Keywords

1 Introduction

In past decades, herbal active principles and natural remedies are being used to cure diseases. The employed herbal active principles are alkaloidic, phenolic, flavonoidic, and polyphenolic in nature. Vitamin C, citric acid, and other phytonutrients present in plant-derived products work jointly to fight against a specific disease (Mahesh et al. 2021a, b). Herbal therapeutic agents need a scientific approach to modify the active principle to change the delivery pattern that suits sustained and target release. This approach helps to increase patient compliance and avoids frequent dosing. As per the reports published by so many researchers, nanotechnology is the best alternative to overcome the toxicity and bioavailability problems associated with conventional dosage forms (Mitchell et al. 2021). The global market assumes the faster growth of the nanotechnology market from $5.2 billion in 2021 to $23.6 billion by 2026 with a 35.5% of growth rate (Dublin-Business Wire 2021).

Extensive research in the field of phytonanoformulations can improve the volume of innovative products, with lesser side effects than existing synthetic and conventional herbal formulations. Researchers investigated various herbal drug delivery techniques to suit the diversified structures of natural compounds, at the same time without loss of any physicochemical and biological properties. World Health Organization (WHO) has provided the suitable technical aid to expand a methodological analysis of plant-derived drugs for safety and quality aspects.

Among the Indian population, approximately 65% of people show interest to use traditional medicines. People of developed countries also demand herbal drugs as well. There is a steady demand for traditional medicines in developed countries. India is in second place, behind China in the herbal market. The AYUSH system of India presently covers 8000 herbal remedies with a domestic market worth of $5 billion.  Annually over half a billion dollars revenue is generated through Ayurveda, Siddha, and Unani. The global market expects a profit of 111 billion  dollars through plant-based medicines by 2023. Still, the phyto-pharma sector is in a nascent stage in India and in so many developed countries. The advancements in nanotechnology and advantages of nanoformulations over conventional products may increase the demand for phytopharmaceuticals, thereby offering an excellent opportunity for phytonanoformulations shortly.

The new research approaches in novel drug delivery systems can allow pharmaceutical companies to explore phytonanopharmaceuticals more constructively (Business World 2021).

The combined knowledge of science and technology directs the synthesis of nanoparticles to develop various nanotherapeutics and diagnostic agents in 1–100 nm size range.

Nanoparticles offer the following advantages over conventional formulations (Pandit et al. 2022).

  1. 1.

    Improved solubility thereby enhancing the bioavailability

  2. 2.

    Increased resident time in the body

  3. 3.

    Promotes targeted drug delivery

  4. 4.

    High carrier capacity with high stability

  5. 5.

    Maintenance of balance between efficacy and toxicity of a therapeutic compound.

1.1 Different Approaches to Synthesize Phytonanoparticles

Currently, various approaches are available to incorporate the herbal active principles into nano delivery vesicles to reach the target thereby being involved in the enhancement of therapeutic activity. Figure 1 outlined various approaches in the synthesis of phytonanoformulations (Roy et al. 2022).

Fig. 1
A model diagram identifies various approaches for preparing phytonanoformulations, including nanoparticles, magnetic nanoparticles, liposomes, carbon nanotubes, dendrimers, micelles, solid lipid nanoparticles, nanosponges, Niosomes, and Transferosomes. Each part explanation is described.

Various approaches in the synthesis of phytonanoformulations

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Phytonanoparticles have wide applications in various sectors like agriculture, medicine, and industry. Figure 2 briefly depicts the applications of phytonanoparticles in various fields (Ahmed et al. 2021).

Fig. 2
A model diagram illustrates different applications of phytonanoparticles in various fields. There are nodes for agriculture, environment, cosmetics, medical, diagnosis, drug delivery, and industrial. Each node has specific applications listed on the right side.

Thrust areas of phytonanoformulations

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The smaller size and greater surface capacity of a drug containing nanoparticles may establish the rise in solubility and facilitate the bioavailability, in addition, overcome the barrier limitations in various routes of administration. Undoubtedly, people who are taking the conventional herbal formulations for various conditions may shift to the biogenic phytonanoformulations because of their added advantages. The advancements in nano-drug formulations and their delivery can occupy a significant market place and motivate various manufacturers involved in herbal formulations in the coming future (Abhijeet et al. 2021). Figure 3 describes the schematic depiction of phytonanoformulation synthesis and its uses.

Fig. 3
A schematic diagram depicts the collection of plant parts like fruit, rizome, flower, bark, leaf, root, and seeds for the formulation of active principles into Liposomes, Silver NPs, Nanorods, S L N Ps, Nanoemulsion, Z n O N Ps, then use for biomedical applications anti cancer, anti-microbial, thrombolytic, neurodegenerative, and metabolic disorders.

