From plants to particles: herbal solutions and nanotechnology combating resistant vulvovaginal candidiasis

Abstract

Despite having current advanced therapy, vulvovaginal candidiasis (VVC) remains a common yet debated healthcare-associated topic worldwide due to multi-drug resistance Candida species. In our review, we outlined and highlighted upcoming values with scope of existing and emerging information regarding the possibility of using various natural molecules combined with modern technology that shows promising anti-candida activity in VVC. Furthermore, in this review, we compiled herbal drug molecules and their nanocarriers approach for enhancing the efficacy and stability of herbal molecules. We have also summarized the patent literature available on herbal drug molecules and their nanoformulation techniques that could alternatively become a new innovative era to combat resistance VVC.

Plain language summary

There is a type of fungi called Candida that is responsible for infections like vulvovaginal candidiasis in the human vagina. Due to resistance of currently available antifungal medicines, there are side effects on the body. Therefore, researchers are studying and preparing natural-based medicine from plants which may provide very good effects on human health. Also, herbal-based medicines have shown evidence based good antifungal activity. Combinations of herbal drugs with very small-sized particles called nanomaterials have added advantage as it helps herbs (drug) to reach their target. Its activity is enhanced as it stays for longer time in the body. So, in the future more research is needed to make sure plant medicines are safe and work well on vaginal infections and its uses should be promoted so that could be a good solution for treating vaginal candidiasis.

Graphical abstract

Plain language summary

Executive summary.

Background

• Vulvovaginal candiasis is mucosal infection of lower female reproductive tract. It is caused due to polymorphic Candida albicans, a fungus of yeast family. C. albicans exists in human microbiota and commonly colonizes lower female reproductive lumen (vaginal lumen) asymptomatically.

Major challenges in marketed antifungal medication

• Emergence and fast development of resistance.

• Adverse side effects.

• Patient non-compliance issues.

Objective toward using herbal medicine

• Design and development of herbal based medication is necessary to counteract resistance and also it has lesser side effects and notably they are well accepted in the masses.

• Herbal drug molecules alone or in combination with application of novel drug-delivery systems may be useful in combating bacterial resistance.

Importance of integration between nanomaterials & natural constituents

• Traditional herbal formulations and phytoconstituents have limitations like penetration to the target area, stability and compatibility.

• Nanocarriers-based approach could be beneficial to enhance the efficacy and to overcome challenges associated with delivery of herbal drugs.

• This review is focused on various nanocarrier delivery systems encapsulating herbal drug molecules or essential oils.

Vulvovaginal candidiasis (VVC) is a chronic and prevalent multifactor infectious disease primarily caused by Candida albicans. It is one of the most widespread mucosal infection after bacterial vaginosis and accounts for 50–72% of mucosal infection cases [1,2]. In optimized conditions, C. albicans grows in vaginal mucosa resulting in symptomatic VVC [3]. The visual symptoms of VVC are swollen major and minor labia, thrush patches around the vaginal opening and cottage cheese-like vaginal discharge of the female genital tract [4,5]. This infection limits the promising quality of life and patient compliance and is estimated to affect 158 million cases globally till the 2030s [6]. In USA; the VVC treatment cost burden has escalated to be total of $368 million and $4.8 billion for recurrence [7]. Currently, available synthetic antifungal agents offer several limitations like fast development and high index of resistance, local and systemic side effects including high cost [8–10]. As per recent reports C. albicans have developed azole resistance due to a change in their genetic structure and hence, more chances of recurrence of VVC [11,12]. Available antifungal medications have narrowed Candida spectrum, and ineffective to lessen recurrence rate in the future [13,14]. Natural products (phytochemicals) and polyherbal preparations containing essential oils have many potential benefits like no resistance and considerable toxicity unlike synthetic drugs [15,16]. Herbal nano-formulations have added advantage of penetration to reach their target in active form, apart from being stable and compatible [17].

In present review a broad range and insights into various innovative and investigated herbal approaches including phytoconstituents and novel bioactive compounds with their formulation has been discussed. The objective is to provide an update to the researchers to improve refining vaginal microbiome health [18].

Previously various authors have reported studies either about herbal formulation legacies on VVC or their implementation solely [19]. But none of them have considered the compilation of data regarding herbal combinations and their comparison with synthetic medications. Recent novel works with different herbal nano-formulations have also been ignored. So, this review provides the required novel herbal nanoformulation that offers potential alternatives with enhanced tolerance against Candida.

A range of keywords including VVC, standard antifungal drug resistance, novel phytoconstituents with their bioactive compounds, the role of nano herbal formulation, and herbal clinical trial studies have been searched in literature by accessing various databases mainly Science Direct, Lancet, Pub med, Nature, Elsevier, Google Scholar, WIPRO and clinical trials engines.

Pathogenesis

Primarily there are two types of Candida species responsible for VVC namely, C. albicans and C. glabrata. These pathogens were discovered within the vaginal secretion of symptomatic not in asymptomatic colonization [20]. Non albican Candida (NAC) species have fewer inhabitants to vaginal anatomical sites [21]. VVC pathogenesis characterization entails a multifactor mechanism (Figure 1) [22]. A healthy vagina has billion species of micro-ecosystem and out of them Corynebacterium and Lactobacillus species maintain pH and prevent the overgrowth of yeast [23]. Due to factors like pregnancy, sexual activity, necrotic tissue, age and many others, the host vaginal environment gets compromised and leading to VVC. Continuous and excessive use of antibiotics helps in enlarging Candida colonization to 10–30% [24,25] (a). In step 2, the candida colonization rises and, there is manipulation of the immunomodulatory process and formation of HSP, which increases the overgrowth of yeast [26]. This disruption in balance between host and microorganism colonization causes embracement of Candida virulence factors like adhesins, toxins, robust biofilm production and enzymes like aspartyl and serine proteinase, etc. which further accelerate this infection in the vagina [27] (b). In step 3, Candida substitutes their structure to an elongated thread called ‘h’ (hyphae) from its ‘y’ form (round ovoid) with superficially invading squamous epithelium. The mycelium of these species is responsible for hyphae production because of their shape-shifting potential [28]. This changeover is named as phenotypic switching, which indicates the pathogenicity relevance of VVC. Adhesins help to adhere not only to vaginal mucosa but also create hydrophobic interaction (complex to detach from vaginal lumen) [29,30]. Secretion of hydrolytic enzymes like phospholipase, and hydrolases from hyphae tip degrades epithelial cell line and results in invasion/permeation of cellular barrier by claiming affinity toward host epithelial receptor e cadherin. This activity subsequently sends signals to cytokines, NLRP3 and alarmins and PMN (polymorphonuclear) like anti-inflammatory from the lamina propia of the vagina [31]. Toxins including mycotoxin, glycoprotein extract and gliotoxin appear to suppress the host immune system specifically phagocytic properties (c). In step-4, suppression of the host immune system further leads to the outermost infiltration of vaginal mucosa and this infection causes the manifestation of white lesions due to the destruction of cell and keratin protein [32,33]. Adhesin expression, proteinase secretion, and hyphal pathogenicity appear to vary across different Candida species (d). Despite the above, the detailed pathogenic mechanism of VVC is not clear properly, as many authors have concluded that [34].

