Unraveling the Physicochemical Landscape of Organoselenium Compounds in Nanocarrier Systems

Abstract

In recent years, publications on organoselenium compounds have increased markedly, expanding their applications in therapeutic, nutraceutical, agricultural, and environmental fields. However, intrinsic properties such as high lipophilicity and chemical reactivity often limit their bioavailability and therapeutic performance. Advances in self‐assembled nanostructures have enabled more efficient delivery, improving solubility and bioavailability while reducing toxicity. This review is the first to focus specifically on the physicochemical interactions governing the stability and performance of organoselenium‐based nanostructures. We analyze recent formulations, emphasizing hydrophobic, van der Waals, electrostatic, and hydrogen bonding interactions that control nanocarrier behavior. Additionally, we discuss emerging strategies and future applications for the rational design of safer and more effective organoselenium delivery systems.

Main nanocarriers employed to enhance the bioavailability and transport of organoselenium compounds. The image illustrates the key interaction forces that stabilize these organoselenium species in solution, enabling their application in drug delivery systems, catalysis, photoelectronic devices, and sensing technologies.

1. Introduction

Organoselenium compounds represent a significant class of organochalcogens, offering versatility across various areas of chemistry, including catalysis, organic synthesis, the synthesis of natural products, and the development of new pharmacological compounds. Various studies have verified the pharmacology and toxicology of organoselenium compounds, emphasizing their anti‐inflammatory, hypoglycemic, chemotherapeutic, and antimicrobial activities [1, 2]. However, their clinical translation and technological applications often require carrier systems to enhance their stability, bioavailability, and functionality, since these compounds are usually poorly water‐soluble.

The considerable progress in the pharmacology and toxicology of chalcogens has fueled interest in the synthesis and reactivity of new organic and inorganic derivatives [3, 4, 5, 6, 7]. The distinctive reactivity of these compounds has driven extensive research in both areas. A search conducted in the Web of Science database in November 2025 using the terms ‘organoselenium,’ ‘organotellurium,’ and ‘selenium inorganic’ retrieved 22,505; 21,919; and 7176 articles, respectively, highlighting the rapid scientific advancement in this field (Figure 1).

FIGURE 1.

Data extracted from the Web of Science database (November 2025). The dataset includes cumulative publications from 1975, beginning with the period 2010–2025.

Recent advancements in nanotechnology, particularly in nanoencapsulation, have significantly expanded the possibilities for delivering active pharmaceutical compounds in aqueous and nonaqueous environments [8, 9, 10] (Figure 2). These developments have been crucial in improving the solubility, bioavailability, dosing, and stability of organoselenium compounds. Innovations in nanostructured drug delivery have led to the design of novel systems that overcome the solubility and stability challenges associated with these compounds [11, 12, 13, 14].

FIGURE 2.

Percentage of the literature found on nanocarriers and organoselenium compounds. Data extracted from the Web of Science database (November 2025). The dataset includes publications indexed between 1975 and 2025.

Recent reviews [11, 15, 16] highlight the diversity of self‐assembled nanostructures developed for this purpose, including liposomes, nanocapsules, nanospheres, nanoemulsions, micelles, and polymeric micelles. These delivery systems enhance the therapeutic potential of organoselenium compounds by facilitating their solubility, stability, controlled release, and vectorization in biological environments.

Despite the growing number of studies on organoselenium‐based delivery systems, most reports focus primarily on pharmacological effects. At the same time, fundamental aspects of the physical‐chemical interactions between the nanocarrier components and organoselenium molecules remain underexplored. Understanding these molecular‐level interactions is key to rationally designing nanocarriers with improved performance, including fine‐tuned release mechanisms, physicochemical compatibility, and structural stability under physiological conditions. Moreover, the intrinsic chemical properties of selenium, such as polarizability and unique redox behavior, can play a critical role in the dynamics and architecture of nanostructured systems.

As an emerging field closely linked to the chemistry of organoselenium compounds, this review explores interactions within nanostructured systems and the mechanisms underlying their stability and consequent bioavailability. A detailed understanding of these interactions is essential for the rational design of controlled release systems, providing insights into functionality, performance, and therapeutic efficacy. Recent studies increasingly emphasize the balance between bioavailability and toxicity, highlighting the importance of optimizing nanostructured carriers to enhance absorption while minimizing adverse effects. Elucidating the physicochemical determinants that govern both delivery efficiency and safety is therefore critical for advancing these systems toward practical biomedical applications.

2. An Overview of Organoselenium Compounds

2.1. Importance of Selenium

Selenium is an essential trace element for human health, playing a crucial role in antioxidant defense, thyroid hormone metabolism, and immune function. Its biological activity is mainly associated with its incorporation into selenoproteins, such as glutathione peroxidases and thioredoxin reductases, which regulate redox homeostasis and protect cells against oxidative stress [17, 18]. Selenium deficiency has been linked to cardiovascular diseases, thyroid dysfunction, impaired immunity, and neurological disorders [18, 19, 20, 21].

In addition to its physiological importance, selenium also has significant implications for cancer prevention. Several studies have demonstrated that adequate selenium intake is associated with a reduced incidence of certain types of cancers, due to its ability to modulate DNA repair mechanisms, apoptosis, and tumor cell proliferation [22]. However, these benefits depend strongly on dose and chemical form, as selenium exhibits a narrow safety margin, being both essential and potentially toxic. Recent studies report a U‐shaped correlation between selenium status and cancer risk. A safe intake has been estimated to range from 110.8 to 124.4 µg/day. A similar U‐shaped association was also observed across multiple subgroups, including men and women, ever‐ and never‐smokers, individuals with BMI < 23 kg/m² and ≥ 23 kg/m², ever‐ and never‐drinkers, and for cancers of the stomach, colon, rectum, and lung [23].

Selenium supplementation has also been investigated in relation to infectious diseases. Recent research highlights its role in improving the immune response to viral infections, including HIV and influenza, by supporting immune cell proliferation and reducing viral replication [24]. These findings reinforce selenium's potential as an adjuvant in nutritional strategies to strengthen immunity. Moreover, selenium has also been investigated in environmental and technological contexts. Its application in nanotechnology, for instance, has enabled the development of selenium nanoparticles (SeNPs) with potential antimicrobial, anticancer, anti‐Alzheimer's, antidiabetic, antioxidant, and antirheumatoid arthritis activities, thereby opening new perspectives for biomedical applications [15, 25]. Therefore, selenium represents a key element at the interface of biology, medicine, and nanotechnology, with significant implications for human health and technological innovation.

