicates that Schisandra chinensis could serve as a supportive phytotherapeutic agent in ED patients.130 Tephrosia purpurea decreased fertility in male rats by lowering levels of protein, fructose, and sialic acid, while increasing testosterone and luteinizing hormone levels.131 Croton bonplandianum helped to improve NO and diphenyl-2-picrylhydrazyl scavenging activity. These findings indicate its potential antioxidant properties through enhanced removal of reactive species.132

PHYTOCHEMICAL-BASED NANOMEDICINE

Phytochemicals demonstrate considerable potential for the treatment of sexual health disorders. However, their clinical applications are limited due to inadequate solubility, low bioavailability, and rapid metabolism and excretion from the body. Nanotechnology offers new ways to overcome these challenges, given that phytochemical encapsulation in nanocarriers has been shown to enhance therapeutic efficacy (Figure 1). Nanocarriers such as liposomes, exosomes, nanoparticles, and micelles have been developed to improve the solubility, stability, and bioavailability of these phytochemical compounds. Nanomedicine formulations of phytochemicals may enable better absorption, prolonged circulation time, and greater therapeutic efficiency compared to conventional plant extracts. This strategy represents a safer, more targeted, and cost-effective therapeutic approach.

Moreover, nanocarriers enable the targeted delivery of bioactive molecules to specific sites such as penile muscle tissues and hormone-producing glands. Phytonanomedicine may enhance defense mechanisms against oxidative stress and inflammation, which are crucial for vascular health and address common sexual health issues. Recent nanoformulations of the phytochemical apigenin have shown significantly improved therapeutic efficacy against malignant tumors compared to its natural form. Additionally, a nanoformulation combining doxorubicin with the alkaloid berberine has demonstrated effective mitochondrial targeting, inhibiting tumor cell proliferation and pulmonary metastasis.133 Polylactic acid nanoparticles encapsulating the essential oil of Pistacia lentiscus var. chia were developed; they exhibited enhanced features concerning mean diameter, polydispersity index, and percentage of encapsulated essential oil.134 Another study aimed to develop polymeric nanoparticles comprising chitosan and hydroxypropyl methylcellulose for a new strategy to co-administer ceftriaxone and an extract of Schinopsis brasiliensis for the treatment of Enterobacteriaceae infections.135 Biosynthesized chitosan nanoparticles produced using the aqueous extract of fresh Eucalyptus globulus leaves exhibited nanosizes in the range of 6.92–10.10 nm.136 Additionally, cardamom oil-loaded chitosan nanoparticles were fabricated with a size range of 50–100 nm using an ionic gelation strategy.135 Panax ginseng (Araliaceae) is a popular herbal plant used in the treatment of ED. Ginsenosides, steroidal glycosides, have been reported to exert a direct effect on triggering erections, mediated through the release of endothelial NO. A cream formulation containing ginsenoside nanoparticles presents a promising approach for providing on-demand erectile effects in patients with ED.92

Injectable papaverine hydrochloride has disadvantages such as priapism and pain, which limit its use. A recent study formulated a papaverine hydrochloride-loaded lyotropic liquid crystal for transdermal delivery, with the 2.5% (w/w) formulation demonstrating improved diffusion and significantly enhanced skin penetration. This method could potentially replace injections for ED treatment and warrants further clinical trials.137 The poly(lactic-co-glycolic acid) nanoparticles and clay nanosystems containing babassu oil achieved 90% encapsulation and high bioavailability for the treatment of benign prostatic hyperplasia. These findings highlight the potential of nanomaterial-based therapies in clinical applications for benign prostatic hyperplasia treatment.138 Another study investigated the use of Panax ginseng nanoparticles to counteract nicotine-induced reproductive disorders in male rats. The nanoparticle formulation demonstrated superior protective efficacy compared to regular ginseng, effectively preventing reproductive toxicity and enhancing the function of the hypothalamus–pituitary–testis axis.139 Phytochemical-based nanomedicine represents a new frontier in treating sexual health disorders due to its improved delivery, stability, and bioavailability. This approach maximizes therapeutic benefits while offering a holistic and safer option, thereby opening new frontiers in sexual health.4 Continued research in nanotechnology and phytochemical interactions will drive the development of more effective and targeted therapies, improving patient outcomes.

NANOCARRIER-BASED DELIVERY

Topical drug delivery, though non-invasive and patient-friendly, has historically shown limited effectiveness in ED due to poor skin permeability, inadequate tissue retention, and local irritation (Supplementary Table 3). Conventional formulations often fail to penetrate deeply enough to affect the corpus cavernosum or smooth muscle effectively. Nanoparticle-based delivery systems are specifically designed to overcome these challenges by enhancing drug penetration, bioavailability, and localized therapeutic efficacy.20,140,141 Recent advances in nanocarrier technologies, including liposomes, nanoemulsions, solid lipid nanoparticles (SLNs), and exosomes, have demonstrated the ability to effectively transport therapeutic agents across the penile dermis and into the underlying smooth muscle and endothelial tissues.19,142 These systems utilize their nanoscale size, surface charge, and controlled-release properties to improve transdermal permeation and facilitate deeper tissue accumulation, while minimizing systemic exposure and reducing side effects. For instance, Nam et al.143 demonstrated that nitric oxide-loaded nanoemulsions significantly improved transdermal delivery and erectile response in animal models. In another study, researchers developed nanoemulsions of Panax ginseng dry extract and evaluated their effects on bisphenol-A (BPA)-induced male infertility in rats. The nanoemulsion of Panax ginseng offers a promising strategy for combating male infertility through hormonal recovery and oxidative stress reduction in vivo.144 These systems leverage their nanoscale size, surface characteristics, and controlled-release profiles to facilitate deeper tissue penetration while minimizing systemic exposure and irritation.145 Nanocarrier-based delivery systems offer a promising advancement in the treatment of ED by enhancing efficacy and reducing the side effects of therapeutic agents.142,146 Nanocarriers such as liposomes, polymeric nanoparticles, dendrimers, and solid lipid nanoparticles provide several advantages in delivering ED medications.147 These carriers can encapsulate both hydrophilic and hydrophobic drugs, improving solubility, stability, and bioavailability. Encapsulation protects therapeutic agents from degradation and premature metabolism, ensuring that a greater proportion of the drug reaches the target tissue intact.145,148

