Nanoherbals: A Modern Approach in Herbal Medicine

Herbal medicines have been integral to human healthcare for millennia, with documented systems like Ayurveda, Traditional Chinese Medicine, and Unani dating back over 5,000 years [1]. These traditional remedies remain deeply rooted in modern healthcare due to their perceived safety, holistic benefits, and affordability. However, their widespread acceptance is constrained by intrinsic limitations—particularly poor aqueous solubility, instability, and low bioavailability of active phytoconstituents [3]. Nanotechnology has emerged as a transformative solution to these challenges. By integrating herbal constituents into nanoscale delivery systems—such as liposomes, nanoemulsions, polymeric and solid lipid nanoparticles—researchers have significantly enhanced solubility, stability, and absorption, while enabling controlled and targeted release of bioactive compounds [3]. This convergence of nanotechnology and phytotherapy gives rise to the concept of nanoherbals—a modern adaptation of herbal medicine utilizing engineering at the nanoscale.

Figure 1: Nanoherbals: A Modern Approach in Herbal Medicine – from traditional herbal challenges to nanotechnology integration, applications, and future prospects

Recent reviews have captured the breadth of these developments. Applications span across diverse herbal nanosystems that bolster therapeutic efficacy, broaden drug delivery routes, and circumvent pharmacokinetic hurdles typical of conventional herbal formulations [1]. A bibliometric analysis of the field further highlights its rapid expansion, identifying key research hotspots, prevalent delivery platforms, and evolving trends in the use of herbal nanoparticles from 2004 to 2023 [6]. Despite their promise, nanoherbals also pose challenges—standardizing herbal raw materials, ensuring long-term safety and biocompatibility, scaling up manufacturing, and navigating regulatory landscapes remain major hurdles [7]. In summary, nanoherbals represent a powerful fusion of age-old medicinal wisdom with cutting-edge nanotechnology. This hybrid approach seeks to enhance therapeutic outcomes, improve pharmacokinetic profiles, and broaden delivery options, heralding a new chapter in herbal medicine. In the following sections, this review will delve deeper into the applications, technical underpinnings, advantages, hurdles, and future prospects of this promising field.

3. What are nanoherbals?

3.1 Concept and Definition

Nanoherbals, also known as herbal nanoparticles, represent an advanced delivery system where bioactive compounds from medicinal plants are encapsulated within nanoscale carriers (typically 1–100 nm) to enhance their therapeutic properties. These nanoparticles are formulated using techniques such as green synthesis, ionic gelation, coacervation, or encapsulation in nanocarriers like liposomes or polymeric nanoparticles [20]. Herbal nanoparticles merge the wisdom of traditional herbal remedies with cutting-edge nanotechnology, aiming to overcome limitations such as poor solubility, instability, and low bioavailability [10]. They deliver herbal actives more effectively, while reducing toxicity and enabling targeted delivery [3].

3.2 Nanotechnology Principles Applied to Herbal Medicine

Nanotechnology enhances herbal medicine through several fundamental principles:

• Nanosizing for Improved Solubility & Stability: Reducing the particle size of herbal actives increases surface area, facilitating better dissolution and protecting labile compounds from degradation [1].
• Encapsulation in Nanocarriers: Herbal extracts are loaded into liposomes, nanoemulsions, polymeric nanoparticles, solid lipid nanoparticles (SLNs), niosomes, and more—enhancing compatibility, protection, and controlled release [3].
• Controlled & Sustained Release: Nanocarriers allow gradual release of the herbal actives, maintaining therapeutic levels and reducing dosage frequency [8].
• Targeted Delivery & Enhanced Permeability: Nano-scale particles can pass biological barriers effectively—exploiting the Enhanced Permeability and Retention (EPR) effect for passive targeting and potentially further functionalized for active targeting [10].
• Biocompatibility & Lower Toxicity: Many nanocarriers use biodegradable polymers and natural materials, offering safer profiles than conventional systems [14].
• Green Synthesis Approaches: Some nanoherbals are produced via eco-friendly methods using plant-derived agents—avoiding toxic chemicals while ensuring enhanced bioactivity, safety, and environmental sustainability [13].

3.3 Key Objectives of Developing Nanoherbals

The development of nanoherbals aims to address multiple therapeutic and formulation challenges:

• Enhance Solubility and Bioavailability: Many phytoconstituents are hydrophobic; nanoformulations improve their absorption and systemic availability [1].
• Protect Herbal Actives: Encapsulation shields unstable compounds from environmental degradation, preserving efficacy [10].
• Provide Controlled & Sustained Drug Release: Offers prolonged therapeutic activity and better dosing compliance [13].
• Targeted & Site-Specific Delivery: Enhances delivery precision to disease sites (e.g., tumors, brain, inflamed tissues), improving effectiveness and reducing side effects [10].
• Improve Safety and Reduce Dosage: Increased efficiency enables lowering therapeutic doses, minimizing adverse effects [8].
• Enable Novel Applications: Nanoherbals extend herbal usage into areas like cancer therapy, neurodegenerative disease management, wound healing, cosmetics, nutraceuticals, and functional foods.