2.2. Organoselenium Compounds

In recent years, organochalcogen compounds, particularly those derived from selenium and tellurium, have gained increasing attention due to their high reactivity, selectivity in novel reactions, and fundamental roles in pharmacology and toxicology [2, 3, 4, 26]. Studies have demonstrated that organochalcogens facilitate the oxidation of sulfhydryl groups in biologically active molecules [4, 27, 28]. Notably, the neurotoxic effects induced by these compounds in experimental animals have been attributed, at least in part, to their ability to modulate the sulfhydryl groups of glutamatergic neuron receptors [4, 28]. Furthermore, organochalcogen compounds have been shown to inhibit the activity of sulfhydryl‐dependent enzymes, including δ‐aminolevulinate dehydratase (δ‐ALA‐D), Na⁺/K⁺‐ATPase, and 5‐lipoxygenase, likely due to their interactions with sulfhydryl groups [4, 28, 29].

Organoselenium compounds are gaining prominence due to their versatility across multiple disciplines, including biomedicine, materials science, and electronics [1, 5, 6, 30, 31, 32, 33]. These compounds exhibit antibacterial, anti‐inflammatory, and antioxidant properties and hold significant potential in cancer therapy [2, 31, 34]. In materials science, organoselenium compounds are being explored as innovative fluorescent probes, while selenium‐containing heterocycles play a crucial role in the development of organic conductors, semiconductors, and optoelectronic devices [35, 36, 37, 38]. Additionally, advances in nanotechnology have further expanded their biological applications, reinforcing their multidisciplinary importance.

The continuous development of new synthesis routes has enabled the production of a wide range of selenium‐containing molecules with potential applications. Notable examples include additions of selenium to alkenes, alkynyl and vinyl selenides, selenoesters, selenium‐substituted heterocycles, and other complex structures such as indoles, imidazoles, azaindoles, lactams, oxazolines, oxazoles, selenium‐containing carbohydrates, dialkyl(aryl) diselenides, chalcogenophosphates, and others [1]. Selenium serves as an isosteric substitute for sulfur, often enhancing pharmacological activity without increasing toxicity [1, 39]. Selenium‐containing heterocycles have shown potential for treating cerebral ischemia, while selenocyanate derivatives have demonstrated vigorous antiparasitic activity against Trypanosoma cruziwith minimal toxicity [1, 40, 41]. These compounds represent promising therapeutic candidates for diseases such as diabetes, neurodegenerative disorders, and cancer, primarily through redox modulation via the thioredoxin system. Despite initial concerns regarding toxicity, many selenium‐containing molecules exhibit lower toxicity than the inorganic form of selenium, and their catalytic roles in oxidative reactions further highlight their medicinal and synthetic relevance.

A critical characteristic of organoselenium compounds is their high lipophilicity, which restricts their solubility primarily to organic solvents or oils. This property significantly limits their administration routes [11]. For example, Ebselen and its analogs, recognized for their antioxidant and anti‐inflammatory properties as glutathione peroxidase mimetics, have undergone several clinical trials [27, 28, 42]. In a clinical study evaluating Ebselen for acute ischemic stroke, the compound was administered orally as a bulk suspension in water, a nonoptimized dosage form [11, 42]. It has also been found that Ebselen has low selectivity in binding to reactive cysteines, as it is nucleophilically attached through the amino acid thiol functionality to the electrophilic selenium. However, several clinical trials have shown no signs of acute or long‐term toxicity [42].

Ebselen (2‐phenyl‐1,2‐benzisoselenazol‐3(2H)‐one) was first synthesized and characterized in the early 1980s as a synthetic organoselenium compound designed to mimic the activity of glutathione peroxidase (GPx). This key antioxidant enzyme detoxifies reactive oxygen species (ROS). Initially investigated for its antioxidant and anti‐inflammatory properties, Ebselen also demonstrated cytoprotective, neuroprotective, and antimicrobial activities, prompting early clinical interest in conditions such as ischemic stroke and noise‐induced hearing loss. Over the past 5 years, reviews have further highlighted its antioxidant properties (glutathione peroxidase‐mimetic activity), anti‐inflammatory effects (modulation of the NF‐κB and Nrf2/Keap1 pathways), antiviral action (covalent inhibition of the SARS‐CoV‐2 Mpro and PLpro proteases), neuroprotective effects (reduction of oxidative stress and preservation of synaptic integrity), and antidiabetic potential (improvement of insulin sensitivity via SHIP2 inhibition), establishing it as a multifunctional organoselenium compound of broad therapeutic relevance [43, 44, 45].

Similarly, diphenyl diselenide ((PhSe)₂), another organoselenium compound, exhibits potent antioxidant and anti‐inflammatory activities and presents a solubility profile comparable to related selenium derivatives [28, 41, 46, 47, 48]. Luchese et al. (2013) reported that (PhSe)₂reduces inflammation in a carrageenan‐induced pleurisy mouse model by inhibiting leukocyte infiltration, pleural exudation, and the production of pro‐inflammatory cytokines (TNF‐α, IL‐1β, IL‐6, and IFN‐γ), as well as by decreasing myeloperoxidase (MPO) activity. The antioxidant properties of (PhSe)₂are closely associated, at least in part, with its anti‐inflammatory effects. However, (PhSe)₂also displays strong plasma protein binding, requiring relatively high doses to reach pharmacologically active concentrations in biological tissues [49, 50]. Improving the aqueous solubility of such compounds could help overcome these pharmacokinetic limitations, expand possible administration routes, and enhance their therapeutic potential (Table 1).

TABLE 1.

Summary of nanocarrier types reported in the last 10 years publications involving organoselenium compounds as cargo or carrier materials.