Figure 1.

Pathogenic mechanism of vaginal candidiasis.

Candida virulence factor like adhesin plays an important role in adhering fungus on the surface of the host epithelium and are characterized by ALS genes such as Als5 and Als6 [35,36]. Apart from that Hwp1 is responsible for the adhesion of fungal cells [37,38]. SAP gene expression in Candida (except C. glabrata) regulates hydrolytic enzymes like Secreted aspartyl proteases (sap) where as a cluster of 11 YPS genes regulate proteolytic enzymes which lead to degrading host defense proteins (lactoperoxidase, α-macroglobulin, etc.) [39,40]. Transcription factors like Efg1, Cph1, Tec1, Czf1, Ndt8 and Rim101 are responsible for Candida phenotypic switching that leads to host tissue invasion [41,42]. Recently candidalysin has been identified as causing damage to vaginal epithelial cells and regulated by ECE1 gene [43,44]. Pra1p in fungus reduces the effects of PMN which leads to unable of killing Candida [45,46].

Current marketed antifungal approach in VVC

According to previous reports, resistance occurs due to the lower affinity of current over the counter (OTC) antifungal drug toward cytochrome p45014dM, further target/regulatory gene alteration [47]. Table 1 enlists an overview of herbal-based marketed antifungal drugs and Supplementary Table 1 enlists an overview of marketed antifungal formulations [48,49]. It has also given reason for necessary use of herbal-based medication in the field of VVC treatment options [50–52]. Figure 2 depicts a schematic representation regarding mechanism and Candida resistance of standard therapies available in the market.

Table 1.

Marketed antifungal herbal-based medication.

Sl. number	Herbs used	Formulation	Brand
1.	Centella asiatica, hyaluronic acid and prebiotic	Vaginal gel	Palomacare®
2.	Boric acid, aloe vera, tea tree oil	Vaginal tablet	Shecrett
3.	Celery seed, parsley leaf, dandelion leaf, rhubarb root, garlic bulb, clove stem and flower bud	Capsule	NaturesPlus Candida Cleanse™
4.	Tea tree oil	Vaginal suppository	Tea Tree Therapy
5.	Cardamom, persian rose, triphala	Vaginal gel	Himalaya V-Gel
6.	Varuna, shatavari, ashoka and ashwagandha	Tablet	Gynoveda
7.	Boric acid, cocoa butter and TTO	Suppository	HoneyPot
8.	Symplocos racemosus, Quercus infectoria, Terminalia chebula, Fumaria officinalis L., Woodfordia fruticosa, Mucuna pruriens, Nelumbo nucifera, Rose, Pistachia, Vera Linn, Lavendula steochas	Cream	Vagitot
9.	Origanum vulgare, Spilanthes acmella, Calendula officinalis	Oil	Herb Pharm
10.	Coconut and Palm kernel oil	Tablet	Azo

Figure 2.

Illustration of antifungal Candida resistance.

Natural products based molecules/formulations in vaginal candidiasis

Various herbs have developed numerous novel medications throughout the history of mankind as it got various medicinal properties [53]. Supplementary Table 2 enlists an overview of various existing works regarding successful implementation of herbs in vaginal candidiasis.

Phytochemicals in VVC

Terminalia chebula

Chebulinic acid (CA) is an unexplored molecule in this regard. Following the exploration study first time conducted by Sharma et al. 2020 and in their study, ketoconazole, itraconazole, fluconazole and CA were targeted to candida protein ALS3 by in silico approach. In their study, they demonstrated that C. albicans growth failed to suppress at a minimum inhibitory concentration (MIC) of 1.5 μg/ml because of fluconazole resistance. Almost the same intensity was shown by ketoconazole and itraconazole for targeting affinity toward Candida at their MIC 0.05 and 0.048 μg/ml respectively. CA was shocked to appear with having not only the highest potency on C. albicans cell growth inhibition but also declined overall expansion by continuing log and lag phase of candida at MIC of 0.025 μg/ml [54].

In another study, Waseem et al. evaluated the target efficiency of chebulinic acid toward the KIX domain in the Med15a Mediator subunit of Candida glabrata species. In their in silico study they have demonstrated that CA has the strongest binding interaction with fungal target protein and has been identified as a novel potential fungus inhibitor that could be used in the future across VVC [55].

Seaweeds extracts

During a study by Arumugam et al. it became known that seaweed algae like Turbinaria ornata, Dictyota bartayresiana, Halimeda tuna, Sargassum white, Chaetomorpha sp. and Padina spp. extracts got anti-Candida activity with suppressing virulence properties for the first time. Methanolic extracts were able to have good inhibition with a mean zone from 0 to 17 mm whereas Dictyota bartayresiana (17.4 ± 0.62) and Halimeda tuna extracts exhibited maximum region of growth and fungistatic C. albicans mechanism inhibition. All seaweed with different extracts was capable of suppressing 100% filamentation [56].

Woodfordia fruticosa

Within this recent observational In-vitro study, alcoholic extracts of W. fruticosa have been evaluated to validate its broad sensitivity region toward the vaginal sample of 33 women suffering from symptomatic VVC. Thereafter it was learned that dhataki had revealed hindrances of Candida's various mechanisms like altering the DNA of cells, and complexing its protein by impeding various cellular processes. C. albicans found most susceptible from 26 mm to 22 mm after W. Fruticosa extracts (Athira CN et al.) [57].

Propolis & geopropolis extracts

Bonfim et al. first time investigated and characterized both in vitro and in vivo studies of mucoadhesive thermo-responsive delivery (MTS) of two formulations (F14 and F16) containing propolis extracts. Results of their study showed that F16 of propolis comparatively reduced the growth of candida and almost 44–51% of Candida isolates were restrained at 167.5 μg/ml of propolis concentration. At the concentration of 2534.40 μg/ml, F16 formulation significantly reduced candida cell viability and fungal load inhibitions without any toxicity/adverse reactions [58].