3.4 Traditional Herbal Formulations vs. Nanoherbals

Table 1 Traditional Herbal Formulations vs. Nanoherbals

4. Types of Nanoherbals

Nanoherbals encompass a variety of nanoparticulate delivery platforms designed to enhance the bioavailability, stability, and therapeutic efficacy of herbal compounds. Below are key types employed in current research:

4.1 Polymeric Nanoparticles (PNPs)

These are biodegradable particles—often made from polymers such as PLGA, chitosan, or natural polymers—designed to protect herbal actives, enable controlled release, and cross physiological barriers (e.g., for CNS delivery) [14].

4.2 Nanocapsules & Nanospheres

• Nanocapsules: Comprise a core–shell architecture where herbal actives reside in the inner core, enclosed within a polymeric shell.
• Nanospheres: Dense, matrix-like structures that encapsulate actives within a polymer network [21].

Figure 1 Types of Nanoparticles

4.3 Solid Lipid Nanoparticles (SLNs)

SLNs are made of solid lipids, offering enhanced stability, protection against degradation, controlled release, and improved bioavailability of herbal actives [14].

4.4 Nanostructured Lipid Carriers (NLCs)

These are advanced lipid systems combining solid and liquid lipids, thereby providing higher drug loading, better stability, and improved release profiles compared to SLNs [17].

4.5 Liposomes

Phospholipid bilayer vesicles that encapsulate herbal molecules in an aqueous core—offering biocompatibility and enhanced delivery efficiency [18].

4.6 Nanoemulsions

These are fine oil–water emulsions stabilized by surfactants, excellent for improving the solubility, dissolution, and skin or oral absorption of herbal extracts [19].

4.7 Micelles & Phospholipid Micelles

Self-assembling amphiphilic aggregates that enhance solubilization and delivery of hydrophobic phytochemicals [12].

4.8 Dendrimers

Highly branched, tree-like nanostructures that can load multiple herbal molecules simultaneously, offering high payload and potential for targeted delivery [14].

4.9 Metallic & Inorganic Nanoparticles

Nanoparticles composed of metals like gold or silver, utilized for their unique physicochemical and therapeutic properties—e.g., enhancing anticancer activity when used with herbal compounds [20].

4.10 Magnetic Nanoparticles & Quantum Dots

Used for diagnostics and as specialized payload carriers; quantum dots also serve imaging roles due to their fluorescent properties [14].

4.11 Other Systems (Micelles, Micellar Systems, etc.)

• Polymeric Micelles: Stable assemblies for hydrophobic phytochemicals [14].
• Nanomicellar Systems, Nanotubes, Nanogels: Emerging platforms explored for their unique structural and functional capabilities [21].

5. Key Characteristics of Nanoherbals

5.1 Enhanced Solubility & Bioavailability

Nanoherbals significantly improve the solubility and bioavailability of poorly water-soluble phytoconstituents. By reducing particle size, these systems increase surface area and facilitate better dissolution and absorption [1].

5.2 Improved Stability & Protection

Encapsulation within nanoparticle systems shields herbal actives from degradation due to light, heat, enzymes, and pH variations—preserving therapeutic potency [10].

5.3 Controlled & Sustained Release

Nanoformulations enable the sustained and controlled release of herbal compounds, maintaining therapeutic levels over prolonged periods and potentially reducing dosing frequency [13].

5.4 Targeted Delivery & Passive Accumulation

Size and surface characteristics allow nanoherbals to exploit the Enhanced Permeability and Retention (EPR) effect, resulting in passive targeting to disease sites such as tumors or inflamed tissues [12].

5.5 Versatile Loading Capacity

Nanoherbal systems can carry both hydrophilic and hydrophobic phytochemicals, offering versatility for formulating diverse herbal extracts in a single carrier [10].

5.6 Biocompatibility & Lower Toxicity

Nanoherbals are usually biodegradable, non-toxic, and biocompatible—especially when made using natural polymers or 'green' techniques, making them safer compared to some synthetic carriers [7].

5.7 Dose Reduction & Reduced Side Effects

Improved delivery efficiency and stability can translate into lower required doses and fewer systemic side effects, enhancing patient compliance [8].