System	Used as	Formulation	Organoselenium compound	Ref
Nanocapsules	Drug delivery	Poly(ε‐caprolactone) Span 80 Medium chain triglycerides Tween 80 (polysorbate 80)	p,p’‐Methoxyl‐diphenyl diselenide	[51, 52]
Nanocapsules	Drug delivery	Canola oil, PCL, Span 80, MCT, Tween 80, PEG	Diphenyl diselenide	[53, 54, 55]
Nanospheres	Catalytic activity	Fmoc‐phenylalanine‐based selenide hydroperoxides (ROOH)	Phenylalanine‐based selenide	[56]
Nanoemulsion	Drug delivery	Cationic surfactants, N,N‐bis[3,3′‐(trimethylammonio)propyl] alkylamide dichlorides Oleic acid Mixed medium chain mono‐ and diglycerides propylene glycol monocaprylate (Capmul PG‐8)	2‐n‐Propylbenzisoselenazol‐3(2H)‐one (BSe)	[57]
Nanoemulsion	Drug delivery	Captex 300 EP/NF, Kolliphor ELP tea tree oil	Ebselen	[58]
Micelles	Drug delivery	Tetronic 1107 (T1107) and Tetronic 904 (T904)	Selenodiazoles	[59]
Micelles	Drug delivery	Organoselenium dendritic polymers	Selenium dendritic	[60]
Micelles	Drug delivery	Amphiphilic block copolymer	Methylseleno‐aspirin	[61]
Nanoemulsion and micelles	Solubility	CTAB Tween 20 SDS	Fosforoselenides compounds	[62, 63]
Liposome	Drug delivery	HSPC/Egg PC/DOPE/mPEG2000‐ DSPE/cholesterol/DDA	Diselanediylbis decanoic acid (DDA)	[64]

3. Major Interactions Between Organoselenium Compounds and Nanocarrier Systems

As stated in earlier sections, organoselenium compounds have attracted significant attention due to their broad spectrum of biological activities. However, their practical application is often limited by low solubility, instability, and unfavorable pharmacokinetics. To overcome these drawbacks, nanocarrier systems, such as liposomes [64], polymeric nanoparticles [65], micelles [59, 60], and dendrimers, have been explored as effective delivery platforms [11]. Nanocarriers are engineered structures that encapsulate, protect, and deliver bioactive molecules, thereby improving their stability, solubility, and targeted delivery. In this context, understanding the major interactions between organoselenium compounds and nanocarrier systems is essential, as these interactions dictate not only the efficiency of encapsulation and release but also the over all therapeutic performance (Table 1).

The interactions governing the association between organoselenium compounds and nanocarrier systems are diverse and can significantly influence their physicochemical behavior and biological performance. Among them, the hydrophobic effect plays a central role, where the nonpolar domains of organoselenium molecules are stabilized within the carrier's hydrophobic core. In addition, hydrogen bonding and van der Waals interactions contribute to the stabilization of organoselenium compound‐nanocarrier systems, while electrostatic forces often dictate loading efficiency and release kinetics depending on the charge characteristics of both organoselenium and nanostructures (Figure 3). In some cases, stronger covalent bonds may be established, leading to more durable conjugation strategies. Surface adsorption phenomena can also occur, affecting organoselenium distribution at the nanocarrier interface. Together, these mechanisms provide a comprehensive framework for understanding how nanocarriers can be tailored to optimize the delivery of organoselenium compounds (Table 2). This section aims to discuss the fundamental types of interactions involved and how they enhance the biomedical applicability of organoselenium compounds.

FIGURE 3.

Description of the main forces involved in the stabilization of organoselenium compounds by nanocarriers. These forces depend on the nature of the stabilizing systems and the intrinsic properties of the organoselenium compounds.

TABLE 2.

Physicochemical forces, assembly mechanisms, and functional performance across nanocarrier systems.

System	Dominant self‐assembly forces	Other significant contributions	Role in encapsulation/effect on performance	Ref.
Micelles	Hydrophobic driving force (solvent‐mediated) ∼ 3–10 kJ mol−1 per –CH2equivalent (size‐dependent); van der Waals (London dispersion ∼ 0.5–5 kJ mol−1(both scale with aggregate size)	Electrostatic (for ionic surfactants), hydrogen bonds (headgroups), solvation/ solvophobic effects, steric packing	Controls core formation and size, determines capacity for solubilizing lipophilic drugs; corona interactions determine colloidal stability	[63, 66, 67, 68]
Emulsions/nanoemulsions	Hydrophobic (oil–water immiscibility), van der Waals (Hamaker attraction between droplets; depend on Hamaker constant A and distance; Hamaker constants for organic systems ∼ 5–50 × 10−20J)	Steric/electrostatic repulsion from surfactant/polymer layers, interfacial tension, hydrogen bonding at interface	Determines droplet stability vs. coalescence, partitioning of active (oil vs water), interfacial loading influences release	[57, 58, 62]
Polymeric nanocapsules/solid nanoparticles	Hydrophobic interactions (for lipophilic actives), hydrogen bonds (polymer–drug, ∼5‐40 kJ mol−1typical ranges), van der Waals (dispersion cumulative can be tens of kJ mol−1per interacting motif)	π‐π stacking (aromatic organoselenium/polymers stacking energies vary ∼ 5–15 kJ·mol−1), electrostatic interactions (charged polymers), crosslinking (network rigidity)	Controls drug‐matrix affinity (entrapment efficiency), diffusional release, mechanical/structural retention	[53, 69, 70, 71]
Adsorption (surfaces: silica, oxides, carbon)	Van der Waals (universal), electrostatic (surface charge attraction/repulsion) can range from small to > 100 kJ mol−1depending on charge and separation, hydrogen bonding (surface OH)	Hydrophobic adsorption (on nonpolar surfaces), coordination/chemisorption (thiols, phosphates to metals), π‐π (graphitic surfaces)	Determines binding strength, selectivity, and capacity; strongly pH/ionic strength dependent	[72, 73]
Liposomes (lipid vesicles)	Hydrophobic effect (bilayer formation), van der Waals (lipid tail packing), hydration repulsion between bilayers	Electrostatic interactions (charged lipids), hydrogen bonding (headgroups), steric/PEG repulsion, bending elasticity (Helfrich energy)	Allows dual encapsulation: hydrophilic compounds in the aqueous core and hydrophobic molecules within the bilayer; bilayer rigidity/fluidity modulates loading, leakage, and release	[64, 74]

Hydrophobic interactions are critical for the encapsulation and stabilization of organoselenium compounds into amphiphilic carriers such as micelles, liposomes, and polymeric nanocapsules. This one refers to the aversion of nonpolar solutes to water, and organoselenium compounds are generally hydrophobic. These interactions minimize the system's free energy by sequestering organoselenium compounds within hydrophobic cores. When hydrophobic ligand‐coated NPs are dispersed in water, for example, hydrophobic interaction serves as an attractive force between NPs. A similar mechanism occurs in the formation of self‐assembly systems such as micelles, liposomes, and others. The hydrophobic environment within carriers reduces oxidative degradation of sensitive organoselenium compounds. In drug delivery, for example, encapsulation of organoselenium compounds such as Ebselen in polymeric micelles has demonstrated enhanced bioavailability and targeted release [59, 72], while lipid‐based carriers stabilize organoselenium compounds in physiological environments, extending their therapeutic half‐life.