In another study by Júnior et al. they prepared ethanolic extracts of Geopropolis vaginal gel (pH 4.6–4.8 and cPs viscosity 535,600–920,400) and evaluate its in vitro potential at suitable concentrations against six candida species responsible for VVC pathogenicity. UHPLC-PDA-qTOF-MS/MS method was used to analyze the chemical profile of extracts also carbomer 980 was used to prepare herbal gel (F1, F2 and F3). F2 formulation with 40% propylene glycol got the best adhesion time and distance leakage properties [59].

Satureja khuzistanica & carvacrol

The aim of Mahboub et al. investigation was to assess aerial parts of Satureja khuzistanica EO against 30 clinical Candida strains of women. Within their exploration, they'd gone for germ tube inhibition test, anti candidal evaluation of EO at different concentrations including 0.5, 0.75, 1, 1.5 μl and Carvacrol concentrations including 0.473, 0.945 μl. Their findings indicated that Satureja khuzistanica (1.5 μl concentration) and Carvacrol had a higher zone of anti-Candida activity and could be used further [60].

Camellia sinensis

Thakur et al. 2023 have formulated Camellia sinensis loaded optimized (3² factorial design, design expert used) herbal cream at concentrations like 500, 1000 and 1500 μg/ml. Within their investigation they have investigated that, this natural origin-based cream has potential anti-candida properties also not have any skin tissue irritancy sign with pH 6.7 while applying it. No signs of Candida growth have been observed at MIC 800 μg/ml, that's why C.sinensis could be a satisfactory alternative treatment for VVC resistance isolates [61].

Mitracarpus frigidus

In another study, Campos et al. evaluated Mitracarpus Frigidus extracts antifungal activity against C. albicans. Within their study, they investigated that; these herbal extracts had promising anti-candida activities without any toxicity observed [62].

Campos et al. 2020 studied and evaluated methanolic extracts of M. frigidus-loaded chitosan gel at concentrations like 2.5, 5.0 and 10.0% against mucosal infection in vaginal candidiasis. Findings of their study were, 80.69 and 89.43% of fungal load reduction observed at concentrations like 2.5 and 5.0%, respectively. They also noticed, at the end of the treatment complete and faster removal of fungal cells seen at 10% of herbal gel concentration [63].

Solanum torvum fruits

For the first time, Harley et al. reported aerial parts of Solanum torvum fruits (STF) against fluconazole resistance Candida isolates. And their research revealed that, at MIC 0.016 and 0.032 mg/ml of 3-oxo-friedelan-20α-oic acid constituents from S. torvum possessed maximum fungus inhibitory action, biofilm and biomass inhibition properties against every candida strain collected. MIC like 16 μg/ml and 32 μg/ml of betulinic acid and oleanolic acid appeared to carry out fluconazole resistance candida inhibitions property [64].

Brevundimonas abyssalis

Sushmita et al. have evaluated the anti-biofilm and anti-hyphal activity of Brevundimonas abyssalis to explore its antifungal therapeutic potential. In their study, they have demonstrated that, 3-hydroxy coumarin (3HC) compound from B. abyssalis able to inhibit candida biofilm at MBIC of 250 μg ml^-1. It also inhibited fungal adhesion and its pathogenic transition by down-regulating fungus virulence genes without non-toxic characteristics to human erythrocytes and buccal cells [65].

Rosa damascena (Petals), Punica granatum L (Peel), Querqus infectoria Oliv. (Fruit), Myrtus communis L. (Fruit) & Nardostachys jatamansi (Rhizome)

Khalilzadeha et al. first time formulated 200 mg dried herbs extracts loaded vaginal tablet (Ward) to assess its effectiveness by designing a parallel double-blinded block randomized placebo-controlled. Results revealed that all clinical symptoms of VVC dramatically and comparatively reduced in the ward group and from this study it was also noticed that, a significant reduction of Candida smear and culture was observed after Ward exposure [66].

Terminalia brownii

Salih et al. have demonstrated the invitro anti-Candida potential of T. brownii extracts at MIC 12 to 2500 μg/ml. From the antifungal study, it was observed that acetone leaf extracts of T. brownii showed the highest Candida growth inhibition diameter of 28–38.6 mm at 312 μg/ml of concentration. After that, 40–40.6 mm of C. glabrata inhibition zone was shown by acetone and methanolic root extracts at 312 μg/ml of concentration. At MIC 625–1250 μg/ml, bark comparatively got extensive Candida inhibitory activity than stem wood [67].

Berberine (BBR)

The present study (Zhao et al.) focused on Candida virulence factor adhesins inhibited by Berberine at 32–256 μg/ml concentrations by down-regulating ECE1, FKS1 and FKS2 genes that are responsible for fungal morphological transformation to hyphae and β-glucan synthesis. Authors noticed that anti-Candida potential with minimal toxicity of Berberine was found to be time-dependent and adhesins to A431 cells were comparatively and strongly blocked by highly regulating ICAM-1 and mucin1, mucin4 expression. Berberine worked by decreasing IL-2 pro-inflammatory and increasing IL-4 anti-inflammatory to rebuild immune homeostasis during the pathogenesis of VVC [68].

Similarly in another study, the anti-candidal combined activity of berberine hydrochloride (BBH) + fluconazole (0.03–0.06 FICI value) was tested in fluconazole resistance strains by Rh6G Efflux Assay. They have noticed that BBH + Fluconazole inhibited cell viability and resistance strains and also it enhanced fluconazole activity. Hyphal growth and candida adherence was absent in combination group exposure. Multidrug resistance and virulence-specific gene expression reduced after exposure to BBH + Fluconazole (Yong et al.) [69].

Xie et al. 2020 determined anti candidal potential of berberine in planktonic (MIC 10, 20, 40, 80 and 160 μg/ml) and biofilm conditions by performing an in vitro study of 6 fungal clinical isolates and 5 standard strains. Observed results were, that BBR showed efficacy in concentration concentration-dependent manner and all species showed biofilm inhibitory effect after 24 and 48 h of BBR treatment [70].

Boswellia

Moghadam et al. evaluated the effect of a vaginal gel consisting of 2% Boswellia on the gene that expresses oxidative stress and apoptosis in vaginal epithelium cells. Analysts have designed an open-label clinical trial and they investigated that, markers of oxidative stress and VVC clinical symptoms were drastically reduced after administrations of vaginal gel [71].

Jaroš et al. studied anti Candida potential of Bioswellix extracts (EtOH and DMSO) from Boswellia serrata against candida planktonic, adhering cells and biofilm with its metabolic activity. A notable suppression in the metabolic activity and biofilm of C. krusei and parapsilosis at 500 mg L^-1 concentration suggests that Boswellia could be an alternative futuristic herbal approach toward VVC [72].

