As the body’s largest organ with substantial metabolic activity, the skin serves as a dynamic immunologic and physicochemical interface between the self and the environment. Continuous exposure to ultraviolet radiation, atmospheric pollutants, and endogenous oxidative stress provokes a cascade of redox-driven inflammatory responses that contribute to diverse dermatologic pathologies, including acne vulgaris, atopic dermatitis, hidradenitis suppurativa, psoriasis, photoaging, and chronic wounds.¹ Despite their differing clinical presentations, these disorders share a common pathogenic axis characterized by dysregulated cytokine signaling and oxidative imbalance, which together impair epidermal barrier function and accelerate tissue degeneration. At the molecular level, the cutaneous redox-inflammatory network is governed by transcriptional regulators such as nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and activator protein-1 (AP-1), which coordinate antioxidant defense, cytokine release, and extracellular-matrix remodeling. When these pathways are disrupted, excessive production of reactive oxygen and nitrogen species (ROS/RNS) ensues, promoting lipid peroxidation, sustained inflammation, and progressive dermal injury.² This biochemical disequilibrium not only manifests as visible skin disease but also underlies age-related degradation of dermal architecture. Conventional therapies—topical or systemic—achieve only partial efficacy, hindered by poor transdermal penetration, limited bioavailability, molecular instability, and occasional adverse reactions.³ These limitations highlight the need for sustainable, biocompatible, and mechanistically precise treatment strategies that restore cutaneous homeostasis while minimizing iatrogenic risk.

In this context, nanotechnology-enabled drug delivery has emerged as a promising solution, offering controlled release and enhanced localization of bioactive compounds.³ Nanocarriers can modulate pharmacokinetic profiles, extend local residence time, enhance epidermal permeation, and reduce systemic toxicity. Yet, their conventional chemical or physical synthesis often relies on toxic solvents, surfactants, and high-energy processes, raising concerns about environmental and biological compatibility. Globally, interest in safer and more sustainable therapies is rising. According to the World Health Organization’s estimates, more than 80% of the global population relies on herbal or plant-based remedies for primary health care, with a growing share directed toward dermatologic and cosmeceutical use.⁴ In parallel, according to an industry forecast, the green nanotechnology sector—which unites plant chemistry with nanoscale engineering—is projected to exceed USD 370 billion by 2034,⁵ underscoring the momentum of eco-conscious biomedical innovation. The convergence of these fields positions phytochemical-driven nanomedicine at the forefront of sustainable dermatologic therapy.

To overcome the limitations of conventional nanoparticle synthesis, green fabrication methods employ extracts from medicinal and aromatic plants as natural reducing and capping agents.⁶ This phyto-mediated synthesis harnesses the redox potential of phytoconstituents such as flavonoids, terpenoids, alkaloids, and phenolic acids, which not only facilitates nanoparticle formation but also endows the resulting nanocomposites with intrinsic pharmacological activity. Phytochemicals are well established for their antioxidant and anti-inflammatory effects: they scavenge ROS/RNS, enhance endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase), and regulate pro-inflammatory signaling via the NF-κB, mitogen-activated protein kinase (MAPK), and cyclooxygenase-2 (COX-2) pathways.⁷ Collectively, these mechanisms foster dermal repair by stimulating collagen synthesis, angiogenesis, and cellular regeneration. However, the clinical translation of phytochemicals remains constrained by chemical instability, oxidative degradation, and limited skin permeability.⁸ Encapsulating these compounds within green-synthesized nanocarriers—a field increasingly referred to as nanocosmeceuticals—offers a biocompatible route to stabilize sensitive molecules, enhance epidermal delivery, and sustain therapeutic release.⁹ This approach bridges traditional botanical pharmacology with modern nanoscience, reflecting a paradigm shift toward sustainable, precision-guided skin therapeutics.