The addition of an apolar molecule, like organoselenium compounds, in water, promotes the redistribution of ordered water molecules near apolar molecules and a consequent decrease of the Gibbs energy of the system, which is termed as hydrophobic interaction. This interaction occurs between hydrophobic groups such as benzene rings (π‐π stacking too) or hydrocarbon chains and the hydrophobic regions of biomolecules, with an energy range of 12–20 kJ mol⁻¹. The mechanism of organoselenium compounds with nonpolar moieties involves interaction with the hydrophobic segments of surfactants or lipids, thereby promoting self‐assembly [62].

Beyond stabilizing organoselenium compounds, hydrophobic interactions also dictate the morphology and loading capacity of nanocarrier systems. Stronger hydrophobic interactions tend to produce more compact nanostructures with reduced surface energy, thereby improving colloidal stability and extending in vivo circulation time. Moreover, by modulating the hydrophobic–hydrophilic balance of carrier components, it is possible to fine‐tune the release kinetics of organoselenium compounds, allowing either sustained or stimuli‐responsive delivery. Importantly, the shielding provided by hydrophobic cores not only protects organoselenium compounds from hydrolysis and oxidation but also reduces premature leakage during systemic transport. Taken together, these effects highlight the central role of hydrophobic interactions in optimizing both the physicochemical properties of nanocarriers and the pharmacological performance of organoselenium compounds.

Figure 4 illustrates representative nanostructured systems in which hydrophobic interactions enable the incorporation of organoselenium compounds into amphiphilic carriers such as micelles, liposomes, and emulsions. In micellar systems, nonpolar diselenide derivatives preferentially localize in the hydrophobic core via interactions with surfactant alkyl chains, thereby stabilizing them in aqueous environments [63]. Comparable behavior occurs in liposomal formulations, where poorly water‐soluble organoselenium compounds partition into the lipid bilayer rather than the aqueous phase, occupying the hydrophobic domains of the membrane. Liposomes containing diselenide (Se—Se) bonds may further exhibit redox‐responsive behavior, since cleavage of the Se–Se linkage under specific redox conditions can trigger the release of the encapsulated drug [74]. Hydrophobic domains also play a key role in emulsion‐based systems, where organoselenium compounds are encapsulated in nanoemulsions prepared by rapid dilution and stabilized by bifunctional cationic surfactants. These formulations show high physical stability and improved bioavailability of the active compound, while enhancing antimicrobial activity against Candida albicans [57]. Collectively, these examples demonstrate how hydrophobic microenvironments within nanocarriers facilitate the incorporation and stabilization of organoselenium compounds, supporting their application in biomedical delivery systems.

FIGURE 4.

Representative physicochemical interactions between organoselenium compounds and nanocarrier systems. (a) Reprinted from [63]. Copyright (2011), with permission from Elsevier. (b) Reproduced from [74] licensed under CC BY 4.0. (c) Reprinted from [57]. Copyright (2016), with permission from Elsevier.

Hydrogen bonding represents one of the most relevant noncovalent forces in the association between organoselenium compounds and nanocarriers, playing a pivotal role in stabilizing organoselenium compounds within polymeric matrices and surfactants. These interactions are significant because selenium‐containing groups, such as selenols, selenides, and selenoamides, can act as both hydrogen‐bond donors and acceptors depending on their chemical environment and oxidation state [75, 76]. The relatively high polarizability of selenium atoms enhances these interactions, facilitating the formation of directional hydrogen bonds with hydrophilic components of polymeric matrices [77].

In polymer‐based nanocarriers, hydrogen bonds often form between the drug's selenium moieties and polar groups such as hydroxyl, carboxyl, and amide within the polymer backbone. While selenium can participate in hydrogen bonding, it is not a primary mechanism for stabilizing nanocarriers through interactions with standard polar groups, which are far more likely to form hydrogen bonds with other electronegative parts of the encapsulated organoselenium compound. However, such interactions can increase encapsulation stability and reduce premature drug release by promoting intermolecular cohesion within the carrier matrix. The strength and persistence of hydrogen bonds can modulate the release profile of organoselenium compounds. Stronger or multiple hydrogen bonds tend to retard diffusion, leading to sustained release behavior, whereas weaker, transient interactions facilitate faster release under physiological conditions [78].

These noncovalent interactions are fundamental in maintaining molecular organization and controlling drug mobility, ultimately influencing the physicochemical and biological performance of organoselenium‐based systems. Through directional bonding, hydrogen bonds facilitate the self‐assembly of organoselenium compounds into organized supramolecular architectures, which can be harnessed for both therapeutic and catalytic applications. In micellar or liposomal systems, for example, hydrogen bonding between the organoselenium molecule and the polar headgroups of surfactants [62] or phospholipids may anchor the drug near the interface, influencing both its orientation and release dynamics [57].

Many organoselenium compounds possess ionizable groups or polarizable moieties, where their charge distribution can vary depending on the medium's pH, enabling dynamic interactions with charged polymers, surfactants, or inorganic surfaces. In such cases, electrostatic interactions govern the association of charged organoselenium compounds with oppositely charged carrier systems, providing an effective strategy for improving encapsulation, retention, and controlled release. For instance, SeNPs can interact strongly with positively charged polymers such as chitosan or quaternized chitosan derivatives, forming stable colloidal assemblies [79].