Quercus infectoria gall

Wahab et al. have evaluated the in vitro and in vivo antifungal potential of three formulations of vaginal cream consisting of 10, 20 and 30% of aqueous Q. Infectoria gall extracts at MIC 1.094, 0.547 and 0.068 mg/ml against collected Candida, respectively. Formulations like 30% of FEC (Formulation extracted cream) got comparatively highest inhibition diameter (MIZ) than 20% followed by 10% respectively. Over 2 weeks of FEC vaginal cream administration, no noticed inflammation and necrosis was observed with minimized adverse/side effect reactions in rat model cervical tissue [73].

Hibiscus rosa-sinensis

In vitro anti-Candida activity of both methanolic and ethanolic leaf extracts of Hibiscus rosa sinensis at different concentrations like 1000, 500, 250, 125, 62.5 and 31.25 mg/ml have evaluated by Zuhaira et al. Findings of this study were, methanolic extracts showed 8.0 (C. albicans), 7.3 (C. tropicalis) and 6.7 mm (C. glabrata) zone of inhibitions at concentration of 1000 mg/ml [74].

Copaifera lucens

Madboly et al. evaluate anti-virulence and anti-biofilm activity of galloylquinic acid (GQAs) from Copaifera lucens leaves by isolating 20 multi-drug resistance C. albicans species. From in vivo study, it was found that GQAs is a promising agent that could potentially be used in VVC by eradicating 80% of Candida bio films [75].

Lactic acid

Jang et al. have evaluated in vitro and in vivo antifungal potential of isolated Lactobacillus against vaginal candidiasis. In their study, Candida growth and its hyphal morphogenesis inhibition were observed and from the in vivo assay, they demonstrated that clear Candida clearance was observed without toxicity [76].

In another study, MacAlpine evaluated anti-Candida potential of Lactobacillus by inhibiting DYRK1-family kinase. In their study, filamentation assays, biofilm assays and viability assays of C. albicans have been performed. Authors observed that Candida adhesion and its yeast-to-filament transition have promisingly inhibited [77].

Clitoria ternatea Linn

Sharma et al. have developed aqueous extracts Clitoria ternatea linn fabricated herbal formulation against Candida dominated vaginal infections. In their study, they have formulated 8 herbal creams (HC) and out of all eight formulations, HC5 (99.32% flower extracts) exerted most satisfactory and optimum results. After comparing with clotrimazole, it was reported that C. ternatea linn have excellent anti fungal characteristics [78].

Cyanthillium cinereum, Khaya senegalensis & Lippia multiflora

Fanou et al. have demonstrated anti fungal activity of these plant extracts against Candida. In their study they found that, C. glabrata and krusei shown higher zone of inhibitions toward aqueous extracts of plants. Candida strains were sensitive to K. Senegalensis extracts, but C. cinereum got extensive inhibitions of Candida growth and virulence factor activity on C. albicans and glabrata than K. Senegalensis [79].

Ipomea cairica Linn

Dwivedi et al. evaluated the antifungal properties of Ipomea cairica Linn loaded herbal cream and outcomes revealed that; Herbal Cream13 (21.24 ± 0.19 mm zone of Candida inhibitions) formulation was a more effective antifungal characteristics than Herbal cream HC5 (20.33 ± 0.04 mm) with drug release at 96.26% and 91.28% after 10 h of safe and effective administration against Candida infections [80].

Herbal combination in VVC

Nigella sativa & honey

Korabi et al. first time demonstrated the impact of vaginal cream (30% honey and 3% N. sativa hydro alcoholic extract) consisting of N. sativa + Honey (n = 40) and compared with 1% clotrimazole (n = 39) by performing triple-blind block randomized controlled. Key points of this study were; mycelium, hyphae, yeast cells and discharge samples of the vagina was collected to run this trial study and it was noticed that 29 (72.5) and 25 (64.1) % of participants were very satisfied with N. Sativa + Honey vaginal cream and its method. So this herbal-based combination got promising antifungal potential in VVC [81].

Quercetin & gallic acid

Giordani et al. first time performed a combination action of Quercetin (Q) and Gallic acid (GA) loaded liposome (LP) and developed 3 formulations namely; LP-Q, LP-GA and liposome comprising both polyphenols against C. albicans. Analysts have discussed that LP-Q + GA formulation got no signs of any inflammation/irritancy, cytotoxic qualities, and tissue damage also showed maximum antioxidant activity. They also noticed that, at the concentrations of 0.5 and 2.5 μg/ml, nitric oxide was intensely inhibited (79%) by LP-Q + GA. Also, Q has more anti-inflammation properties than GA as reported [82].

Citrus limon, Cupressus sempervirens, Litsea cubeba & Melaleuca alternifolia EO

In vitro anti-biofilm potential and in vivo toxicity study of EO combination with themselves and with Clotrimazole like C. limon + M. alternifolia (A), L. cubeba + M. alternifolia (B), L. cubeba + C. limon (C), C. sempervire + C. limon (D), C. limon + M. alternifolia (E), M. alternifolia + Clotrimazole (F) and C. sempervire + CLOT (EO + CLOT) against four reference strains and vaginal isolates of candida have been performed (Silva et al.). In their study scientist have found that, equal to or greater than 4000 μg/ml of concentration, EO showed maximum MBIC (Minimum Biofilm-Inhibiting Concentration) and ranging from 0.25 to 4 μg/ml, CLOT exhibited MBIC [83].

Pea protein & grape seed

Esposito et al. developed a medical device containing combinations of pea protein and grape seed to compare its antifungal activities with the standard drug fluconazole. Promising reduction of Candida burden and VVC clinical symptoms without any toxicity observed by the herbal-based device. It was also noticed that post-treatment drawbacks have been overcome by this device and could be used further [84].

Sclerocarya birrea leaves (SBL) & stem, bark (SBB)

Harley et al. have first time reported 70% ethanolic extracts of SBL and SBB against eight C. albicans isolates and fluconazole resistance strains at MIC of 12.21–97.66 μg/ml by comparing with synthetic drugs. In their study, SBL got synergistic activity with nystatin was comparatively better than SBB. On the other hand, at MIC of 12.49–164.42 μg/ml of concentration, SBB showed higher biofilm inhibitions and stronger anti-Candida activity than SBL [85].