Previous reviews have broadly examined plant-derived nanoparticles across pharmacologic contexts; however, this article focuses specifically on their dermatologic applications, emphasizing anti-inflammatory and antioxidant mechanisms within phytochemical-based green nanocarriers. By integrating developments from pharmacognosy, materials science, and clinical dermatology, this review delineates how eco-engineered nanostructures can advance both efficacy and safety in topical treatments. Specifically, it (i) outlines the principles and methodologies of green nanoparticle synthesis; (ii) classifies the key phytochemical groups relevant to cutaneous pharmacology; and (iii) elucidates the molecular mechanisms driving their therapeutic action. It further discusses the toxicologic, regulatory, and translational considerations essential for clinical adoption. This convergence between phytochemical pharmacology and nanoscale delivery systems defines the emerging field of green nanocosmeceuticals, which this review explores through the lens of dermatologic therapy.

Green nanotechnology aims to synthesize nanomaterials using environmentally benign methods that avoid hazardous chemicals and harsh conditions. In practice, this often involves phytochemical-mediated reduction of metal ions, whereby plant extracts rich in antioxidants and organic acids can convert metal salts into nanoparticles.^10,11 When the extract is mixed with a metal-ion solution, these plant-derived molecules donate electrons to the ions, thereby initiating the formation of nanoscale metallic particles. Structurally, this transition reflects the reduction of isolated solvated ions (eg, Ag⁺, Au³⁺) to zero-valent atoms, which coalesce into multi-atom clusters, forming a solid metallic core characteristic of elemental nanoparticles. For example, mixing an aqueous plant extract with a metal salt (eg, AgNO₃, HAuCl₄) under optimum ambient temperature and pressure can rapidly convert Ag⁺ or Au³⁺ ions into elemental nanoparticles.¹¹ Green synthesis methods have been shown to convert diverse metal precursors, including Ag⁺, Au³⁺, Zn²⁺, Ti⁴⁺, into nanoscale metals or oxides.¹¹ This conversion is driven by phytochemicals such as phenolic compounds, including flavonoids, which donate electrons to reduce metal ions in situ, initiating nanoparticle formation without the need for external reducing agents.¹² However, a well-recognized limitation of this approach is the intrinsic variability of plant extracts, as phytochemical profiles vary with species, season, extraction solvent, plant age, and environmental conditions, which directly affect nucleation rate, nanoparticle size, shape, and zeta potential (the electrostatic surface charge that governs colloidal stability).¹³

A key feature of green synthesis is the dual role of plant biomolecules as both reducing and capping agents, where capping refers to the adsorption of molecules onto the nanoparticle surface to prevent aggregation and enhance colloidal stability. Polyphenols, terpenoids, alkaloids, saponins, proteins, and polysaccharides first donate electrons to metal ions to initiate nanoparticle nucleation, and then chelate or absorb onto the nascent particle surface, where their hydroxyl, carbonyl, and other functional groups provide natural capping that prevents aggregation and stabilizes the colloid.^11,12,14 Final nanoparticle characteristics are strongly governed by synthesis parameters such as pH, temperature, extract concentration, and the extract-to-metal-salt ratio, which modulate reduction kinetics and direct nucleation and growth, ultimately determining morphology, size distribution, and surface charge.¹⁵ Once these initial physicochemical conditions shape the emerging metallic core, the bound phytochemicals form an organic, encapsulating corona that provides both electrostatic and steric stabilization and imparts specific surface functionalities.¹⁶ In practice, the same phytochemicals that initiate nucleation also stabilize the nascent nanoparticles. Electron-rich metabolites donate electrons to reduce metal ions and influence early size distribution, whereas higher-molecular-weight components adsorb onto the forming core to generate an organic corona that provides electrostatic and steric stabilization. This coordinated reduction-capping process yields more uniform, colloidally stable, and biocompatible nanostructures, a particularly desirable feature for dermatologic applications.^12,16,17 Through this synergy, a simple plant extract can replace multiple reagents (chemical reductants, surfactants, or toxic solvents) that conventional nanofabrication typically requires.

