Optimizing oil selection for curcumin-based nanoemulsions formulation through molecular self-assembly

Optimizing oil selection for curcumin-based nanoemulsions formulation through molecular self-assembly | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Optimizing oil selection for curcumin-based nanoemulsions formulation through molecular self-assembly Aina Hazimah Bahaman, Prapasiri Pongprayoon, Bimo Ario Tejo, Mohd Basyaruddin Abdul Rahman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8023845/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Curcumin is a bioactive compound with anti-inflammatory and anticancer activity, which is poorly water solubility and stability that limiting its therapeutic potential. Curcumin delivery can be improved by oil-in-water nanoemulsions by providing a hydrophobic core, but it is challenging to develop stable systems due to oil-drug compatibility. Molecular dynamics simulations were used to compare two oil cores of linoleic acid (LA) from safflower oil and oleyl laurate (OL) from palm kernel oil esters for curcumin nanoemulsions. The LA structure exhibited smaller structural movements, reduced radius of gyration (Rg) and more persistent intermolecular hydrogen bonds than the OL system. The higher number of CC-LA hydrogen bonds suggest the curcumin molecules become more densely packed with LA to form a tightly ordered hydrophobic core with its amphiphilic character enables a closely packed self-assembly with curcumin. Based on these findings, an optimized nanoemulsion was formulated by adding lecithin (LC) and Tween 85 (T85) into CC-LA (CC-LA-LC-T85), with LC and T85 appearing to enhance the aggregation rate. In simulations, self-association of surfactants occurred at the droplet interface with exposed polar head groups, a uniform shell around a CC-LA core. The ultimate aggregate was near-spherical and structurally hard, as shown by a stable Rg and minimal molecular diffusion. The dense hydrophobic core formed by LA, stabilized by persistent interactions with LC and T85, demonstrated a compact and organised self-assembled structure. These intermolecular interactions collectively ensured effective encapsulation and well-defined nanoemulsion, rendering its potential suitability as a carrier for future curcumin encapsulation in drug delivery applications. Curcumin Safflower Oil PKOEs Nanoemulsion Molecular Dynamics Simulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Conventional emulsions are often used for the delivery of lipophilic molecules which are prone to phase separation, coalescence and low bioavailability [ 1 ]. Nanoemulsions as colloidal dispersions with droplet sizes (> 200 nm) offer higher kinetic stability and better encapsulation efficiency [ 2 ]. Their formation and long-term stability are strictly controlled by molecular self-assembly, a fundamental process driven by non-covalent interactions that allow molecules to spontaneously organize into stable, structured arrangements [ 3 ]. This process provides a comprehensive framework for understanding the formation and stabilization of nanoemulsions [ 4 ], which are promising drug delivery systems for bioactive compounds [ 5 ] including curcumin. Curcumin (CC), the principal curcuminoid extracted from the rhizome of Curcuma longa , has emerged as a highly potential therapeutic molecule with its potent antioxidant, anti-inflammatory, antimicrobial, antiviral and anticancer activities [ 6 ]. Interestingly, curcumin also shows inhibition effects against dengue virus, influenza A, HIV and SARS‐CoV‐2 [ 7 ]. However, several key obstacles limit its effectiveness as a therapeutic agent. Curcumin shows poor water solubility (< 8 µg/mL), poor bioavailability and rapid metabolism [ 8 ]. Thus, many studies have been attempted to search for suitable methods to enhance curcumin’s effectiveness [ 9 ]. One potential strategy is the use of nanoemulsions, which offer the potential to enhance absorption, protect active compounds from degradation and facilitate controlled release [ 10 ]. To obtain an effective nanoemulsion, suitable oils and surfactant is required for optimizing nanoemulsion formulations [ 11 ]. Oils like safflower oil (SO) or palm kernel oil esters (PKOEs) emerged as promising oil-based components for curcumin nanoemulsion formulations due to their good solubilizing capacity, improved oxidative stability and biocompatibility proven applications in drug delivery [ 12 – 14 ]. Moreover, SO and PKOEs were found to improve droplet size distribution and exhibit sustained release and high encapsulation efficiency [ 15 ]. PKOEs were reported to act as potential oil phase in drug nanoemulsions such as ibuprofen [ 16 ], diclofenac [ 17 ], ketoprofen [ 18 ], whereas SO was widely used in food, cosmetic nanoemulsion formulations [ 12 ]. Moreover, SO and PKOEs were widely studied as curcumin nanoemulsion [ 15 ]. In a previous work, CC-loaded SO core nanoemulsions was found to form stable droplets with sustained release and high encapsulation efficiency for pulmonary delivery [ 15 ]. Also, with good viscosity and osmolality attributes, CC-loaded SO and PKOE nanoemulsions have been suggested to be a promising therapeutic candidate for pulmonary application [ 19 ]. Linoleic acid (LA) is the main component in SO, while oleyl laurate (OL) serves as the major compound in PKOEs (Fig. 1 A). LA-based nanoemulsions were found to improve CC stability and antioxidant activity under physiological conditions [ 20 ], whereas OL helps to stabilize the oil-water interface [ 21 ]. Both LA and OL appear to facilitate the formation