5.8 Multifunctional & Application Versatility

Nanoherbals can be tailored for various therapeutic and functional applications—ranging from anticancer and antimicrobial uses to cosmeceuticals, nutraceuticals, functional foods, and environmental uses like water purification [19].

5.9 Adaptable Formulations & Nanocarriers

Common nanoherbal carriers include nanoparticles, nanocapsules, liposomes, micelles, solid lipid nanoparticles (SLNs), dendrimers, nanoemulsions, nanogels, and more—each offering different physicochemical and release properties to suit specific applications [15].

5.10 Green Synthesis & Traditional Integration

Some nanoherbal systems leverage eco-friendly (green) synthesis methods, utilizing plant-based materials, or even draw inspiration from traditional Ayurvedic practices like "bhasma"—metal-based nanomedicines used for targeted delivery and immunomodulation [14].

6. Methods of Preparation of Nanoherbals

Figure 2 Method of Preparations

6.1 Top-Down vs. Bottom-Up: The Two Master Routes

Top-down approaches start from bulk material and break it down to the nanoscale by mechanical or physicochemical energy (e.g., high-pressure homogenization for solid-lipid nanoparticles; high-energy emulsification for nanoemulsions) [15]. They are attractive for scale-up and regulatory familiarity but can generate broader size distributions and may expose heat-/shear-sensitive phytoconstituents to stress. High-pressure homogenization (HPH) is the workhorse for lipid nanocarriers and has been translated from lab to industrial scales for SLNs and NLCs.

Bottom-up approaches build nanoparticles from molecular or colloidal precursors via precipitation/assembly—e.g., nanoprecipitation (a.k.a. solvent displacement), solvent evaporation (single or double emulsion) for polymeric carriers (PLGA, chitosan), and supercritical CO? processes that crystallize or encapsulate actives under mild temperatures. They excel at gentle processing, narrow sizes, and high loading for hydrophobic botanicals but require careful solvent selection, mixing control, and post-processing to meet residual-solvent limits.

6.2 Core Bottom-Up Methods Used in Nanoherbals

6.2.1 Nanoprecipitation (Solvent Displacement)

Concept: A polymer (e.g., PLGA) and the herbal active dissolve in a water-miscible organic solvent (e.g., acetone, acetonitrile, EtOAc). Upon addition to an aqueous phase containing stabilizer (PVA, poloxamer), rapid solvent diffusion reduces polymer solubility, yielding nuclei that grow into nanoparticles. Particle size depends on solvent type, polymer concentration, addition rate, interfacial mixing, and surfactant. Membrane-assisted or microfluidic variants improve mixing and reproducibility.

Why it suits herbal actives: Many phytochemicals (curcuminoids, flavonoids, terpenoids) are hydrophobic; nanoprecipitation provides high encapsulation and narrow size with minimal heat, preserving labile constituents. Recent work underscores how solvent choice (e.g., acetone vs. acetonitrile vs. EtOAc) strongly tunes size and polydispersity—critical for bioavailability and stability [18].

6.2.2 Solvent Evaporation (Single/Double Emulsion)

Single emulsion (O/W): Polymer and hydrophobic herbal actives dissolve in a volatile organic solvent (e.g., EtOAc). Emulsification into an aqueous surfactant solution creates droplets; solvent removal (stirring or reduced pressure) hardens droplets into nanoparticles.

Double emulsion (W/O/W): For hydrophilic phytoconstituents (glycosides, polyphenolic acids), a first W/O emulsion is formed (internal aqueous herbal extract in organic polymer phase), then re-emulsified into an external aqueous phase (W/O/W). Solvent removal traps the hydrophilic actives in the polymeric matrix. This route is widely reported for loading delicate biomolecules and botanical hydrophiles.

Advantages/considerations: High entrapment efficiency (with process tuning), tunable size (200–500 nm common), but shear and multiple steps can challenge very labile compounds; surfactant residues and solvent grades must comply with pharmacopeial limits.

6.2.3 Supercritical Fluid (SCF) Technology (e.g., scCO?)

Principle: Supercritical CO? (T > 31 °C, P > 7.38 MPa) has gas-like diffusivity and liquid-like solvating power. In RESS, SAS, SEDS, or related modes, rapid expansion or anti-solvent action induces precipitation of nanosized drug/polymer composites with narrow PSDs—often at low temperatures, minimizing thermal degradation of phytoactives. Case studies include polyphenols (e.g., resveratrol) and plant pigments [.

Why it’s attractive for nanoherbals:

• Green: CO? is non-flammable, recyclable, and leaves minimal solvent residues.
• Quality: good control over morphology and crystallinity; potential for continuous manufacture.

Caveats: Capital cost and process tuning (pressure/temperature/co-solvent) are non-trivial; not all polymers/drugs show sufficient solubility without co-solvents.