Importantly, the strength of electrostatic binding is highly sensitive to pH variations, which alter the protonation state of both the organoselenium compound and the carrier. Under acidic conditions, amino groups become protonated, strengthening interactions with negatively charged organoselenium compounds; at higher pH, deprotonation weakens these attractions and promotes molecular release. This property allows for pH‐triggered drug release, a key feature for site‐specific delivery in tumor environments [65]

Covalent attachment of organoselenium compounds to carrier matrices represents a robust and widely explored strategy to achieve long‐term stability, sustained release, and enhanced specificity. Unlike noncovalent interactions, covalent bonding provides a permanent linkage between organoselenium molecules and the carrier, minimizing premature leakage and improving pharmacokinetic control. This approach has been effectively used in therapeutic delivery systems, where covalent conjugation converts the carrier–organoselenium complex into a prodrug‐like platform, enabling bond cleavage under specific biological stimuli such as redox potential, pH variations, or enzymatic activity [80]. Recent studies illustrate this trend: selenide‐functionalized hydrogels have been engineered to provide ROS‐triggered degradation [81], and diselenide‐crosslinked polymeric micelles have shown enhanced stability, on‐demand cleavage, and improved delivery efficiency for hydrophobic drugs [66, 67]. Together, these systems highlight how covalent bonding enables precise control over organoselenium release kinetics and bioactivity, positioning covalently conjugated organoselenium‐carrier assemblies as a promising class of intelligent, stimuli‐responsive therapeutic platforms.

Charge transfer and chalcogen bonding interactions are increasingly recognized as key contributors to the stabilization and functionality of organoselenium compounds in encapsulated systems. While weaker than covalent bonds, these directional and tunable interactions confer selectivity and reversibility, enabling controlled self‐assembly, electronic modulation, and stimulus‐responsive release behaviors [82, 83]. Chalcogen bonds are noncovalent interactions involving electrophilic regions of chalcogen atoms (such as selenium) interacting with a Lewis base in the same molecule or with another molecular entity (e.g., O, N, or π‐systems). They are particularly relevant for organoselenium compounds, given selenium's capacity to act both as donor and acceptor in supramolecular architectures [84, 85]. Recent studies provide additional examples of functional applications: Sari et al. (2022) [11] demonstrated that organoselenium compounds formulated in nano‐based carriers enhance stability and controlled release, and Chauhan et al. [82] showed that chalcogen bonding can boost the cellular uptake of organoselenium molecules, highlighting its role in designing responsive nanocarrier systems.

Van der Waals interactions play a critical role in the stabilization and organizing organoselenium compounds within nanostructured carriers. These noncovalent forces, including London dispersion and dipole‐induced dipole interactions, become particularly significant in systems where covalent or electrostatic bonding is limited. Dispersion interactions arise from the transient polarization of electron clouds between adjacent molecules or molecular segments. In organoselenium‐loaded nanocarriers, these interactions primarily occur between the aromatic or aliphatic moieties of the organoselenium compounds and the hydrophobic domains or pore walls of the carrier material, thereby enhancing molecular packing, sustaining retention, and controlling release kinetics. Recent studies provide supporting evidence: Lorenzoni et al. [86] highlighted the role of hydrophobic and dispersive interactions in the stabilization of organoselenium‐functionalized nanoparticles; del Olmo et al. [60] demonstrated that the balance between hydrophobic and hydrophilic domains in dendritic polymers enhances retention and delivery efficiency of organoselenium compounds. These findings underscore the fundamental importance of Van der Waals and hydrophobic interactions in the design of nanocarrier systems for controlled organoselenium delivery.

Adsorption processes constitute an important strategy for incorporating organoselenium compounds into nanostructured and self‐assembled delivery systems. In porous hydrophobic surfaces—such as granular activated carbon—adsorption is predominantly governed by nonelectrostatic interactions, including van der Waals forces, hydrophobic interactions, and binding at localized surface sites. Experimental studies using selenocysteine and selenomethionine have demonstrated adsorption behaviors that fit both Langmuir and Freundlich isotherms and exhibit pseudo‐second‐order kinetics, confirming a mechanism driven by surface affinity rather than a chemical reaction [73]. In self‐assembled nanocarriers, hydrophobic domains, such as micellar cores, can act as reservoirs that stabilize organoselenium compounds through hydrophobic and dispersive interactions, thereby reducing their susceptibility to oxidative degradation and improving solubility. These micelles can subsequently be integrated into layer‐by‐layer (LbL) assemblies, where adsorption onto oppositely charged or chemically complementary layers occurs primarily via electrostatic attraction, hydrogen bonding, and hydrophobic contributions, depending on the nature of the polyelectrolytes employed. This combination of hydrophobic compartmentalization and multilayer structuring enables sustained release profiles and preserves the catalytic activity of organoselenium molecules, as reported for micelle‐embedded Ebselen coatings used in biomedical interfaces [72].

Taken together, the various interaction mechanisms governing the association of organoselenium compounds with nanocarrier systems define a finely tuned balance between stability, responsiveness, and functionality. Hydrogen bonding and van der Waals forces contribute to the initial stabilization and structural homogeneity of organoselenium compounds within polymeric and lipid matrices, supporting supramolecular organization and preventing aggregation. If electrostatic interactions occur, usually, enhanced encapsulation and pH‐sensitive release, particularly in polyelectrolyte and tumor‐targeted systems, are the driven mechanisms of stabilization. Charge transfer and chalcogen bonding interactions have emerged as sophisticated design tools that couple structural stabilization with electronic modulation, enabling the creation of redox‐responsive, catalytic, or photoactive materials.

Collectively, these diverse forces enable precise control over encapsulation efficiency, release kinetics, and bioactivity of organoselenium compounds, highlighting the central role of intermolecular chemistry in the design of advanced organoselenium‐based nanoplatforms. A comprehensive understanding of these interactions not only deepens the fundamental insight into organoselenium compound‐nanocarrier behavior but also provides a molecular framework for the rational design of multifunctional, adaptive, and biocompatible delivery systems aimed at therapeutic, diagnostic, and catalytic applications.

The intricate physicochemical interactions governing organoselenium compounds within nanocarrier systems not only determine the structural stability and encapsulation efficiency but also directly influence their functional performance. While understanding these forces provides insight into carrier design and stabilization, it is their downstream impact on biological outcomes that ultimately defines their utility. Consequently, evaluating how these interactions translate into bioavailability, pharmacokinetics, and potential toxicity is essential to assess the therapeutic potential and safety of organoselenium‐based nanostructures fully. The following section, therefore, focuses on the current knowledge of bioavailability and toxicological considerations, linking molecular‐level interactions to biological behavior.