The green synthesis approach offers numerous advantages. By leveraging natural phytochemicals, the process eliminates the need for hazardous reducing agents or expensive capping chemicals—in most cases, no toxic solvents or reagents are necessary.¹² Reactions typically occur in water at neutral pH and mild conditions, aligning with green chemistry principles of reduced waste and energy use. The method is generally cost-effective and straightforward, often proceeding readily at room temperature with minimal inputs and yielding nanoparticles within minutes.¹¹ Moreover, the bio-origin capping enhances the surface functionality of the nanocarriers. The phytochemical coating modifies the surface chemistry to improve colloidal stability and biocompatibility, while also providing reactive sites for further functionalization.¹⁰ In some cases, residual plant molecules on the nanoparticle surface can impart additional bioactivity; for example, antioxidant or antimicrobial functional groups from the extract can synergistically enhance the nanoparticle’s biological effects.¹⁰ Despite these advantages, scaling up green synthesis remains challenging, as larger batch volumes often alter phytochemical-to-metal ratio, mixing uniformity, heat transfer, and sterility, leading to inconsistent particle size and reproducibility.¹⁸

Even with these limitations, green-synthesized metal nanoparticles, notably Ag, ZnO, and Au, have become increasingly relevant in dermatologic nanotherapy. Their intrinsic antimicrobial, anti-inflammatory, and antioxidant activities, combined with the plant-derived capping layer obtained during green synthesis, make them especially suitable for skin applications.^17,19,20 These phytochemical-coated metals can scavenge ROS, modulate cytokine expression, and promote wound healing, all of which are key mechanisms in inflammatory and oxidative skin disorders.^21,22 In parallel, polymeric nanoparticles made from chitosan, alginate, or cellulose derivatives contribute complementary benefits. As naturally derived, biodegradable polymers, these materials are fully compatible with green synthesis principles. They can be crosslinked or assembled using phytochemical-rich extracts rather than synthetic surfactants or toxic reagents. Their intrinsic properties enhance electrostatic interactions with the negatively charged skin surface, improving epidermal retention and permeation of phytochemicals.^17,23 Polymer formulations typically rely on ionic gelation or polyelectrolyte complexation, techniques that produce nanocarriers with high encapsulation efficiency and robust structural integrity.²⁴

Across these metals, careful physicochemical characterization is essential to ensure safe and reproducible skin delivery. Particle size in the approximate range below 300 nm favors skin contact and potential follicular uptake, while zeta potential magnitudes of ≥±30 mV are associated with colloidal stability and reduced nanoparticle aggregation.^25,26 Morphology assessed by transmission or scanning electron microscopy provides insight into structural uniformity and surface architecture, parameters often linked to release behavior and cutaneous interaction. High encapsulation efficiency is equally important for maintaining the integrity of encapsulated therapeutic agents and protecting labile phytochemicals from hydrolysis, oxidation, and photodegradation.²⁷ Hybrid nanocomposites that integrate polymeric, lipidic, or metallic components with herbal extracts rely on similar formulation principles and often exhibit enhanced resistance to hydrolytic and oxidative degradation, improved photostability, and greater colloidal stability, while also enabling combined functions such as drug delivery alongside intrinsic antioxidant, antimicrobial, or anti-inflammatory activity. Optimized systems maintain their particle-size distribution and encapsulation efficiency while withstanding physicochemical stresses relevant to topical application, such as acidic skin pH, ultraviolet exposure, and oxidative environments. Newer designs increasingly incorporate ultraviolet (UV)-absorbing moieties or antioxidant shells to bolster long-term bioactivity and stability.^28–30

Phytochemicals contained in a nanocarrier’s corona have the potential to achieve a synergistic increase in transdermal penetration, bioavailability, stability, and targeted delivery of active compounds to areas containing ROS or expressing inflammation. Stratum corneum penetration is achieved by interrupting barrier interactions. Phenols can disrupt the stratum corneum lipid matrix, allowing nanocarriers with phenol-containing coronas to fuse with ceramide-rich domains and thereby lower diffusional resistance.^61,62 Terpenoids further enhance penetration by reversibly disrupting the well-organized lamellar layers of the stratum corneum.⁶³ In model sebum systems, terpenoids with greater lipophilicity exhibit sebum partitioning and enable follicular entry as they preferentially “sink” into follicular ducts, thus enhancing efficacy against follicular disorders while also promoting transport of actives across the stratum corneum.⁶⁴ Polyphenols are known to interact with lipid headgroups via hydrogen bonding and dipole interactions, and lipid-polyphenol interactions have been shown in model membranes to alter lipid packing; such properties suggest that polyphenol coronas may modulate stratum corneum lipid structure and enhance epidermal contact, although definitive in-skin evidence remains limited.^65,66 The addition of a polysaccharide’s hygroscopic nature increases stratum corneum hydration and swelling, further decreasing barrier function while simultaneously improving epidermal residence time through bioadhesive interactions suggesting potential to maintain the hydration gradients that keep the stratum corneum and follicular orifice more permeable.^67,68 However, before these nanocarriers reach viable epidermal cells, they first encounter the dynamic surface microbiome.