6.3 Green Synthesis (Plant-Mediated Nanoparticle Synthesis)

Concept: Plant extracts (leaves, peels, barks, seeds) serve as reducing and capping agents to produce metallic or metal-oxide nanoparticles (e.g., Ag, Au, ZnO), where phytochemicals (polyphenols, flavonoids, sugars, proteins) reduce metal ions and stabilize the colloids. Reaction pH, temperature, and extract composition dictate nucleation, growth, and final size/shape.

Relevance to nanoherbals:

• Bio-origin capping layers can confer inherent antioxidant/antimicrobial attributes complementary to the herbal payload.
• Eco-friendly: avoids toxic reductants/surfactants; fits clean-label/natural product narratives.
• Versatility: extensive reports detail Ag/Au NPs made with diverse botanicals, enabling topical antimicrobials, wound-healing gels, and coatings.

Considerations: Batch-to-batch variability from plant extract composition (seasonality, extraction method) can affect reproducibility; robust characterization (UV-Vis, DLS, TEM, FTIR, XRD) and specification of extract chemistry are essential for translation.

6.4 Encapsulation Platforms Widely Used for Herbal Actives

6.4.1 Liposomes & Phytosomes

Preparation methods:

• Thin-film hydration (Bangham): dissolve lipids in organic solvent → evaporate to a thin film → hydrate with aqueous herbal extract → size-reduce (sonication or extrusion).
• Ethanol/ether injection: rapid injection of lipid solution into aqueous phase yields small unilamellar vesicles.
• Reverse-phase evaporation, detergent depletion, microfluidics, and even SCF-assisted liposomes are additional routes.

Why for nanoherbals: Amphiphilic bilayers can solubilize both hydrophilic and lipophilic phytochemicals; vesicle size (80–200 nm) and lamellarity control release/targeting. Phospholipid complexes (“phytosomes”) improve oral absorption of flavonoids and saponins.

6.4.2 Solid Lipid Nanoparticles (SLNs) / Nanostructured Lipid Carriers (NLCs)

Preparation: Hot or cold high-pressure homogenization of a lipid melt (plus surfactant) dispersed in water; for NLCs, a solid lipid is blended with liquid lipid to increase payload and prevent expulsion. Suitable for thermosensitive herbs with careful temperature control and brief exposure. Industrial homogenizers enable scale-up.

Use-case: Oral and topical nanoherbals (e.g., curcumin, essential-oil components) benefit from improved solubility, occlusive effect on skin, and controlled release.

6.4.3 Nanoemulsions

High-energy methods: high-pressure homogenization or ultrasonication breaks coarse emulsions into nano-droplets (typically 50–200 nm).

Low-energy methods: phase-inversion temperature/ composition or spontaneous emulsification leverage interfacial phenomena and surfactant chemistries to self-assemble nano-droplets. For volatile essential-oil actives (eugenol, thymol), nanoemulsions enhance dispersion and stability.

Trade-offs: High-energy routes are robust and food/ cosmetic friendly; low-energy routes save energy but may require higher surfactant loads—important in nutraceutical contexts.

6.4.4 Polymeric Nanoparticles (e.g., PLGA, chitosan)

Routes: Nanoprecipitation (Section 2.1), single/double emulsion–solvent evaporation (Section 2.2), ionic gelation for chitosan, or microfluidics to refine sizes/PDIs. PLGA is favored for its biodegradability and regulatory track record; double emulsion is especially useful for hydrophilic herbal polysaccharides and phenolics.

6.5 Surface Modification (Functionalization) for Stability & Targeting

Improve colloidal stability (salt/serum), extend blood circulation, reduce opsonization, and achieve active targeting to tissues/cells (e.g., tumors, inflamed endothelium, gut mucosa).

• PEGylation: grafting polyethylene glycol reduces protein adsorption, prolongs circulation, and can mitigate immunogenicity—used across liposomes and polymeric NPs.
• Ligand conjugation: attaching folate, peptides, antibodies, or sugars (e.g., mannose for macrophage targeting) enables receptor-mediated uptake; orientation and density of ligands critically influence binding and biodistribution.
• Charge/hydrophobicity tuning: surface charge (ζ-potential) and hydrophobic domains modulate mucus penetration, cellular uptake, and hemocompatibility; excessive cationic character may trigger toxicity, so balanced designs are advised.
• Metallic NP coatings: biopolymers, lipids, proteins, and phytochemical shells improve stability and biocompatibility of plant-mediated Ag/Au NPs and allow further ligand coupling.
• Analytical confirmation: FTIR/XPS (surface chemistry), DLS/ζ (size/charge), TEM/cry-EM (morphology), DSC/XRD (crystallinity for lipid/drug), and in-vitro protein corona assays map how coatings alter biological identity.