Schematic depiction of phytonanoformulation synthesis and their potential uses

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The following section highlights the biomedical applications of herbal nanoformulations that were fabricated with various phytoactive principles.

2 Phytonanoformulations and their Diversified Therapeutic Applications

2.1 As an Anticancer Agent

Targeted drug delivery of nanoformulations overcomes the insolubility and toxicity problems associated with conventional chemotherapeutic agents against cancer. The anticancer activity containing bioactive molecules is isolated from abundant plant parts like fruits, flowers, grains, etc. Plant-derived phyto-medicines are comparatively harmless and well compatible in healthy cells even in high doses than synthetic chemotherapeutic agents. Numerous examples of phytonanoparticles that are currently utilizing for cancer treatment are summarized here.

Extracts of various parts of Moringa oleifera reported anti-cancer activity (Charlette et al. 2018). Gold nanoparticles (AuNPs) were synthesized by flower parts of this plant (Anand et al. 2015). Niazimicin is the active principle found in M. oleifera that ascribes to anticancer activity. The flowers are fabricated to AuNPs that are cytotoxic to lung cancer cells (A549). The anticancer potentiality also exhibited against MCF7 (Michigan Cancer Foundation-7), HCT116 (human colorectal carcinoma)/Caco2 (human colorectal adenocarcinoma cells), and HepG2 (Human hepatoma cell line) cells with the nanoformulations of leaves and roots of the plant (Abd-Rabou et al. 2017).

Syzygium cumini fruit (Malabar plum) extract was used for formulation of AgNPs and exhibited significant anti-neoplastic and antioxidant potential on Dalton lymphoma cell lines (Mittal et al. 2014).

AgNPs derived from Origanum vulgare (Oregano) plant extract have high amounts of monoterpenoid phenols, exhibited increased anti-neoplastic activity on lung carcinoma culture (A549) with increased concentration (Sankar et al. 2013).

Compared to other chemotherapeutic drugs, AgNPs synthesized by green technology using Morinda citrifolia (MC) (Noni fruit) exhibited a higher cytotoxic effect against HeLa (cervical carcinoma cells of Henrietta Lacks) cell lines (Suman et al. 2013).

Zinc oxide nanoparticles (ZONPs) of Salvadora persica (toothbrush tree) extract were synthesized under optimum conditions (Miri and Sarani 2019).

Apigenin is a familiar class of flavanoid obtained from parsley, chamomile, celery, vine-spinach, artichokes, and oregano. Apigenin exhibits anticancer activity by the following mechanisms such as apoptosis of cells and autophagy, regulating cell cycle, hampering the cell migration, invasion, and initiating the immune responses (Yan et al. 2017). Different nanoformulations of apigenin and its anticancer potential were shown in Table 1.

Table 1 Phytonanoformulation as anticancer agents (Abd-Rabou et al. 2017; Mahesh et al. 2021a, b; Yongvongsoontorn et al. 2019; Wang et al. 2018a, b; Manatunga et al. 2017; Minaei et al. 2016; Zhang et al. 2018; Zhu et al. 2017; Hu et al. 2018; Wang et al. 2015)
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Resveratrol is a phytoestrogen obtained from grapes, peanuts, cocoa, and berries of Vaccinium species. Because of its significant and multi-activity against many cancers, it has drawn so many researcher’s attention (Jiang et al. 2017). The nanoformulations developed using resveratrol improved the solubility, bioavailability, and reversed the drug resistance acquired in transformed cell lines (Mondal and Bennett 2016). Some of the resveratrol nanoformulations and their potential uses were described in Table 1.

Curcumin, the bioactive principle isolated from the Curcuma longa roots. Curcumin is the familiar traditional herbal component employed in various applications like heart burn, ulcerative colitis, antiseptic, and antimalarial agent (Wilken et al. 2011). A list of the curcumin nanoformulation was shown in Table 1 with their potential uses.

Green tea contains a profuse amount of polyphenolic catechins which shows its impact on cancer cells proliferation, growth, and metastasis. Because of its less stability and low solubility, results in poor bioavailability. Table 1 describes the EGCG nanoformulations with their advantages compared to the conventional formulation.

Ginger is the most common spice used abundantly for the treatment of various ailments. The isolated herbal active principle, 6-Gingerol, was formulated into nano-composites to conquer the obstructions associated with traditional formulation thereby to enhance the medicinal activity. Gingerol nanoformulations were listed with their biological activity in Table 1.

Various fruit and vegetables such as apples, onions, and red grapes contain a profuse amount of quercetin (QUR), which is a pentahydroxyflavone, evidenced to exhibit diversified pharmacological benefits (Kulisic et al. 2012). Verma et al. (2013), delivered formulated core–shell structure of magnetic NPs of QUR through nebulisation and studied the cytotoxic capability of QUR against cancer carcinoma cells. Anticancer activities of quercetin in combination with other chemotherapeutic agents were shown in Table 1.