Before reaching viable skin layers, topically applied nanoparticles first encounter the skin’s surface microbiome comprised of a community of bacteria and fungi (eg, Cutibacterium acnes, Staphylococcus spp., Malassezia) embedded within secreted enzymes, lipids, and extracellular polymeric substances (EPS). Recent biofilm-nanoparticle studies observing skin-relevant organisms show that microbial EPS matrices can impede nanoparticle diffusion, adsorb particles, and alter their aggregation, charge, and mobility, effectively reshaping nanoparticle behavior before they even reach the stratum corneum or follicular openings.^69,70 These interactions can create a secondary bio-corona composed of microbial polysaccharides, proteins, and extracellular DNA, which may influence downstream penetration and biological reactivity. Thus, the skin’s surface/follicular microbiome should be considered an active, biochemically reactive interface which could substantially affect subsequent penetration or delivery.

Once a green nanocarrier traverses the microbiome, sebum, and stratum corneum barriers and enters the viable epidermis or dermis, it comes into close contact with live skin cells (keratinocytes, fibroblasts, and endothelial cells). At this stage, nanoparticle internalization generally proceeds via active endocytotic pathways rather than passive diffusion. Depending on particle size, surface charge, coating, and corona composition, the dominant cellular entry routes are clathrin-mediated endocytosis or caveolae (lipid-raft)-mediated endocytosis, along with other forms of pinocytosis or micropinocytosis.^71,72 For example, studies show that nanoparticles between ~20 and ~100 nm preferentially use caveolae-mediated uptake, while those around 100-200 nm are often internalized via clathrin-coated pits.^73,74 After membrane wrapping and vesicle scission, the particles are sequestered in endosomes or caveosomes; subsequent intracellular trafficking, via endosomal maturation, lysosomal fusion, or Golgi routing, then determines the fate of the nanoparticle cargo (eg, degradation, release, recycling).⁷³ Importantly, these uptake pathways are strongly influenced by nanoparticle physicochemical properties (size, corona, charge, stiffness), meaning that the engineered phytochemical corona of green nanocarriers can modulate not just penetration through the skin, but also cellular uptake efficiency and intracellular fate.⁷⁵ A mixed corona integrating these classes of phytochemicals produces a multi-targeted enhancement of delivery, increasing both the rate of follicular uptake and the cumulative amount of material retained and delivered.

The same phytochemical interactions that stabilize green-synthesized nanoparticles during formation also extend the effective half-life of the contained actives on the skin. Polyphenol-rich coronas exhibit strong antioxidant and electron-donating capacities, thereby enhancing resistance to ROS-driven degradation.^76,77 Terpenoid constituents increase hydrophobic packing within the corona, thereby enhancing barrier interactions and stabilizing the nanocarrier in lipid-rich environments, whereas polysaccharides form hydrated, viscoelastic shells that buffer pH, limit oxygen diffusion, and provide steric protection.¹¹ Together, these molecular classes generate a multifunctional protective interface unique to green-synthesized systems. Importantly, in vivo, this engineered phytochemical corona is rapidly remodeled by the adsorption of endogenous proteins, forming a secondary ‘bio-corona’ that alters cellular uptake, biodistribution, and immune recognition. Thus, the performance of green nanocarriers in the skin reflects both the contributions of the phytochemical capping layer and the subsequent protein corona.^78,79