6.6 Practical Selection Guide for Nanoherbal Methodology

• Hydrophobic, labile actives (e.g., curcuminoids, resveratrol): polymeric NPs via nanoprecipitation or SLN/NLC via HPH; consider SCF for solvent-lean processing.
• Hydrophilic phytoconstituents (glycosides, polysaccharides): double emulsion (W/O/W) PLGA or liposomes (aqueous core).
• Volatile/essential-oil actives: nanoemulsions (high-energy HPH/sonication for food/cosmetic compliance).
• Antimicrobial topical systems: plant-mediated Ag/Au NPs (green synthesis) with biopolymer capping; confirm reproducibility of extract chemistry.
• Need for long circulation/targeting: add PEGylation and ligand decoration post-encapsulation.

7. Applications of Nanoherbals

7.1 Cancer therapy

Principle

Multiple plant-derived compounds modulate oncogenic signaling (PI3K/Akt/mTOR, Wnt/β-catenin, JAK/STAT, MAPK), apoptosis, ferroptosis, and tumor microenvironment. Nanoformulation of these hydrophobic molecules consistently improves tumor exposure and antitumor readouts in vivo; early clinical studies are emerging [17].

Example: Curcumin (nanocurcumin)

• Evidence base: Systematic reviews (2021–2024) conclude nanocurcumin enhances antitumor efficacy and safety versus free curcumin in preclinical cancer models; early clinical signals include symptom relief and improved quality of life, supporting further trials.
• Mechanisms enhanced by nanoformulation: greater cellular uptake, sustained release, and pathway modulation (e.g., PI3K/Akt/mTOR, JAK/STAT), with reports of ferroptosis induction.
• Case studies:
  • PLGA/other polymeric nanoparticles: Curcumin-loaded PLGA NPs showed anti-metastatic activity; several formulations decrease invasion and metastasis in breast cancer models.
  • PGMD–curcumin NPs (≈110–218 nm): Demonstrated cytotoxicity against breast cancer lines, illustrating polymer choice and size control for efficacy.
  • Targeted protein nanocages (H-ferritin): pH-sensitive Cur@HFn delivered curcumin selectively to breast cancer cells, boosting potency.

Other herbal actives in oncology

• EGCG (green tea catechin): Low oral bioavailability limits free EGCG; nano-EGCG (lipid/polymeric) improves stability and cytotoxicity in breast, cervical, and lung cancer models; reviews discuss nano-encapsulation to bridge bench-to-bedside.
• Resveratrol: Nanoparticle delivery elevates anticancer potency vs. free compound; comprehensive 2023–2024 reviews summarize design trends and advantages (solubility, controlled release).

Takeaway: Across tumor types, nano-herbal systems most robustly improve exposure and tumor uptake; clinical translation is advancing fastest for curcumin and catechins, with multiple formulations poised for larger trials.

7.2 Neurological disorders (Alzheimer’s, Parkinson’s)

Principle

The blood–brain barrier (BBB) excludes most small molecules and nearly all macromolecules. Nanocarriers (lipid/polymer micelles, SLNs, exosomes, ligand-decorated NPs) can leverage receptor-mediated transcytosis, adsorptive transport, or cell-membrane cloaking to cross the BBB and/or restore BBB integrity, enabling delivery of herbal neuroactives (curcumin, resveratrol, berberine, ginsenosides).

Nano-curcumin for AD/Parkinson’s (preclinical and clinical signals)

• BBB & disease modulation: Recent reviews detail nanocarriers that ferry neuroprotective agents across the BBB and even repair BBB dysfunction—a relevant AD/PD pathology.
• Preclinical case study: Nanoencapsulated curcumin reversed memory impairment and neuroinflammation in a validated AD rat model (ICV-STZ), outperforming free curcumin.
• Clinical signal (nanocurcumin): Triple-blind randomized trials of curcumin-containing nanomicelles have reported immunomodulatory effects in CNS disease contexts, suggesting systemic immune-neuro crosstalk benefits; broader reviews of AD trials provide context for where phytochemical nanosystems fit among disease-modifying strategies.

Takeaway: For neurodegeneration, nanoherbals principally address BBB penetration and neuroinflammation/oxidative stress, with encouraging animal data and early human signals for nanocurcumin.

7.3 Cardiovascular diseases (CVD)

Principle

Cardiovascular indications benefit from anti-inflammatory, antioxidant, antiplatelet, lipid-lowering, and anti-fibrotic effects of polyphenols (resveratrol, quercetin, curcumin). Nano-delivery can target plaques or injured myocardium, improve bioavailability, and enable combination therapies.