In addition to the examples covered under Table 1, some other researchers had investigated multiple nanoformulations loaded with phytoactive principles for anticancer activity (Amer et al. 2021).

2.2 As Antimicrobial Agents

Plant and plant derivatives of nanoformulations are extensively used in chronic wound gauzes, tissue grafts, drips, and blood transfusion sacks because of their germicidal activity. The potential antimicrobial activity of various phytonanoformulations has been studied collectively on bacterial pathogens, fungal, and viral microorganisms (Roy and Bharadvaja 2019). Because of the added advantages, all the phytonanoformulations exhibit better antimicrobial activities than the traditional herbal formulations.

The active principles of plant parts can enhance the native germicidal activity of AgNPs (Elani et al. 2018). The AgNPs fabricated with phytochemicals altered permeability property of membrane and lead to destruction of Candida sp. and allow the intracellular components to burst out from fungi (Logeswari et al. 2013).

Shyam et al. (2016), studied the formulation of AgNPs using Saraca indica leaf extract. This was utilized to determine the antibacterial capability on Escherichia coli, Staphylococcus aureus, and Micrococcus luteus, exhibited potential antibacterial activity with round-shaped AgNPs of herbal extract.

Homogenous root extract of S. persica utilized in formulation of AgNPs and was examined its activity on two bacterial pathogens (Arshad et al. 2021).

Ag and AuNPs synthesized from rhizome extract of C. longa exhibited significant activity on commonly occurring contaminants (Sharma et al. 2020). The freely soluble extract of Angelica pubescens Maxim was broadly used to make AgNPs to control pathogenic bacteria (Markus et al. 2017).

Leaf extract of Garcinia mangostana-based AgNPs were expressed activity on various drug-resistant pathogens. Artemisia nilagirica (Asteraceae)-based AgNPs also displayed superior action on numerous organisms. AgNPs of marine seaweed Sargassum wightii showed effective antibacterial activity against S. aureus, Klebsiella pneumoniae, and Salmonella typhi. Silver NPs of Ocimum sanctum leaf extract, Origanum vulgare (Oregano), Coptidis rhizome, Carissa carandas (Karonda) berry water extract, and Salicornia bigelovii displayed competent antibacterial activity on common microbes that comparable with generic antibiotics.

Plant-based AgNPs also exhibited antifungal activity against various fungal pathogens. The most commonly occurring fungal infections are due to Candida species (Wilson 2019). Recent studies showed the inhibition of opportunistic human fungal pathogens with Tulsi (O. sanctum)-mediated AgNPs (Rout 2012). Synthesized AgNPs with extracts of Shoreatum buggaia, Boswellia ovalifoliolata, and Svensonia hyderobadensis showed inhibitory activity against different species of Aspergillus niger, Aspergillus flavus, Curvularia sp., Fusarium sp., and Rhizopus sp. (Savithramma et al. 2011). Svensonia hyderobadensis showed higher anti-fungal activity with other nanoformulations compared to synthesized AgNPs.

Plant-based AgNPs were reported to contain bioactive principles isolated from various plants and exhibited antiviral activity against feline coronavirus (FCoV), Influenza virus, HIV, Adenovirus, Herpes simplex virus, Dengue virus, Chikungunya virus (Sharma et al. 2019), and Norovirus. The intrinsic antiviral activity of AgNPs is demonstrated by different mechanisms by inhibiting viral reproduction or by denaturing viral protein (gp120) that can block the entrance into host cells. A list of the phytonanoformulations with antiviral activity were shown in Table 2.

Table 2 Phytonanoformulation as antiviral agents
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2.3 As Wound Healing Agents

Wounds are if unprotected, susceptible to microbial attack and pathogenesis. Wound dressings loaded with phytonanoparticles provide certain advantages such as reduction in healing time, inhibiting a variety of bacterial organisms, and exhibiting more antibacterial activity than AgNPs. Wound dressings encapsulated with phytonanoparticles are used in the control of burns, chronic ulcers, and diabetic foot ulcers (Cavanagh et al. 2010). Table 3 described some examples of wound dressings loaded with phytonanoparticles.

Table 3 Phytonanoformulations as wound dressings
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2.4 As Drug and Gene Delivery Agents

The main objective of nanoformulation is the site-specific release of entrapped drug formulations. A green approach to nanoparticle synthesis is finding a way to overcome the toxic effects associated with synthetic nanoparticles. Trichoderma viride AuNPs conjugated with vancomycin are very effective in the suppression of vancomycin-tolerating S. aureus at minimum concentration (Mohammed Fayaz et al. 2011). Nps of Butea monosperma leaf extract was fabricated and conjugated with anticancer drug doxorubicin showed enhanced anticancer activity by inhibiting cell proliferation. Another study showed the effective delivery of doxorubicin by Peltophorum pterocarpum mediated green-synthesized AuNPs (Patra et al. 2015).