Salvia officinalis & clotrimazole

Ahangari et al. initially carried out a triple-blind randomized control clinical trial by comparing the intervention of Salvia officinalis (SO) loaded vaginal tablet with the combination of SO with Clotrimazole. In their study, they formulated three different combinations for three patients group, for instance, 400 mg of SO as a vaginal tablet with a placebo Clotrimazole (a), 100 mg of Clotrimazole vaginal tablet with SO placebo (b), a vaginal tablet of both SO and Clotrimazole (c) OD × 7 days. Within their trial study, it was noticed that the healing rate of the vagina turned out to be maximum in the ‘a’ (100%) group than the ‘b’ and ‘c’ group of cases. In addition, combinations of SO with Clotrimazole noticeably reduce VVC symptoms by reducing its clinical symptoms promisingly [86].

Coconut oil & clotrimazole

Mustapha et al. have prepared coconut oil based clotrimazole suppository and evaluated their synergistic activity against VVC. Authors have noticed that, this combination got comparatively good anti Candida activity with promising inhibition zone than clotrimazole and coconut oil alone [87].

Citrus aurantium L. EO (CAEO), fluconazole & amphotericin B

Nidhi et al. have first time demonstrated the synergistic potential of CAEO with fluconazole and amphotericin B against two C. albicans fungal strains like ATCC90028 and MTCC277 at MIC-0.15 and 0.31% of CAEO, respectively. Investigators have discussed that; ATCC90028 and MTCC 277 fungal strains exerted 25.3 ± 0.47 (0.15% MIC) and 19 ± 0.02 (0.31% MIC) mm of clear zone candida growth inhibitions, whereas inhibitions shown by fluconazole and amphotericin B comparatively lower after 48 h. It was also revealed that synergistic activity with amphotericin B is more effective than fluconazole and could be used further [88].

Pomegranate rind extract and Zn (II)

Celiksoy et al. have evaluated the synergistic activity of pomegranate rind extract and Zn (II) against C. albicans. In their study, they reported that this combination had considerable anti-Candida activities and could be used to combat fungal resistance mechanism in the future [89].

Comparative study of herbal drug molecules & synthetic drug

Lawsonia inermis (henna) & clotrimazole

Yaralizadeh et al. have first time designed a parallel randomized control trial by allocating two patient groups such as n = 40 (henna) and n = 40 (clotrimazole) against Candida activity in VVC. Outcomes revealed as, after administering herbal cream, total removal of burning sensation revealed in 92.5% cases, whereas 45% results seen in clotrimazole participants. In henna group after 4 weeks of intervention, colony formations have completely reduced down. It was also examined that herbal cream magically and comparatively improves lactobacillus in the vaginal microbiome more than conventional drug clotrimazole [90].

Calendula officinalis (CO) & clotrimazole

Saffari et al. performed a triple-blind randomized clinical trial by comparing vaginal cream (1% concentration of extracts) containing Calendula officinalis with clotrimazole by allocating 75 estrogenic-age women in two groups. They have also the first time demonstrated the in vivo anti-Candida potential of 70% ethanolic extracts. In this investigation, CO showed slower but long-term prominent anti-candida activity than clotrimazole [91].

Althaea officinalis L. (Marshmallow) & clotrimazole

Amini et al. compared the antifungal potential of 4% aqueous extracts of marshmallow +1% clotrimazole (CLOT-M) as target (n = 50) with 1% CLOT vaginal cream (n = 50) as control. In their study, patients reported continuous improvement of yeast culture without any systemic, local side effects. After 30 days of treatment, promising suppression of symptoms was observed in CLOT-M with no recurrence found whereas the CLOT group had five recurrences report, respectively [92].

Kundur (Boswellia serrata Roxb. Ex Colebr) & miconazole

A randomized controlled trial has proposed to compare the effectiveness of 1 g Kundur vaginal insert tablet with 2% w/w Miconazole suppository and also performed primary and secondary outcomes studies based on administering both for 21 and 7 days (Inamdar et al.). From the primary outcomes study it was learned that, in Kundur groups symptoms were significantly and promisingly reduced than standard drugs. And secondary outcomes indicated promising antifungal effects that could further be used in VVC [93].

Ocimum gratissimum L., Lantana camara L. & Pteleopsis suberosa Engl. & Diels

Klotoe et al. have evaluated in vitro and in vivo antifungal activity of aqueous, ethanolic and hydroethanolic extracts of above-mentioned plants at 100; 50; 25; 12.5; and 6.25 concentrations against 1MA, 3MA isolates in VVC and ATCC 90028 reference strain. In this present study, it was reported that ATCC 90028 strains inhibited at 33.52 mg/ml MIC by every extract of Pteleopsis suberosa also this plant's aqueous extracts have comparatively higher zone of anti-candidal activity. Moreover, Pteleopsis suberosa and Lantana camara L. aqueous extracts got inhibition activity for reference strain [94].

Foeniculum vulgare Mill EO & Clotrimazole

Huambo et al. have assessed a comparative experimental study upon the in vitro antifungal effect of aqueous and methanolic extracts of Foenifulum vulgare Mill EO with clotrimazole (control) toward C. albicans two strains (ATCC 90028 and nativa). Prepared 50% concentration of EO inhibits nativa Candida of 12 mm whereas medium and extreme Inhibitions of 30 and 50 mm were found after 75 and 100% of EO exposure respectively. On the other hand, at 100% concentration of clotrimazole, ATCC 90028 and native inhibitions of 38 and 35 mm were observed [95].

Lavandula stoechas L., Melissa officinalis L., Mentha × piperita L., Origanum vulgare L., Rosmarinus officinalis L., Salvia officinalis L. & Thymus vulgaris L EO

In vitro, candida and biofilm inhibitions of collected seven EO (Lamiaceae) against 44 strains of different Candida species have been investigated by Karpiński et al. From the antimicrobial study, it was indicated that, at 0.1–100 mg/ml of concentration, Candida growth inhibitions were observed. Authors noticed that all EO showed potential antifungal effects and 90% of biofilm inhibition was showed by thyme and oregano EO, while 75–85% of anti-biofilm activity exerted by L. stoechas, mint and R. officinalis EO [96].

Anethum graveolens L (Dill Seed) EO & Clotrimazole

Authors have compared dill seed fabricated vaginal cream with 1% clotrimazole by performing a double-blind block randomized clinical trial by having 186 women and dividing them into three groups by giving 1% Clotrimazole (n = 56), vaginal cream loaded 2% dill seed total extracts (TEE, n = 60) and 2% dill seed EO (n = 59) respectively (Sarhadinejad et al. 2018). Investigators demonstrated that, itching drastically reduced in the TEE and EO group of patients. From the above trial study authors noticed that the TEE formulation had promising anti-Candida activity and could potentially be used in the future without any toxicity [97].