Clinical and translational highlights

• Nanocurcumin & CVD risk factors: A meta-analysis of placebo-controlled RCTs found nano-curcumin interventions improve lipid profiles, glycemic control, inflammatory mediators, and sometimes BP—validating a nutraceutical-to-cardiometabolic bridge.
• Microvascular angina model: In patients with coronary slow flow phenomenon (a microvascular ischemia model), 80 mg/day nanocurcumin for 8 weeks improved endothelial function and inflammatory markers versus placebo.
• Quercetin clinical pilot (STEMI): Add-on quercetin limited infarct size and reduced intramyocardial hemorrhage in first anterior STEMI patients (pilot study)—a signal for flavonoid cardioprotection that motivates nano-quercetin development.

Nano-resveratrol and nano-quercetin for atherosclerosis & MI (preclinical/engineering)

• Resveratrol nanocarriers: Reviews emphasize that nanoparticle delivery resolves resveratrol’s solubility/PK issues; recent studies show plaque-modulating actions and mechanistic links (e.g., LDLR upregulation, ferroptosis pathways).
• Targeted delivery: Biomimetic, macrophage-membrane-coated NPs carrying resveratrol show MI-site targeting and cardioprotection in preclinical models.
• Quercetin & ischemia-reperfusion: Reviews summarize antioxidant/antiapoptotic mechanisms relevant to MI; nanoformulations are being engineered to enhance delivery to ischemic myocardium.

Takeaway: In CVD, the strongest human data today are risk-factor improvements with nano-curcumin and pilot cardioprotection with quercetin; nanocarrier engineering for plaque targeting and injury-site homing is rapidly evolving (preclinical).

7.4 Antimicrobial & Antiviral therapies

Principle

Essential oils (EOs) and phenolics (thymol, carvacrol, eugenol, oregano or eucalyptus oils) show broad antimicrobial activity but are volatile, hydrophobic, and unstable. Nanoemulsions, SLNs, and polymer-encapsulated systems increase dispersion in aqueous environments, control release, and enhance contact with microbial membranes/biofilms; plant-mediated silver nanoparticles (AgNPs) provide a green-synthesized, inorganic nano-antimicrobial option.

Representative case studies

• EO nanoemulsions (food and biomedical contexts):
  • Oregano/carvacrol/thymol nanoemulsions (50–85 nm) prepared by ultrasound showed enhanced antibacterial and antibiofilm activities, supporting food and oral-health applications.
  • Thymus vulgaris oil nanoemulsions overcome volatility/hydrophobicity limits, improving antimicrobial performance versus free oil.
  • Comparative studies and reviews conclude nano-sizing increases active surface area and can amplify antimicrobial effects, though formulation details (surfactant, droplet size) critically determine outcomes; a 2024–2025 literature stream documents improved control of S. aureus, E. coli, C. perfringens and foodborne pathogens.
• Green-synthesized AgNPs:
  • Plant-mediated AgNPs (using phenolic-rich extracts from neem, turmeric, Ficus spp., etc.) display potent antimicrobial activity with eco-friendly synthesis routes; recent reviews detail synthesis parameters, phytochemical roles, and biomedical applications.

Caveat: Antimicrobial claims depend strongly on assay conditions; method papers emphasize standardization challenges for EOs. Formulation and testing protocols must be carefully controlled to ensure reproducible MIC/MBC values.

7.5 Anti-inflammatory & Immunomodulatory uses

Principle

Herbal actives frequently modulate NF-κB, Nrf2, COX/LOX, cytokine networks, and immune cell phenotypes. Nano-encapsulation enhances tissue exposure at inflamed sites and can shift systemic immune markers in clinical studies.

Examples & evidence

• Nanocurcumin in inflammatory conditions: Clinical and translational studies report reductions in CRP and pro-inflammatory cytokines and improvements in clinical symptoms in inflammatory milieus (e.g., autoimmune contexts), attributed partly to improved bioavailability and immune pathway modulation.
• Arthritis models: Curcumin nanocarriers (polymer/lipid) demonstrate better joint targeting, stability, and anti-inflammatory efficacy than free curcumin; reviews summarize platform choices and release kinetics.

Takeaway: For inflammation, the most mature nanoherbal is nanocurcumin, with human biomarker improvements and robust preclinical disease-model benefits.

7.6 Nutraceuticals & Functional foods

Principle

Functional foods often require aqueous processing, thermal/photostability, and palatability—a poor fit for many hydrophobic botanicals. Food-grade nano-delivery (nanoemulsions, casein micelles, plant-protein nanoparticles, biopolymer complexes) improves dispersibility, stability, and bioaccessibility of polyphenols and essential oils in drinks, dairy, and snacks.