Supplementary Table 3.

Different types of drug delivery systems for erectile dysfunction

Delivery system	Example	Advantages	Limitations	Clinical	Reference
Oral tablets	Sildenafil, Tadalafil, etc.	Convenient, non-invasive, rapid onset	Systemic side effects, contraindications with nitrates	Most ED patients with mild to moderate	127 128 129
Topical creams	Vitaros (alprostadil cream)	Localized delivery, avoids first-pass metabolism	Variable absorption, possible skin irritation	Patients preferring non-invasive methods	9 130
Intracavernosal injections	Alprostadil, Papaverine	Direct delivery to target site, high efficacy	Invasive, risk of pain, fibrosis, patient discomfort	Patients unresponsive to oral meds or with severe ED	131 132 133
Intraurethral	Alprostadil prostaglandin E1	Minimally invasive, better than oral in some cases	Lower efficacy, urethral discomfort	Those contraindicated for injections	134 135
Intranasal	PT-141 (Bremelanotide)	Bypasses GI tract, rapid CNS effect	Short duration, CNS side effects	Those with psychogenic ED or PDE5 non-responders	39 136 137
Transdermal Patch	Testosterone patches	Steady hormone release	Skin reaction, compliance issues	Patients with hypogonadism	138 139 140
Nanoemulsions	Tadalafil nanoemulsions	Enhanced skin and mucosal penetration	Stability issues, needs specialized formulation	Icariin nanoemulsion, herbal NO donors	141
Liposomes	avanafil liposomes, Liposome encapsulated prostaglandin E1	Biocompatible, can encapsulate hydrophilic and lipophilic drugs	Complex formulation, short circulation time	Enhance penetration of the drug into the deep cavernosal bodies and increase peak systolic flow velocities in ED patients	142 143 144
Dendrimers	PAMAM dendrimers	High drug-loading, precise targeting	Cytotoxicity, complex synthesis	Icariin, Vardenafil	145 146
Exosomes	Corin is a type-II, pro-atrial natriuretic peptide	Natural vesicles, excellent biocompatibility and targeting	High cost, limited clinical translation	Stem cell-derived exosome therapies	147 148 149

ED: erectile dysfunction; NO: nitric oxide; PDE5: phosphodiesterase 5; CNS: central nervous system; GI: gastrointestinal; PAMAM: polyamidoamine

CONCLUSIONS

Phytochemicals have demonstrated promising therapeutic potential in enhancing sexual function. These natural bioactive molecules, such as flavonoids, alkaloids, terpenoids, and saponins, exhibit strong antioxidant effects, regulate hormones, increase NO production, reduce oxidative stress, and promote vasodilation, all of which are important for supporting sexual health. Ginsenosides, ICA, and various other physiologically active plant compounds have shown considerable potential in improving penile function. However, the clinical application of phytochemicals is limited by poor solubility, low bioavailability, rapid metabolism, and reduced therapeutic effectiveness. The incorporation of nanotechnology into phytochemical-based treatments represents a major advancement in sexual healthcare. This approach enhances therapeutic effects, reduces side effects, improves molecular stability, and enables targeted delivery to specific tissues, positioning phytochemical-based nanomedicine as a promising alternative to conventional treatments for sexual health disorders. Nanocarrier systems such as liposomes, nanoemulsions, and dendrimers improve the absorption and bioavailability of bioactive substances. Nanoemulsions also enhance the solubility and stability of phytochemicals by facilitating more efficient transport across cell membranes.

Similarly, exosomes and SLNs have demonstrated potential in this domain. Despite encouraging findings, several challenges remain in translating current research into clinical applications. Encapsulation using nanocarrier systems is crucial for improving treatment outcomes. Further research should focus on optimizing delivery systems, enhancing targeting capabilities, and evaluating long-term safety and efficacy through extensive clinical trials. Moreover, to address the regulatory challenges posed by these advanced drug delivery systems, it is essential to strengthen the framework for managing nanotechnology in medicine. The integration of phytochemicals and nanotechnology offers a breakthrough opportunity in the treatment of sexual health disorders and holds the potential to substantially improve patients’ quality of life.

AUTHOR CONTRIBUTIONS

RB conceptualized the content of the paper. Both authors wrote the first draft of the manuscript, contributed to all versions of the manuscript and illustrations, and read and approved the final manuscript.

COMPETING INTERESTS

Both authors declare no competing interests.