Laurus nobilis, T. vulgaris, M. piperita, Cymbopogon citratus, Lippia junelliana & Calamintha officinalis EO

Cordoba et al. first time compared in vitro antifungal activity of these six aromatic plants EO at 0.8 to 800 mg l^-1 concentration against patient's clinical isolates of candida. L. nobilis and T. vulgaris EO most active and highly inhibit all candida isolates. T. vulgaris and M. piperita caused disruption of fungal cell membrane and its permeability also its mechanism, enzymatic dysfunction and growth [98].

Essential oils in VVC

Vapor-phase of EO

Oregano vapor phase of EO

Gas chromatography has been performed to analyze the vapor phase of oregano EO (VP-OEO) and evaluate its antifungal potential against resistant vaginal isolates like C. albicans (Ca1-Ca3), glabrata (Cg1-Cg8), krusei and guilliermondii. Findings of this study include; DC-OEO (direct control of EO) and VP-OEO showed 38.3 ± 1.2–68.0 ± 3.5 mm and 31.3 ± 2.3–57.3 ± 2.5 mm of Candida IZ respectively. The highest inhibitions zone (IZ) observed in Cg4 and Cg2 along with that, VP-OEO inhibits Ca2 and Cg8 biofilm and its mature form more effectively (Fernandes et al. 2023) [99].

Similarly in another study, Fernandes et al. 2022 characterized the antifungal effect of VP-OEO and vapor phase of white thyme EO (VP-WTEO) toward planktonic growth and compared it with resistance Candida biofilm formation on simulated vaginal fluid (SVF) and Sabouraud Dextrose Broth (SDB). Authors have observed that all EO has the potential to inhibit biofilm and its mature form. Ca2, Cg7 and Cgi1 isolate mature biofilm reduction observed after VP-OEO vaginal administration also candida inhibitions with its inhibition zone ranges from 27 to 77 mm found by VP-OEO exposure [100].

Tea tree Vapor Phase of EO, Cajeput and Niaouli EO

Similarly, the vapor phase of tea tree oil (VP-TTEO) and its antifungal potential have been conducted by Fernandes et al. against 13 vaginal isolates of resistance candida. In this study, it was found that biofilm inhibitions of Ca2 and Ck1 (2 Log CFU/ml), Cg7 (2.5 Log CFU/ml) and Cgi1 (4 Log CFU/ml) were observed. Mature biofilm with its metabolic activity reduction, Candida cellular membrane damage and altered hyphal activities found by VP-TTEO. It was found that VP-TTEO could be potentially used in VVC without any considerable toxicity [101].

Thymus albicans EO

Roxo et al. evaluated the antifungal (C. albicans) and anti-inflammatory properties of the aromatic plant T. albicans EO. From the biofilm inhibitions study, it was found that T. albicans EO promisingly inhibited fungal biofilm and complete inhibitions of germ tubes found at sub-MIC of 0.64 μl/ml concentrations. They also noticed that, considerable anti-inflammatory activity by reducing iNOS (inducible nitric oxide synthase) levels [102].

Mechanism of plant-derived drugs in combating VVC

There are various herbal drug modes of action (MOA) toward candida such as by inhibiting its pathogenic transitions to hyphae condition, membrane destabilization and permeabilization also enhancement of apoptosis observed [103,104]. Moreover, herbal-based drugs work by altering fungal extracellular matrix by reducing the amounts of polysaccharides in it [105]. Virulence factors of Candida such as biofilm inhibitions noticed after exposure to natural constituents, which works by decreasing the production of extracellular DNA [106]. Various terpenes reduced ERG2, ERG3 and etc gene expression to reduce the synthesis of ergosterol in C. glabrata species [107]. Various natural constituents enhance IFD6 gene expression which leads to inhibiting biofilm matrix production in Candida species [108]. In addition, H+-efflux, germ tubes and adhesins inhibition were also noticed after administration of herbal-based medication [109]. The major role of herbal medication in VVC is to overcome drawbacks like resistance in fungal strain through a different mechanism like efflux pump, ergosterol inhibitions and Ras-cAMP-PKA signalling pathways [110,111]. Some natural constituents also work via the reduction of an enzyme (aspartyl protease) activity in c. albicans occurs via ALS gene down-regulation [112] and induces oxidative stress, an energetic collapse that leads to rupture of yeast cells [113]. Figure 3 depicts a schematic representation of plant-derived drug MOA toward VVC.

Figure 3.

Comparison and relationship between herbal based drugs with nanoherbal formulation approaches for vulvovaginal candidiasis treatment options.

Herbal novel nano formulation in vaginal candidiasis

Nano-drug delivery systems have brought us various futuristic and advanced approaches with their optimized activity in recent years that can also be used in conjunction with traditional methods [114]. Figure 3 provides a comparative illustration between herbal-based drug MOA and integration of nanomaterials with plant-derived drugs, as it enhances its activity and overcomes various drawbacks related to herbal molecule delivery like penetrating to reach their target in active form, stability, compatibility and higher systemic bioavailability. This offers potential alternatives with enhanced tolerance against Candida by enabling plant-derived drug versatile release (pH sensitive, thermosensitive, targeted, controlled). It brings tremendous influence on therapeutic outcomes in patient-specific and non-specific complications [115]. Nanomaterials play a major role in providing synergistic activity with plant-derived drugs which provide advanced therapeutic action with the advancement of herbal medicine [116]. In the area of fungal infection, nanomaterials improve herbal drug distribution in tissue with less toxicity and reduce drug frequency [117,118]. Supplementary Table 3 provides an overview of various herbal-based novel formulations used in VVC.

Clove EO encapsulated on nanocarrier

This study implies that Clove EO-loaded nanoemulsified system to formulate a new semisolid pharmaceutical form for VVC treatment. In their study, they demonstrated that Emulgel formulations like Ecmc, Bcmc (carboxymethylcellulose-based) and Ealgi and Balgi (formulation on sodium alginate) showed no phase separation. Outcomes in their study were; MIC of clove EO (0.04%), Ecmc (51.25–102.5), Bcmc (0.09–25%), Ealgi (60.8–121.7) and Balgi (0.19–1.56%) reported respectively and morphology of Candida disrupts by Ecmc due to nanosystem droplet agglomeration reduction in VVC (Campelo et al.) [119].