Phytochemical coronas can gradually reorganize or desorb under physiological conditions, enabling slow, sustained release of core-encapsulated actives. In inflamed or barrier-disrupted skin, where the microenvironment becomes mildly acidic, protonation of phenolic and polysaccharide groups weakens the intermolecular cohesion of the corona, accelerating disassembly and enhancing drug availability. This pH-dependent release is exemplified by resveratrol-loaded nanoparticles that exhibit significantly higher release at pH 5.2 than at pH 7.4.⁸⁰ Beyond pH shifts, many plant metabolites possess inherent redox sensitivity. For example, EGCG, a specific type of catechin found in green tea, undergoes oxidative destabilization in high-ROS environments.⁸¹ Oxidation of phenolic groups disrupts their coordination with the nanoparticle surface, promoting corona softening and active diffusion specifically in oxidative sites. Thus, green nanoparticles exhibit accelerated release upon ROS- or pH-triggering, enabling targeted deposition to inflamed or ROS-rich areas of the skin.

This environmentally responsive release is intimately linked to the construction of a synergistic antioxidant interface at the nanoparticle surface. Phytochemical coronas rich in flavonoids, phenolics, and proteins not only generate ROS/RNS-scavenging activity but also function as redox-labile shells whose interactions are progressively weakened by oxidative stress. Therefore, in addition to utilizing ROS as a trigger for drug release, the corona simultaneously reduces local ROS concentrations, forming a delivery system that responds to higher oxidative burden while gradually scavenging the ROS that initially activated it.^82,83 The result is a dual antioxidant system: the corona’s intrinsic radical-scavenging molecules buffer oxidative damage while oxidation-induced loosening of the corona increases drug release to where oxidative pathology is greatest. The coupling of antioxidant activity with ROS-dependent delivery demonstrates the relevance of nanocarriers in enhancing therapeutic efficacy in inflamed or stressed skin microenvironments.

In addition to effectively scavenging ROS, phytochemical-containing coronas can react with reactive carbonyl species (RCS) generated during lipid peroxidation, including 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and acrolein.⁸⁴ Their flavonoids, phenolic acids, and amino-rich proteins form Michael adducts or Schiff base condensates with reactive carbonyl species, thereby directly sequestering RCS and preventing downstream protein carbonylation and ECM damage.⁸⁵

A systematic review of flavonoid-loaded nanoparticles demonstrated that encapsulation significantly downregulated pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-18 across multiple in vitro and in vivo models, highlighting the enhanced bioactivity that emerges when these compounds are delivered through nanoscale carriers.⁸⁶ In addition to reducing the presence of specific cytokines, phytochemical-containing nanocarriers also impact core inflammatory signaling pathways. Numerous green-synthesized nanoparticles, including AgNPs, AuNPs, and ZnONPs, have been shown to suppress COX-2 and iNOS expression and inhibit NF-κB activation, effects attributed to the synergistic interaction between the inorganic core and the phytochemical corona that facilitates greater cellular uptake and intracellular delivery.⁸⁷ Consistent with this pattern, phytochemical-associated AgNPs have been reported to reduce IL-12 and TNF-α secretion and to lower COX-2 gene expression, particularly at higher nanoparticle concentrations, further supporting the idea that nanoscale assembly concentrates anti-inflammatory phytochemicals to levels sufficient to enhance inhibition of key inflammatory mediators.⁸⁸ Together, these findings show that nanoparticle-mediated concentration and delivery substantially enhance the suppression of inflammatory-mediating cytokines and reinforce inhibition of COX-2, iNOS, and NF-κB, yielding more potent and multidimensional anti-inflammatory responses.

Phytochemical coronas on green-synthesized nanocarriers help sustain cytoprotective signaling by preventing the rapid degradation or inactivation of Nrf2-activating molecules (eg, flavonoids, phenolic acids), enabling prolonged activation of the endogenous Nrf2/HO-1 antioxidant pathway. In vivo studies of green-synthesized silver nanoparticles (AgNPs) show that topical application enhances cutaneous antioxidant enzyme activity (SOD, catalase, GPx, GR) while suppressing lipid peroxidation in wounded skin, suggesting that the antioxidant corona remains active over time and mitigates oxidative stress during healing.⁸⁹ Moreover, analyses of plant-derived exosome-like nanovesicles (PENs) reveal that their molecular cargo, including polyphenols and other phytochemicals, can modulate oxidative stress and inflammatory signaling, reinforcing the idea that corona-rich nanocarriers create a durable antioxidant shield that persists long enough to protect DNA, lipids, and proteins from UV- or ROS-induced damage.^90,91