4. Toxicity Versus Bioavailability

Selenium possesses a narrow therapeutic window, meaning that the difference between beneficial and toxic doses is small. Selenium deficiency is associated with oxidative stress and immune dysfunction, while excessive intake may lead to selenosis, a condition characterized by gastrointestinal disorders, alopecia, and neurological damage. This duality highlights the need for precise dose control and advanced formulation strategies in the development of organoselenium‐based therapies [19, 87].

In addition to toxicity concerns, poor bioavailability remains a major obstacle [19]. This limitation is further exacerbated by the intrinsic thiol reactivity of many synthetic organoselenium compounds, which readily form selenenyl‐sulfide intermediates with endogenous cysteine‐containing proteins. Such rapid thiol interactions not only contribute to off‐target toxicity but also diminish metabolic stability and reduce the fraction of intact compound available for absorption and systemic distribution, ultimately impairing adequate bioavailability [4]. Many organoselenium compounds exhibit low aqueous solubility, rapid metabolic degradation, and limited permeability across biological membranes, leading to suboptimal pharmacokinetics. Structural features such as molecular weight, lipophilicity, and susceptibility to enzymatic reduction strongly influence their absorption and systemic distribution [11, 88].

To address these limitations, nanocarrier‐based delivery systems have been widely explored for their ability to improve the pharmacokinetic profiles of organoselenium compounds, thereby increasing bioavailability while reducing systemic toxicity. As illustrated in the schematic example presented in Figure 5, nanoencapsulation can modulate key physicochemical and biological properties of these compounds, such as solubility, stability, metabolism rate, and toxicity.

FIGURE 5.

Scheme of the effect of nanoencapsulation on the toxicity and bioavailability of organoselenium compounds. In this figure, diphenyl diselenide was used as a model.

For instance, polymeric nanocapsules containing the compound p,p′‐methoxyl‐diphenyl diselenide demonstrated chemical stability and did not induce toxicity in mice (no significant changes in body weight or organ histopathology). Moreover, these nanocapsules exhibited enhanced antioxidant activity compared with the free compound, suggesting greater therapeutic potential [52]. Another example involves Ebselen, which was incorporated into liposomes. The resulting formulation increased the compound's bioavailability and circulation time while significantly reducing systemic toxicity compared with free Ebselen, demonstrating the potential of nanocarriers to safely enhance the therapeutic efficacy of organoselenium compounds [89].

These findings highlight the central pharmacological challenge of organoselenium compounds: achieving an optimal balance between therapeutic efficacy and safety. From a physicochemical standpoint, parameters such as particle size, surface charge, and encapsulation efficiency critically influence biodistribution and toxicity [90, 91]. For instance, nanosystems within the 100–200 nm range tend to circulate longer and accumulate more efficiently in target tissues through enhanced permeability and retention, whereas larger or polydisperse particles may be rapidly cleared by the mononuclear phagocyte system [92, 93]. Surface charge also modulates biological interactions: positively charged nanocarriers generally exhibit greater cellular uptake. Still, they may increase nonspecific protein adsorption and cytotoxicity, while neutral or slightly negative surfaces often improve biocompatibility and systemic stability [94, 95]. Similarly, high encapsulation efficiency not only ensures sustained release of organoselenium compounds but also minimizes exposure to free selenium species, thereby reducing the risk of off‐target oxidative stress. Together, these physicochemical properties provide essential levers to fine‐tune redox reactivity, improve pharmacokinetics, and ultimately enhance the therapeutic window of organoselenium‐based nanomedicines [10, 96].

In support of these observations, several recent studies have demonstrated that nanostructured delivery systems can effectively improve the bioavailability of organoselenium compounds while simultaneously reducing their intrinsic toxicity. As summarized in Table 3, different nanocarriers have been shown to enhance key parameters, including solubility, metabolic stability, cellular uptake, and systemic distribution of these compounds. These nanostructured systems not only mitigate thiol‐related toxicity but also potentiate antioxidant, antimicrobial, antifungal, and anticancer activities, including in multidrug‐resistant cell models, reinforcing nanotechnology as an essential strategy to expand the therapeutic window of organoselenium compounds.

TABLE 3.

Main findings on toxicology and bioavailability in models applied to nanocarriers of organoselenium compounds.

Compound	Nanocarrier type	Main results	Model	Ref.
p,p′‐Methoxyl‐diphenyl diselenide (OMe‐PhSe2)	Nanocapsules	Improved chemical stability, no toxicity in mice, enhanced antioxidant activity compared to free compound	In vivo	[51]
Ebselen	Polymer‐engineered liposomes	Enhanced solubility of Ebselen, prolonged circulation time, improved tumor accumulation and anticancer efficacy compared with free Ebselen; reduced systemic toxicity.	In vitro/in vivo	[97]
Ebselen	Silver nanoparticles	Improved antibacterial effect, enhanced anti‐inflammatory activity, inhibition of periodontal tissue destruction, and optimized therapeutic performance	In vitro/in vivo	[98]
Ebselen	Nanoemulsion	Increased antifungal activity; improved solubility and stability; enhanced penetration into fungal cells; reduced required therapeutic dose.	In vitro	[58]
Diphenyl diselenide	Nanocapsules	Selective antimelanoma activity in vitro; improved delivery to melanoma cells; reduced cytotoxicity to nontarget cells;	In vitro	[55]
Diselenide‐bridged	Mesoporous silica nanoparticles	Showed low systemic toxicity and high biocompatibility, with no significant adverse effects. Improved local bioavailability at the injury site while minimizing off‐target exposure.	In vivo	[99]
Organoselenium‐functionalized AuNPs	Gold nanoparticles	Enhanced stability and modulation of cytotoxicity. Covalent bonding minimized toxicity, while noncovalent functionalization increased anticancer activity.	In vitro	[86]
ACAT‐Se (organoselenium nucleoside analog)	pH‐sensitive PLGA nanoparticles	Enhanced antioxidant activity and cytotoxicity in drug‐resistant cancer cells while maintaining tumor selectivity and reducing off‐target toxicity. Improved cellular uptake and enabled co‐delivery with doxorubicin.	In vitro	[100]
ACAT‐Se (organoselenium nucleoside)	Transferrin‐decorated PLGA nanoparticles	Improved ACAT‐Se delivery with controlled release, higher cellular uptake, and greater cytotoxicity in 2D/3D tumor models. Also enhanced antioxidant activity, and showed hemocompatibility, resulting in higher efficacy and lower off‐target toxicity.	In vitro	[101]

5. Other Applications of Organoselenium Compounds

Organoselenium compounds have gained increasing relevance across several interdisciplinary domains beyond their well‐established antioxidant, anticancer, and anti‐inflammatory activities. Their versatile redox chemistry and structural tunability have enabled applications that span catalysis, materials science, virology, neuroprotection, agriculture, and surface engineering.