2.5 In Neurodegenerative Disorders

Functional and structural damage of nerves leads to neurodegenerative disorders (NDs). The changes in the nervous system may result in retardation in thinking, motion, perception, and recollection. Alzheimer’s disease (AD) and other types of dementia, Parkinson’s disease (PD), and PD-related other disorders are most common NDs; multiple sclerosis (MS), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS) are the most frequent types. Worldwide, for every four members, one person is going to suffer from NDs (Hodjat et al. 2017). Researchers have been reported the therapeutic benefits of herbal active principles in NDs patients. Phytochemicals such as polyphenols (Davatgaran-Taghipour et al. 2017), alkaloids (Wang et al. 2018a, b), and terpenoids (Khazdair 2015) from a variety of plants were extensively studied and reported. Nanoformulation-based phytochemicals are superior than the conventional dosage forms for curing neurodegenerative disorders-targeting delivery to brain, break down naturally, low toxicity to peripheral organs, modulation of inflammatory events, neuronal tissue restoration, inhibit neural apoptosis or toxicity, and regulate other functions (Seyed et al. 2020). Table 4 describes the phytonanoformulations with their uses in neurodegenerative disorders.

Table 4 Phytonanoformulations in neurodegenerative disorders (Seyed et al. 2020)
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2.6 As an Anti-Diabetic Agent

Phytonanoformulations are studied extensively in the treatment of diabetes mellitus. Nanotechnology-based phytoformulations are recommended for improved therapeutic efficacy against diabetes mellitus (Kesharwani et al. 2018). Nanophytoformulations offer all the advantages of nanoformulations such as delivery of drugs precisely to the target, allowing the various routes of administration, enhanced systemic availability, improved stability of drugs, and reduced risk of toxicity. Table 5 highlighted the plant-based nanoformulations against diabetes. The researchers have investigated the pharmacological effects and enhanced biopharmaceutical properties with various phytoactive principles containing nanoformulations such as rosmarinic acid, berberine, Stevia glycosides, Asiatic acid Glycyrrhizin, α-Eleostearic acid, Scutellarin, Silybum Flavonolignans, Gallic acid, Catechins, Pelargonidin, Thymoquinone, and Ferulic Acid.

Table 5 Phytonanoformulations as anti-diabetic agents (Dewanjee et al. 2020)
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2.7 In the Treatment of Metabolic Disorders

Metabolic disorder or the syndrome is a group of medical conditions that leads to an unhealthy condition in humans. Metabolic syndromes increase the risk of cardiovascular disorders such as atherosclerosis, obesity, resistance to insulin, hypertension, cerebrovascular accident, and atherogenic dyslipidemia (McCracken et al. 2018).

Several phytopharmaceuticals are fabricated into nanoformulations that induce molecular mechanisms against diverse pharmacological targets. Table 6 described the list of phytoactive principles and nanosizing methods employed with their improved pharmacological activities.

Table 6 Phytonanoformulations in the treatment of metabolic disorders
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2.8 As Thrombolytic Agents

To overcome the limitations associated with currently available thrombolytic agents, researchers have investigated various plant-derived products for thrombolytic activity (Ali et al. 2021). Akinola et al. (2020) reported the phytosynthesized TiO2 NPs of distinct Cola nitida plant parts and investigated for thrombolytic activity. Phytosynthesized AgNPs incorporated with leaf and seed extracts of Synsepalum dulcificum were reported for thrombolytic activity (Lateef et al. 2016).

3 Conclusions and Future Prospective

Synthesis of nanoformulations using phytoactive principles is an efficient and eco-friendly method to deliver the therapeutic agent to a specific target. Products extracted from plants have numerous bioactive principles of both reducing and stability properties to with stand the reaction conditions while synthesizing phytonanoformulations. The derived phytonanoformulations offer advantages like improved solubility, thereby enhancing the bioavailability, maintenance of parity between efficacy and toxicity of a therapeutic compound. The synthesized nanoformulations find agricultural, environmental, cosmetic, medical, diagnostic, drug delivery, and industrial applications. The tremendous growth of nanotechnology supports the fabrication of bioactive principles of plant into phytonanoformulations. Because of less toxicity, the natural plant formulations are might be good competitors to the synthetic nanoformulations in the coming future. It is necessary to describe the biomolecular interaction of NPs and the regulation of gene expression. Further investigation is needed for the molecular and submolecular level functions of nanophytoformulations.