Beyond cytoprotection, green nanocarriers have been shown to stimulate regenerative processes, including collagen deposition, fibroblast proliferation, and angiogenesis, effects likely mediated by enhanced dermal penetration and sustained delivery of reparative phytochemicals. In turn, the increased exposure enhances cellular migration (eg, fibroblasts, keratinocytes), collagen synthesis, angiogenesis, and extracellular matrix remodeling, enforcing nanocarrier relevance to dermal repair.^92,93 For instance, topical treatment of murine wounds with green-synthesized silver nanoparticles derived from cucumber pulp extracts,⁹⁴ as well as from Azadirachta indica and Catharanthus roseus markedly increased collagen deposition, accelerated wound closure, and improved tissue regeneration metrics compared to untreated controls.⁸⁹ In a separate model, exosome-like nanovesicles derived from kale (Brassica oleracea var. acephala) were demonstrated to upregulate type I collagen expression in human dermal fibroblasts, suggesting that plant-derived nanocarriers can directly influence fibroblast ECM production at the cellular level.⁹⁵ This combined evidence supports the hypothesis that when phytochemical-rich nanocarriers reach the dermis, they can deliver reparative signals to fibroblasts and vascular cells while increasing keratinocyte motility, thereby enhancing fibroblast proliferation, re-epithelialization, collagen synthesis, and neovascularization, all integral to dermal repair.

Regarding ECM production, additional studies using nanocomposite dressings containing green-synthesized AgNPs report not only enhanced collagen fiber formation and vascularization in healed tissue but also reduced scarring and improved structural organization of the healed skin.^89,96 Taken together, these data imply that phytochemical-corona nanocarriers actively promote skin regeneration, supporting both dermal matrix rebuilding and epidermal barrier restoration after injury or UV insult.

The safety and translational potential of green-synthesized nanocarriers depend on their physicochemical properties, biological interactions, and the integrity of the phytochemical systems that produce them. As nanoparticle dimensions decrease, their catalytic surface area increases, enhancing cellular uptake but also amplifying their capacity to generate ROS. Excessive ROS can exceed antioxidant defenses and induce mitochondrial dysfunction, lipid peroxidation, DNA damage, and apoptosis in keratinocytes and dermal fibroblasts. These effects are often nonlinear; particles in the 20-30 nm range frequently exhibit disproportionately higher oxidative and inflammatory activity,⁹⁷ underscoring the importance of establishing dose-dependent cytotoxicity thresholds for cutaneous applications. Within this framework, green-synthesized nanoparticles generally exhibit improved biocompatibility compared to chemically synthesized analogues.⁹⁸ Plant-derived capping agents moderate surface reactivity, reduce ROS generation, and impart additional antioxidant or anti-inflammatory properties. Yet, “green” does not equate to inherently safe. Toxicity still depends on concentration, dissolution behavior, accumulation potential, and the stability and composition of the phytochemical corona, necessitating rigorous and standardized toxicological evaluation for all nanoformulations.

Regulatory oversight remains a significant barrier to clinical translation. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recognize that nanoscale materials may differ substantially from their bulk counterparts in terms of penetration and biological response,⁹⁹ but nanocosmeceuticals currently lack dedicated regulatory pathways. Instead, developers must navigate existing cosmetic or drug frameworks while providing additional characterization—particle size distribution, aggregation behavior, surface chemistry, and long-term safety—to demonstrate that nano-enabled formulations do not introduce novel risks. These challenges are compounded by the inherent variability of green synthesis. The phytochemical composition varies across plant species, cultivars, harvest seasons, extraction methods, and geographic origins, resulting in nanoparticles with inconsistent size, morphology, and surface chemistry.¹⁰⁰ Such variability complicates reproducibility, scalability, and regulatory assessment, particularly when phytochemical mixtures serve as both reductants and capping agents. Ensuring physicochemical stability during storage is equally challenging; green-synthesized nanoparticles may undergo aggregation, oxidative changes, or loss of capping integrity over time, thereby altering their biological profile.