Human PK and formulation exemplars

• Theracurmin® (colloidal curcumin nanoparticles): In a randomized crossover PK study, a 30 mg nano-curcumin dose achieved a ~27-fold increase in AUC over unformulated curcumin—often cited as proof-of-concept for nutraceutical nano-delivery.
• Across nano-curcumin products: A review of 11 clinical studies reported 9–185× higher relative bioavailability for nanoformulations, albeit with heterogeneity in designs and analytics—important when comparing products.
• Co-encapsulation strategies: Co-loading resveratrol + curcumin in nano-systems improves photostability and antioxidant performance; micro/nanocapsules enable controlled release profiles for functional foods.
• Protein/biopolymer carriers: Soy-protein and dual-polysaccharide-coated micro/nanocapsules achieve high curcumin encapsulation efficiency (≈95%), with improved stability for beverage/dairy applications.

Food safety and antimicrobial packaging

• EO-loaded nanocarriers and curcumin-active packaging films provide antimicrobial action and freshness indicators, extending shelf life while potentially delivering bioactives.

Takeaway: In foods, nanoherbals primarily deliver higher, more consistent systemic exposure and product stability, with human PK advantages well documented for nano-curcumin; careful formulation selection and regulatory compliance (food-grade excipients, GRAS status) are essential.

7.7 Selected recent case studies (quick-scan)

• Oncology: Comprehensive 2024 systematic review—nanocurcumin improves preclinical efficacy; early clinical signals support QoL/toxicity mitigation.
• Neurology: Nano-curcumin improved cognition/inflammation in an AD rat model; BBB-targeted nano-delivery is a major translational avenue.
• Cardiology: RCT meta-analysis—nano-curcumin improves cardiometabolic risk factors; CSFP trial shows endothelial benefit; pilot STEMI trial supports quercetin cardioprotection (basis for future nano-quercetin).
• Antimicrobial: Thymol/carvacrol/oregano oil nanoemulsions demonstrate increased anti-pathogen and antibiofilm activity; green-synthesized AgNPs offer broad antimicrobial potential with eco-friendly fabrication.
• Functional foods: Nano-curcumin PK ↑27× (Theracurmin®); co-encapsulation of curcumin/resveratrol enhances stability and antioxidant power in food matrices.

8. Advantages of Nanoherbals

8.1 Improved Solubility and Bioavailability

Nanoherbals enhance solubility and bioavailability by significantly decreasing particle size, boosting surface area, and optimizing absorption mechanisms. Techniques such as nanocrystals, nanoemulsions, and lipid/polymer carriers elevate dissolution rates, leading to improved pharmacokinetics versus traditional formulations. Specifically, solid lipid nanoparticle (SLN) systems loading puerarin revealed over threefold higher bioavailability compared to suspensions, confirmed by a shorter Tmax. Nanocrystals circumvent the need for carriers, enabling high drug loading and reducing toxicity.

8.2 Controlled and Sustained Release

Nanoherbals can be engineered to deliver phytochemicals at controlled and sustained rates, reducing dose frequency and ensuring maintained therapeutic concentrations. Systems like nanohydrogels, lipid carriers, and NDDS (novel drug delivery systems) support prolonged release and better bioavailability.

8.3 Targeted Delivery (Site-Specific Action)

The nanoscale of these formulations allows enhanced tissue penetration and targeted delivery, either actively (using ligands) or passively via enhanced permeability and retention (EPR) effect—particularly useful in tumor targeting. Additionally, nanotheranostic platforms combine therapy and diagnostics in one system.

8.4 Reduced Toxicity & Enhanced Safety Profile

Nanoherbals enhance safety by reducing systemic exposure and toxicity. Higher targeting precision helps minimize adverse effects, while carrier-free approaches like nanocrystals further lower carrier-related toxic risks. Moreover, using biocompatible, biodegradable, and plant-derived carriers (green synthesis) reinforces favorable safety profiles.

8.5 Improved Patient Compliance

By increasing bioavailability, achieving sustained release, and reducing dosing frequency, nanoherbals make herbal therapies more convenient and improve adherence. NDDS helps reduce repeated dosing and enhance effectiveness, addressing a major gap in conventional herbal treatments.