In green and sustainable chemistry, these compounds serve as valuable catalysts, promoting diverse oxidative and reductive transformations under mild, eco‐friendly conditions and broad compatibility with different functional groups. Both selenides and diselenides are efficient in asymmetric oxidations, epoxidations, and Baeyer‐Villiger reactions, often employing hydrogen peroxide or molecular oxygen as green oxidants [102]. Diphenyl diselenide, for instance, catalyzes the oxidation of alcohols and sulfides in aqueous media with remarkable selectivity [103], while organoselenium‐based catalysts often present recyclability and lower toxicity, reinforcing their potential as sustainable alternatives to heavy‐metal systems.

In addition to their direct catalytic activity, organoselenium motifs have been incorporated into catalytic systems as ligands or functional groups that coordinate transition metals. The soft donor character of selenium enables the formation of stable coordination environments with metals such as Pd, Cu, and Ru, thereby modulating catalytic reactivity and selectivity [104]. This strategy has been extended to heterogeneous catalysis, where selenium‐containing ligands are anchored to solid supports, such as silica or magnetic nanoparticles. In several reported systems, magnetic cores such as Fe₃O₄ are coated with silica and further functionalized with organic ligands containing selenium and amine donor groups, which coordinate catalytically active metals at the nanoparticle surface [105]. These core–shell architectures combine the catalytic activity of metal centers with the advantages of heterogeneous systems, including improved stability and facile catalyst recovery through magnetic separation [104, 105, 106, 107, 108].

In the biomedical field, several organoselenium derivatives have demonstrated antiviral activity through mechanisms that include interference with viral proteases and modulation of host oxidative stress. Ebselen is a notable example, capable of inhibiting the main protease of SARS‐CoV‐2 and thereby suppressing viral replication [109]. Compounds such as selenazoles and selenoureas have also shown broad‐spectrum antiviral activity against viruses like herpes simplex and influenza, primarily by disrupting redox‐sensitive viral enzymes [110]. These findings highlight the promise of organoselenium scaffolds for the development of multifunctional antiviral agents.

Organoselenium compounds’ relevance extend into neuroprotection, where specific organoselenium molecules interact with neurotransmission pathways, offering potential therapeutic value for neurodegenerative and neuropsychiatric conditions. Diphenyl diselenide and Ebselen modulate glutamatergic and GABAergic neurotransmission through redox‐dependent mechanisms, exerting neuroprotective and anticonvulsant effects in experimental models of epilepsy [4]. Additionally, newly designed selenium‐indole hybrids have shown inhibitory activity against monoamine oxidase B (MAO‐B), suggesting future utility in Parkinson's disease management [111].

In materials science and nanotechnology, selenium‐containing polymers and nanocomposites are being explored for applications in electronics, optics, and sensing. Their semiconducting behavior, combined with reversible redox transitions, enhances conductivity, photostability, and charge mobility in organic electronic devices [80]. Poly(selenophene)‐based conjugated polymers, for example, have been investigated in flexible solar cells and biosensors, often outperforming sulfur analogs. Selenium‐doped carbon nanomaterials are also under evaluation as electrocatalysts in energy storage and conversion systems [112].

In agriculture, organoselenium compounds are gaining attention as micronutrient supplements that enhance crop tolerance to abiotic stresses while improving nutritional value. Selenium‐enriched fertilizers have been shown to reduce oxidative damage and stimulate plant development under drought and salinity stress [113]. In animal nutrition, selenium‐enriched yeast and selenoamino acids are incorporated into feed to support antioxidant defenses, strengthen immune responses, and improve reproductive outcomes in livestock [114].

Finally, the integration of organoselenium moieties into polymeric coatings has yielded self‐sterilizing and antifouling materials suitable for biomedical and industrial applications. These selenium‐functionalized surfaces generate ROS in situ, preventing bacterial adhesion and suppressing biofilm formation [115]. Such coatings have been successfully applied to catheters, surgical tools, and water treatment membranes, providing durable antimicrobial protection without relying on leachable biocides [116]

These findings highlight the remarkable functional versatility of organoselenium compounds, whose redox plasticity and structural tunability enable applications ranging from catalysis and therapeutics to materials science and agricultural biotechnology. Although these advances represent significant progress, they also reveal unresolved challenges related to safety, mechanistic understanding, and translational feasibility. Addressing these gaps will be essential for guiding the next generation of organoselenium‐based technologies.

6. Summary and Outlook

This review examined the physicochemical forces governing the organization, stability, and performance of organoselenium‐nanocarrier systems, ranging from noncovalent interactions to covalent anchoring strategies. Hydrophobic interactions strongly influence the self‐assembly of both organoselenium cargos and amphiphilic building blocks, defining core–shell organization and promoting efficient encapsulation. Van der Waals forces modulate intra‐carrier packing and contribute to the cohesive integrity of the nanostructure. In addition, steric stabilization, electrostatic interactions, solvation forces, and hydration repulsion collectively maintain colloidal stability, preventing premature aggregation or phase separation. These interactions are also key determinants of the release profile, as they regulate molecular mobility and diffusion within the carrier matrix, enabling controlled or stimuli‐responsive delivery.