These scientific and regulatory issues intersect with broader ethical and environmental considerations. Large-scale production of green nanocarriers depends heavily on botanical resources, raising concerns about sustainability, biodiversity loss, and ecological strain—particularly when high-demand species originate from regions already under environmental pressure. Many plants used in nanocarrier synthesis, including Centella asiatica (L.) Urb., Curcuma longa L., Azadirachta indica A. Juss., and Psoralea corylifolia L., possess deep ethnomedical histories and are stewarded by communities whose traditional knowledge has guided their therapeutic use for centuries. As these botanicals are incorporated into high-value nanocosmeceutical pipelines, issues of bioprospecting, intellectual property, and equitable benefit-sharing become relevant. Ethical frameworks aligned with the Convention on Biological Diversity and the Nagoya Protocol emphasize fair compensation, community participation, and conservation of biodiversity hotspots—principles that help prevent the repetition of extractive research practices.¹⁰¹ Integrating insights from ethnobotany and medical anthropology can therefore strengthen the sustainability and social responsibility of green nanotechnology by acknowledging traditional knowledge systems, promoting local stewardship, and supporting ethical sourcing pathways.

The environmental fate of nanoparticles warrants consideration as well. Metal and metal-oxide nanomaterials may accumulate in soil or aquatic ecosystems, disrupt microbial communities, or undergo transformations into more reactive or persistent species.¹⁰² Even biogenic nanoparticles require life-cycle assessment, as large-scale extraction generates biomass waste and potential solvent residues that must be managed responsibly. Strategies such as closed-loop extraction, biodegradable nanocarrier design, and green chemistry-aligned fabrication can mitigate environmental burden while supporting the long-term viability of phytochemical-driven nanocosmeceuticals.

As green-synthesized nanocarriers continue to evolve, several emerging avenues offer substantial potential to refine their therapeutic precision and accelerate their translation into dermatologic practice. One of the most promising developments is the integration of computational modeling to better understand phytochemical-nanocarrier interactions. Molecular dynamics simulations, density functional theory calculations, and machine learning models now enable prediction of binding affinities, encapsulation efficiencies, and release kinetics based on the structural features of both the phytochemical and the nanocarrier matrix. These tools can help identify optimal pairings, such as selecting specific flavonoids for chitosan-based nanoparticles or matching terpenoids with lipidic nanostructures, while reducing the need for trial-and-error.^103,104 Computational workflows also facilitate the prediction of nanoparticle behavior at the skin interface, including interactions with stratum corneum lipids, binding to keratin, and partitioning into follicular reservoirs, ultimately guiding the rational design of next-generation nanocosmeceuticals.

Future research is also moving toward synergistic formulations that leverage the complexity of botanical chemistry rather than relying on isolated compounds. Multi-herbal nanosystems—encapsulating combinations of flavonoids, terpenoids, phenolics, and alkaloids from complementary plant sources—may better replicate the polypharmacology of traditional, whole-plant herbal medicine while improving stability and targeted delivery. Green nanocarriers provide an ideal platform for such combinations, enabling co-loading of chemically diverse metabolites and orchestrating their release in response to oxidative or inflammatory cues. These hybrid nanosystems may prove particularly valuable in multifactorial skin disorders such as acne, atopic dermatitis, psoriasis, and photoaging, where targeting a single pathway is seldom sufficient. As the mechanistic understanding of phytochemical crosstalk expands, nanotechnology offers a way to translate these synergistic interactions into controllable, clinically relevant formulations.

A parallel frontier is the development of advanced preclinical testing platforms that more accurately recapitulate human skin physiology. Traditional 2D cell cultures and animal models often fail to capture the complexity of human barrier function, microbiome interactions, and immune responses. In contrast, 3D skin organoids, reconstructed human epidermis, and microfluidic “skin-on-chip” systems provide anatomically and functionally relevant environments to evaluate nanoparticle penetration, retention, and biological activity.¹⁰⁵ These platforms enable real-time visualization of nanocarrier distribution within epidermal and dermal compartments, assessment of immune cell-nanoparticle interactions, and modeling of chronic inflammatory environments. Integrating green nanocarriers with organ-on-a-chip systems may also help address long-term safety concerns, including cumulative ROS exposure and nanoparticle-induced dysbiosis.