Eucalyptus- & lemongrass EO-loaded nanoemulsion

Researchers have demonstrated that eucalyptus and lemongrass EO fabricated nano-emulsions efficacy as an efficient and suitable implementation across vaginal candidiasis cases and compared with standard drug Miconazole (Gündel et al.). As they investigated they found that, these EO-loaded nanoemulsion have shown better antifungal activity than miconazole cream and also showed anti-inflammation, biofilm interference, and greater penetration without any adverse events properties not only in vivo (no CFU observed) but also in in vitro experimental studies [120].

Ipomoea carnea Jacq- & Lavender oil-loaded gel

Kaushik et al. formulated eight carbopol 934-based herbal gels (pH ranges 6.82 ± 0.1 to 7.08 ± 0.2) containing 2, 4, 6% and 0.5, 1% w/w concentrations of methanolic leaves extracts of Ipomoea carnea Jacq and Lavender oil (LO). In their study they first time checked its potential on human beings Candida infection and from the antifungal study they observed that formulations like F6 (E-6%) and F8 (E-6% with LO-1%, carbopol-1%) showed higher zone of C. albicans inhibition. F6 comparatively exerted Candida zone of inhibition than Himalayan V and itraconazole gel against all strains of candida collected without any signs of inflammations noted as compared with marketed drugs [121].

Cymbopogon nardus EO incorporating microemulsion (ME)

Nardus EO loaded (ME + EO) and unloaded (ME) microemulsion and its anti-candida potential have been evaluated by performing in vitro and in vivo studies on C. albicans (CA-ATCC 10231 and CAV strains). Within their study, they observed that MIC and MFC of 31.2/>500 (CA-ATCC 10231) and 62.5/>500 (CAV) exhibited by ME + EO formulation also fungal dead cells and ergosterol membrane disruption found after ME + EO administration. It was also noticed that, after 2, 4, 6 and 8 days of herbal nanoemulsion exposure, no. of infected animals drastically reduced with less cytotoxicity effect (Gaspar de Toledo et al.) [122].

Syngonanthus nitens (Bong.) Ruhland-based nanoemulsion

Ramos et al. developed intra-vaginal delivery of nanoemulsion (F9) by first time loading 12 fractions from S. Nitens methanolic extracts (F9Fr3) and without extracts loading (Fr3) against ATCC 1023 and fluconazole resistance strains like CAV3 and CAS1. During their study investigators reported that the highest anti-microbial potential was exhibited by Fr3 at MIC of 62.5 (ATCC 10231 and CAS1) and MIC 125 μg/ml (CAV3). Comparatively best anti-candida potential was observed by Fr3 loaded nanoemulsion system, on the other hand lesser zone of fungal load was found after 2, 4, 6 and 8 days exposure of F9Fr3 formulation [123].

Syngonanthus nitens Bong. (Rhul.)-based nanostructured system

In another study by Ramos et al. they have similarly formulated and evaluated a liquid crystal precursor system by loading S. Nitens methanolic extracts (SE) and without loading extracts (E) against resistance ATCC 10231 and CAV1, CAV2, CAV3, CAV4 vaginal clinical strains. From the evaluation of the in vitro mucoadhesion study it was reported that compared with S and SE; formulations like S100 and SE100 got maximum mucoadhesive properties. Candida hyphae growth inhibitions have been observed by both S and SE nano formulations after 12 and 24 h of administration [124].

Mucoadhesive liquid crystalline system

p-Coumaric acid mucoadhesive liquid crystalline system

Ferreira et al. 2021 have demonstrated the in vitro and in vivo anti-Candida potential of the p-Coumaric (p-CA) acid loaded liquid crystalline (LC) system to increase its solubility and activity. In their study, 84.5% of p-CA release was observed within 2 h and then constant release was found after 4 h. P24 formulation and fluconazole showed 100% biofilm eradication and it was also noticed that clearance of fungal load and its filamentous form was obtained very effectively after herbal-based system exposure. Authors concluded that this could be a potential antifungal approach against clinical signs and symptoms of VVC [125].

Curcumin mucoadhesive liquid crystalline system

Similarly in another study of Rodero et al. they have taken 1% chitosan to develop a Curcumin-loaded mucoadhesive liquid crystalline system (MCLC) toward clinical strains (CAV4). Curcumin-loaded (F13-CUR and F19-CUR) formulation got great mucoadhesion properties on the vaginal mucosa. From an antifungal study, it was found that rather than unloaded, loaded curcumin MCLC-based systems have greater anti-Candida potential in collected Candida strains. An in vivo study has reported that the infection rate comparatively lowered after herbal-based novel formulation administration [126].

Pelargonium graveolens EO-loaded hydrogel

Santos et al. have formulated a mucoadhesive nanoformulation comprising P. Graveolens EO from various regions (Brazil, Egypt, South Africa, China, Reunion Island-Bourbon, and Albania). They have formulated various formulations like 10% of P. graveolens EO loaded (NPG) nanoemulsion, chitosan hydrogel thickened nanoemulsion (HCNPG), EO unloaded nanoemulsion (NB) and chitosan hydrogel thickened nanoemulsion (HCHI). In their study, they found that EO formulation from South Africa exhibited the best anti-candida activity compared with other regions. The best mucoadhesion properties are provided by HNPG and HCHI formulations compared with others [127].

Lycopene-loaded mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSN) were developed by Carvalho et al. to overcome lycopene lowest aqueous solubility. At MIC and MFC of 500 μg/ml, lycopene and MSN-C (calcination treatment) exhibited anti-candida activity to clinical azole resistance. From this study, it was observed that lycopene-loaded MSN showed the slightest good antifungal activity by obstructing Candida membrane integrity without showing any toxicity [128].

Clove & tea tree oil (TTO) oilmix thermosensitive gel

Alkhanjaf et al. have formulated a mixture of clove and TTO (3:1 w/w ratio of Oilmix) loaded mucoadhesive stable thermo sensitive vaginal gel (MTS) and characterized its synergism antifungal potential during VVC. Carbopol 934 (CP 934) and Poloxamer 407 (POX 407) polymers have been taken to develop MTS gel by composing four batches. Out of that, 0.4% of CP 934 and 20% of POX 407 containing B4 (optimized batch) have comparatively got maximum detachment force (MDF). Cytotoxicity activity was found to be negative and from the ex vivo drug permeation study it was found that, a higher permeability coefficient was shown by the B2 batch. It was noticed that Omix-loaded B4 optimized gel comparatively got maximum candida clearance than conventional gel consisting of Clove and TTO [129].