9. Limitations and Challenges

9.1 Standardization of herbal raw materials

Unlike single-molecule APIs, botanicals are chemically heterogeneous and influenced by species, genotype, soil, climate, harvest time, and post-harvest processing. This variability alters the concentrations of marker compounds and co-constituents, making it difficult to ensure consistent pharmacological performance when herbs are converted into nanoformulations. WHO’s monographs and handbooks underscore the need for stringent identity, purity, and contaminant testing (macroscopy/ microscopy, chromatographic fingerprints, residual pesticides/metals, microbial limits) to control this variability—requirements that many herbal supply chains still struggle to meet. Even when good botanical control is applied, translating a complex extract into a nanosystem adds another layer of variability: the “effective payload” in a nanocarrier depends on the extract’s batch chemistry (e.g., polyphenol content) which in turn affects encapsulation efficiency, stability, and release. Contemporary reviews on herbal quality control emphasize that fingerprints/multi-marker assays are often necessary (single-marker standardization is insufficient) and that lack of harmonized standards hinders interchangeability across regions and manufacturers. Regulatory guidance in Europe (EMA) similarly highlights the special quality problems of herbal medicinal products and the need to specify starting materials, preparation methods, and stability in detail—issues that become more exacting for nano-enabled versions.

9.2 Toxicity and safety concerns of nanoparticles

Nanocarriers can shift biodistribution and biological interactions in ways that are difficult to predict from conventional herbal preparations. A central issue is the protein corona—adsorption of biomolecules onto nanoparticle surfaces—which can modify “identity,” uptake, immune recognition, and organ distribution, sometimes undermining targeting and creating off-target effects. Recent reviews delineate how corona composition is context-dependent and dynamic, complicating translation and safety assessment. Broader nanosafety literature flags potential immunotoxicity, oxidative stress, and long-term accumulation concerns, which must be assessed for each nanoherbal system, its materials (lipids, polymers, inorganics), and its route of administration. Healthcare-focused reviews also emphasize environmental safety (manufacturing/ disposal) as part of risk assessment. Regulators (FDA) stress that products containing nanomaterials may exhibit attributes distinct from non-nano comparators and therefore warrant tailored characterization (size/shape, surface chemistry, aggregation, release, in vitro–in vivo correlations) and risk-based evaluation; there is no blanket presumption of safety or harm.

9.3 Scale-up and manufacturing issues

Reproducibly producing nanoformulations at industrial scale remains challenging. Batch methods often suffer from size/polydispersity drift, mixing/heat-transfer limitations, and batch-to-batch variability as equipment scales up. Reviews of nanomedicine scale-up (including experiences from liposomes and polymeric/lipid nanoparticles) document how process parameters that work at bench scale can fail in large reactors, jeopardizing critical quality attributes (CQAs). Recent analyses argue for continuous manufacturing and intensified/controlled mixing (e.g., microfluidics) to improve reproducibility, yet adoption is still evolving and requires significant process development, modeling, and regulatory engagement. Moreover, nanosystems with multi-step fabrication (core formation, loading, surface modification, sterilization, lyophilization) are especially hard to scale without compromising stability and performance—an obstacle noted across contemporary nanomedicine manufacturing reviews.

9.4 High cost of production

Complex processes, specialized equipment (e.g., high-shear/ microfluidic mixers), advanced analytics (DLS, electron microscopy, nanoparticle tracking, hyphenated chromatography), sterile operations, and often low process yields contribute to higher COGS versus conventional herbal dosage forms. Economic and policy reviews note that high R&D and manufacturing costs remain a major barrier to widespread adoption and equitable access—especially in low- and middle-income settings. Industry-oriented assessments and pharmacoeconomic reviews add that while manufacturing costs are elevated, cost-effectiveness can still be achieved if nanoformulations produce clinically meaningful benefits (e.g., fewer administrations, lower toxicity management costs). Nonetheless, the upfront investment and per-unit costs are typically higher than for non-nano analogs, demanding a clear value proposition.

9.5 Regulatory & ethical concerns

Regulatory. For nano-enabled drug products (including botanicals formulated as drugs), agencies expect robust, case-by-case characterization and control strategies. FDA’s 2022 Guidance for Industry outlines considerations spanning material attributes, manufacturing controls, in vitro/ in vivo testing, and comparability when changes occur. EMA’s horizon-scanning and scientific advice frameworks encourage early dialogue because nanomedicines often raise unique CMC and clinical questions (e.g., bioequivalence criteria for complex nanosystems). For herbal nanosystems, these expectations layer on top of existing herbal quality guidance.

Ethical. Scholarship on nanomedicine ethics highlights: (i) uncertainty and transparency in risk communication; (ii) privacy and data issues for nano-enabled diagnostics/theranostics; (iii) environmental stewardship across the lifecycle; and (iv) equity, to avoid a “nano-divide” where benefits accrue primarily to wealthier populations. Responsible innovation frameworks urge stakeholder engagement and fair access as the field advances.

Comparison: Traditional vs Nanoherbal Formulations

Table 2 Comparison: Traditional v/s Nanoherbal Formulation