The shift toward personalized dermatology further enables the tailoring of nanocarrier-based therapies. Individual variation in sebum composition, skin lipidomics, pH, barrier integrity, and —critically—the skin microbiome influences both phytochemical metabolism and nanoparticle behavior. As microbial profiling tools become more accessible, nanocarriers could be engineered to release cargo in response to microbially derived enzymes, quorum-sensing molecules, or metabolic gradients specific to dysbiotic states. Such microbiome-guided nanotherapy could optimize phytochemical delivery for conditions characterized by microbial imbalance, including acne, seborrheic dermatitis, and atopic dermatitis. In the long term, customizable nanocosmeceuticals may emerge that adjust their release properties in response to real-time microbiome signatures. That said, a major caveat remains: despite growing evidence of nanoparticle–biofilm interactions in vitro and in environmental or infection-related contexts, there is currently little published work examining how green-synthesized, phytochemical-capped nanocarriers behave in realistic skin-microbiome environments (ie, with human skin commensals, naturally formed skin biofilms, sebum/lipids, sweat, etc.). Therefore, while it is plausible that skin surface microbiota will influence corona integrity, nanoparticle diffusion, and bioavailability, the exact dynamics remain hypothetical. Experimental confirmation (ex vivo human skin with its native microbiome, or in vivo models) is required before this may be considered an established phenomenon.

Another emerging dimension involves the epigenetic actions of phytochemicals and how these may be amplified through targeted nanocarrier delivery. Many of the bioactive classes discussed in Section 3—including flavonoids, phenolic acids, stilbenes, and selected terpenoids—modulate DNA methyltransferases, influence histone acetylation and deacetylation, and regulate microRNAs that control NF-κB, Nrf2, MAPK, and mTOR signaling.^106,107 These chromatin-level effects intersect directly with pathways relevant to photoaging, hyperpigmentation, chronic inflammation, and wound healing, positioning epigenetic modulation as a promising but underutilized therapeutic mechanism in dermatology. However, the clinical utility of these compounds has been constrained by their poor solubility, instability, and limited cellular uptake. Green-synthesized nanocarriers address these barriers by stabilizing labile molecules, enhancing transdermal penetration, and improving cytoplasmic and nuclear delivery, leading to more durable intracellular exposure.^9,108 As understanding of cutaneous epigenomics deepens, phytochemical-loaded green nanocarriers may provide a targeted, sustainable platform for modulating environmentally responsive gene expression in chronic skin disease.

Beyond these research directions, important clinical implications are emerging for dermatologic practice. Phytochemical-loaded nanocarriers may enhance the efficacy of topical therapies by improving stratum corneum penetration, increasing local bioavailability, and reducing degradation of labile compounds. These advantages are particularly relevant in conditions such as acne, atopic dermatitis, psoriasis, and photoaging, where multimodal pathogenesis often necessitates combination therapy. By enabling the co-delivery of anti-inflammatory, antioxidant, and antimicrobial agents on a single platform, these systems may reduce reliance on systemic treatments or simplify topical regimens, thereby improving adherence and tolerability. While most applications remain investigational, these technologies reflect a shift toward more targeted, stable, and mechanism-driven dermatologic therapeutics.

Taken together, these developments underscore the transformative potential of phytochemical-based green nanotechnology in dermatologic therapy. By combining the molecular breadth of botanical medicine with the precision of nanoscale engineering, green nanocarriers address the long-standing limitations of phytochemical instability, poor solubility, and limited cutaneous penetration. Continued progress in computational design, synergistic formulation strategies, advanced preclinical modeling, microbiome-informed personalization, and epigenetic modulation will further expand their clinical utility. Ultimately, integrating pharmacognosy, materials science, and dermatology positions green nanocosmeceuticals as a compelling paradigm for sustainable, targeted, and biologically sophisticated skin therapeutics.