Silver nanoparticles

Artemisia annua mediated silver nanoparticles

Khatoon et al. have demonstrated invitro anticandida potential of 5% extracts of Artemisia annua loaded biologically synthesized silver Nanoparticle (AgNP) at MIC/2, MIC/4 and MIC/8 against collected C. albicans, glabrata and tropicalis strains. In their study, they compared MIC/2, MIC/4, MIC/8 and MIC of A. annua synthesized AgNP with control (untreated cells) and 10 mg/ml of fluconazole. The control showed zero activity and considerable ergosterol suppression of Candida exerted by fluconazole. Whereas Candida growth was dramatically inhibited by 4/MIC of herbal synthesized AgNP compared with others [130].

Aqueous honey solution silver nanoparticles

Czernel et al. have formulated 2, 10 and 20% of concentrations of aqueous honey solution synthesized silver nanoparticle (AgNP-H)-based formulations like AgNPs-H2, AgNPs-H10, and AgNPs-H20. They have compared the antifungal potential of the herbal nanoparticle bases system with the marketed standard drug amphotericin B and fluconazole (controls). Researchers demonstrated that the best anti-candida activity observed at MIC of 0.5 μg/ml by 2% honey concentration synthesized AgNPs. Higher inhibitions of Candida exhibited by AgNPs-H20 (1 μg) and authors also concluded that this could be a potential antifungal therapy that could be used further [131].

Miconazole- & farnesol-loaded polymeric nanoparticle

Costa et al. 2017 have demonstrated and evaluated the in vitro and in vivo antifungal potential of miconazole (NQ-MI) and farnesol (NQ-F) loaded mucoadhesive nanostructured (Chitosan) system against ATCC 28367 candida strains. From the nanoparticle (NP) cytotoxicity study it was observed that, up to 125 μg/ml concentrations of miconazole, no toxicity was observed also negative cell viability reduction was noticed by any concentrations of farnesol. Candida pathogenic (yeast to hyphae) transition inhibited by NQ-F also 45.7 and 47% of yeast cell reduction observed in NQ-F and NQ (empty nanoparticle) as reported [132].

Propolis-loaded PLGA nanoparticles

Iadnut et al. have evaluated anti candida potential of three polylactic glycolic acid nanoparticles having propolis ethanolic extracts such as EEP-NP 1, EEP-NP 2 and EEP-NP 3 with mean particle size >500 nm. In their study, they investigated that, Candida metabolic activity reduced to 60% at 2.5 mg/ml concentration of EEP-NP 2 formulation and 40% Candida adherence and morphogenesis suppressed by herbal NP2 (EEP-NP 2) at every concentration. Also, 52.6% of hyphal germination and 55.3% of biofilm inhibitions were noticed by propolis NP2 (propolis encapsulation efficiency-91.5 ± 0.9%). Expression of ALS3 mRNA reduced with less toxicity after EEP-NP 2 exposure [133].

Mentha essential oil (MEO)-based emulgel

In the present study, the in vitro and in vivo antifungal potential of MEO have been characterized by encapsulating it into nanoemulsion-based emulgel systems (F2) such as F0 (placebo) and F1 (2% MEO loaded simple gel) respectively. Percentage of 4.2 ± 0.234 drug found in optimized emulgel formulation also after 90 days no signs of phase separation found in emulgel. Emulgel exhibited 10.00 ± 0.58–12.67 ± 2.66 and simple gel got 2.33 ± 1.20–4.00 ± 1.16 of zone of all tested candida growth inhibitions meanwhile clotrimazole exhibited 13.33 ± 1.76–18.67 ± 0.88 of zone inhibitions (Srivastava et al. 2018) [134].

Lavendula angustifolia-loaded chitosan nanoparticle

Naggar et al. developed bio fabrication of Lavendula angustifolia into chitosan nanoparticles to evaluate its in vitro anti-biofilm activities. From Candida anti-biofilm assay it was come to know that, 66.4 ± 1.76% of C. albicans biofilm architecture necrotization was observed at 1500 μg/ml concentration. Analysts noticed that the present formulation has significant inhibitions of fungal cell proliferation activities and could have upcoming uses in VVC treatment [135].

Patents & clinical trials

Numerous researchers have put forward innovative herbal methods for the treatment of vaginal candidiasis with the intention of obtaining patents to foster further advancements.

While several clinical trials have been conducted but to the best of our knowledge, only one herbal-based approach involving a vaginal suppository containing cumin seed extracts for VVC, has been identified in clinical trial databases [136]. Supplementary Table 4 enlists a compilation of patents and clinical trials related to herbal-based formulations used in the treatment of fungal infections [137–147].

Conclusion

In this review, we outlined and highlighted upcoming values and scope of existing and emerging information regarding the possibility of using various natural constituents and integrated herbal activities with nanotechnology that got futuristic anti Candida potential.

Future perspective

Due to the fast developing resistance of currently available anti fungal drugs, it is necessary to find various herbal approaches with novel mechanism that could be used to combat and addressed these drawbacks of standard medication with multiple human values in next few decades [148]. There are various natural constituents like above mentioned medications got potent anti fungal activities yet unexplored could be come under VVC treatment options in future according to multiple aspects [149]. According to former studies, herbal combinations and combinations having medicinal plants/EO with standard drug also its synergistic activity could effectively exhibited high quality anti-Candida relevance with less side effects and toxicity [150]. Also there are recently various novel strategies like biomimetic that could be used to encapsulate natural cell into targeted delivery of drug toward VVC treatment. Biomimetic got the potency naturally targets and strongly binds with C. albicans and deeply penetrate vaginal epithelial tissue. This strategy got potential anti fungal activity and eradicates Candida in both vaginal fluid and tissue. Along with that phototherapy could be a potential alternative strategy to overcome C. albicans resistance problem via target and bind with C. albicans and simultaneously neutralize the candidalysin. Phototherapy also works by transforming C. albicans toxins which related to infection and resulting effective anti-C. albicans efficacy [151,152].

Author contributions

M Dalabehera: wrote the whole manuscript, draw figures and tables, C Rathore: study concept and design, A Rathee: draw chemical structure, UR Lal: investigation and visualization.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Present review provides required herbal molecule and combinations with recent advancement based formulation that shows promising anti candida activity in VVC as it embrace herbal activity and overcome challenges associated with delivery of herbal drug like penetrate to reach their target in active form, stability and compatibility. This offers potential alternatives with enhanced tolerance against candida. In this context numerous reported studies came up with either herbal formulation their implementation solely. But neither of them concerns regarding compilations of various summarized study regarding herbal and its combinations activities, comparison between herbal molecule and synthetic drug, novel nanoherbal formulations, clinical trials and patents. And their uses against candida that could be implement further towards benefits of mankind.