As a result, the integration of organoselenium compounds into nanocarrier systems has evolved from an emerging concept to an ongoing strategy with many advantages. Many studies have demonstrated that nanoformulations of organoselenium derivatives can enhance their physicochemical performance and improve solubility, stability, and biological availability while decreasing toxicity. However, beyond formulation improvements, a deeper understanding of the molecular interactions between organoselenium compounds and the nanocarrier matrix is a key factor. It seems a central topic to advancing this field, which is our central point of view in this review. These interactions govern encapsulation efficiency, release dynamics, and availability. Therefore, future work should not only report biological outcomes but also elucidate how intermolecular forces and nanoscale organization dictate system performance. Although pharmaceutical and therapeutic applications remain the main driving force for organoselenium‐based nanocarriers, these systems have also found relevance in broader domains such as catalysis and agricultural applications.

Integrating computational calculation and molecular modeling offers a compelling strategy to complement experimental formulation work [117]. Techniques such as molecular dynamics (MD) simulations can provide atomistic and meso‐scale insights into how a given organoselenium molecule might orient, partition, and interact within a candidate nanocarrier. Although we did not identify a study that explicitly applies this approach to organoselenium‐loaded nanocarriers, the literature provides successful precedents in hydrophobic drug systems, validating the concept and motivating its application in this context [118]. In the authors’ opinion, the focus could increasingly shift from empirical formulation toward a molecularly informed design of organoselenium‐encapsulated nanostructures, guided by both experimental characterization and computational insights. This perspective binds interfacial chemistry and nanoscale interaction.

As a promising eco‐friendly strategy, biosurfactants have emerged as amphiphilic agents for the design of environmentally sustainable nanocarriers capable of encapsulating lipophilic compounds [119, 120, 121]. These bio‐based molecules combine interfacial efficiency, biodegradability, and biocompatibility, providing new opportunities for the formulation of nanocarriers. Several recent studies have demonstrated this potential: mannose‐based surfactants efficiently stabilized oil‐in‐water nanoemulsions with low energy input, enhancing the dispersion of hydrophobic phases [122]; surfactant‐stabilized poly(D,L‐lactide) nanoparticles exhibited excellent colloidal stability and skin permeation with reduced cytotoxicity [123]; and triblock polymer–modified liposomes incorporating sodium cholate hydrate acting as a biosurfactant successfully co‐encapsulated hydrophilic and hydrophobic compounds, improving vesicle stability and permeability [124]. Together, these findings illustrate how biosurfactants can act as both structural and functional components in nanocarrier systems, as well as be biocompatible and sustainable, offering an alternative for new nanocarrier formulations. No reports currently describe the use of biosurfactants in combination with organoselenium compounds, highlighting a promising opportunity for further research.

Overall, the perspectives provided in this review highlight the relevance of physicochemical interactions as central drivers of functionality in organoselenium‐based nanocarriers. The size, surface chemistry, and morphology of the resulting nanocarriers substantially influence biological fate, including cellular uptake pathways, circulation time, and toxicity. Consequently, understanding the interplay of intermolecular forces in these systems is essential for rational design, optimization, and safe implementation. A deeper mechanistic understanding of these forces will be critical for guiding next‐generation strategies to enhance bioavailability, reduce toxicity, enable targeted delivery, and expand the scope of organoselenium applications across biomedical, catalytic, and multifunctional domains.

Author Contributions

Romelly Eugenia Rojas Ramírez: conceptualization, formal analysis, investigation, writing – original draft, writing – review and editing. Tielle Moraes de Almeida: formal analysis, investigation, writing – original draft, writing – review and editing. Daiani Canabarro Leite: conceptualization, formal analysis, investigation, writing – original draft, writing – review and editing. Gilson Zeni: methodology, funding acquisition, supervision, writing – review and editing.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (grant 21/2551‐0002314‐7), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (grants PROEX# 88881.844988/2023‐01, AUXPE# 1333/2023), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant 404471/2023‐4).

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Romelly Eugenia Rojas Ramírez received her B.S. degree in Chemistry (2007) and an M.Sc. degree in Chemical Engineering from the Universidad Central de Venezuela (2016). In 2021 she obtained her Ph.D. degree in Chemistry from the Federal University of Paraná (UFPR, Brazil) under direction Prof. Rilton Alves de Freitas. She has served as a Visiting Professor at the Universidade Federal de Santa Maria (UFSM, Brazil) and has extensive experience in research and project development in chemistry, pharmacy, industrial quality, polymers, STEM education, natural gas, and food quality. Her current research focuses on colloidal stabilization, polymers, liposomes, surface interactions, organoselenium–surfactant compatibility, micelles, and pH‐responsive nanocapsules.

Tielle Moraes de Almeida received her B.S. degree in Pharmacy from the Universidade Federal de Santa Maria (UFSM, Brazil) in 2014 and her M.Sc. degree in Pharmacology and Therapeutics from the Universidade Federal do Rio Grande do Sul (Brazil) in 2016. She obtained her Ph.D. degree in Pharmaceutical Sciences from UFSM in 2024, with research focused on the development and biological evaluation of nanotechnological drug delivery systems. From 2024 to 2025, she conducted postdoctoral research in Pharmaceutical Technology at UFSM. She is currently a researcher at the Surface and Macromolecules Laboratory (SM Lab) at UFSM and the CEO/founder of Scivet. Her research interests include nanotechnology, pharmaceutical technology, biomaterials, and drug delivery systems for therapeutic applications in humans and animals.

Daiani Canabarro Leite received her B.S. degree in Chemistry from Universidade La Salle (Brazil) in 2010, and her Master's degree (2013) and PhD degree (2017) in Chemistry from Universidade Federal do Rio Grande do Sul (Brazil). She is currently (2023 ‐ present) an Assistant Professor in the Department of Physics at Universidade Federal de Santa Maria (Brazil). She is one of the leaders of the Surface and Macromolecules Laboratory (SM Lab). Her research interests include the physical chemistry of (bio)polymers and colloids, with emphasis on the development of (bio)polymeric systems for application as adsorbents and drug delivery carriers.

Gilson Zeni received his M.S. degree from the Federal University of Santa Maria‐RS (south Brazil), working under the direction of Prof. A. L. Braga, and his Ph.D. under the direction of Professor J. V. Comasseto (University of São Paulo). He then moved to the Federal University of Santa Maria, where he is now a full professor. In 2003, he received a CNPq Postdoctoral Fellowship to work with Prof. R. C. Larock at the Iowa State University‐USA. His current research interests are the synthesis and reactivity of organochalcogen compounds and the development of new synthetic methods for applying organochalcogen substrates in the cyclization.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.