of nanoemulsion. Nonetheless, no molecular information on such nanoemulsion formation is available. In addition, there is no comparative study explain the advantages and disadvantages of using SO and PKOEs for curcumin nanoemulsion in a molecular level. Thus, in this work, the formation of curcumin-loaded nanoemulsion using SO and PKOEs was studied in comparison. Molecular Dynamics (MD) simulations were performed to obtain a molecular detail. LA (a major components in SO) and OL (a main component in PKOEs) were used as SO and OL representatives. Herein, the molecular mechanisms of CC-loaded nanoemulsion using LA and OL are revealed. The advantages and disadvantages of LA and OL for CC nanoemulsion are also extracted. Our primary results reported that LA acts as more promising oil-phase candidate, therefore further simulations were performed on CC-loaded LA system. Further MD simulation on the assembly of CC, LA, lecithin (LC) and tween 85 (T85) was performed to investigate the mechanism of nanoemulsion formation. LC and T85 were included here to mimic a real nanoemulsion condition. LC and T85 are common chemicals used to enhance stability and encapsulation efficiency. LC acts as both stabilizer and emulsifier [ 22 ], while T85 reduces interfacial tension to support droplet formation [ 23 ]. The insights obtained here will be useful for future design of effective CC-loaded nanoemulsion formulations in food and nutraceutical applications. Materials and method The three-dimensional (3D) structures of CC, LA, OL, LC and T85 were build using Avogadro software [ 24 ]. The structurers were optimized by Automated Topology Builder (ATB) and Repository version 3.0 server [ 25 ]. The topologies were generated using ACPYPE [ 26 ]. The RESP charges of each ligand were obtained from quantum calculation with a HF/6-31G(d) basis set. At the beginning, two systems which are CC-LA and CC-OL were set. CC was placed in a cubic box with a dimension of 10 x 10 x 10 Å 3 . 20 molecules of LA were randomly added into a CC-LA box, while 13 molecules of OL were added in CC-OL box. Each oil was placed at least 10 Å away from each other. A number of LA and OL used in this work are obtained from a previous experimental work [ 15 ]. Then, CC-LA and CC-OL were solvated by TIP3P water models and neutralized by counterions. In case of CC-LA in LC and T85, CC was placed in a cubic box with a dimension of 10 x 10 x 10 Å 3 . 20 molecules of LA, 7 molecules of LC and 7 molecules of T85 were randomly added into a CC-LA-LC-T85 box with a distance of at least 10 Å away from each other. The quantities of LA, LC and T85 used in this study were based on a previous experimental work. The CC-LA-LC-T85 system was then solvated using the TIP3P water model and neutralized with counterions. All the molecular dynamics simulations were carried out using GROMACS version 2022.1 ( www.gromacs.org ) using the AMBER99SB force field [ 27 ]. Each of the systems was placed in a simulation box of cubic shape and solvated with TIP3P water molecules and counterions added to make the system neutral. To resolve steric clashes during system setup, energy minimization was achieved using the steepest descent algorithm for a maximum of 1000 steps. Long-range electrostatic interactions were treated with Particle Mesh Ewald (PME) and a 1.0 nm short-range cutoff, Fourier grid spacing of 0.12 nm and fourth-order spline interpolation [ 28 , 29 ]. Simulations were conducted in the NPT ensemble at constant number of particles, pressure, and temperature. Temperature coupling was done separately for the ions, solvent, and protein with the velocity-rescale thermostat at 300 K and a coupling parameter of 0.1 ps [ 30 ]. Pressure was maintained at 1 bar using the Berendsen barostat and a coupling parameter of 1 ps. The time step of integration was 2 fs, and coordinates were stored at every 2 ps for analysis. All the systems were given a 10 ns equilibration time, following which production runs were taken for 1000 ns, and this was done for reproducibility. Results presented are the average of two independent simulations. The data analysis was carried out using GROMACS tools and homemade scripts. Molecular graphics were generated using PyMOL, VMD, and Discovery Studio 2021. The analysis included observing the evolution of mean square displacement (MSD), principal moments of inertia and eccentricity of each component in order to enable evaluation of nanoemulsion size, shape, diffusion nature and self-assembly dynamics. Structural evolution and stability were monitored at equal intervals during simulations. Results and Discussion The assembly of CC-LA and CC-OL nanoemulsion The results in Fig. 2A illustrates the spontaneous self-assembly of the CC-LA and CC-OL systems, in which droplet formation occurs within 500 ns. In both systems, the hydrophobic tails of LA and OL cluster together with curcumin and shield it from the aqueous phase, while the hydrophilic moieties orient outward to stabilise the micelle-like structure [ 31 , 32 ]. Remarkably, curcumin tends to align with the droplet surface and appear pinched between the oil molecules (Fig. 2A and 3A). The stability of these assemblies was assessed through RMSD and radius of gyration (Rg) analyses (Figs. 2B and 2C). It can be seen that the aggregation of both CC-LA and CC-OL is fast and spontaneous. Both CC-LA and CC-OL are clustered within ~ 50 ns where CC-OL shows lightly higher RMSD (0.251 ± 0.029 nm for CC-OL and 0.224 ± 0.020 nm for CC-LA) (Fig. 2A and 2B). The lower RMSD of CC-LA suggests slightly more rigid CC-LA molecules [ 33 ]. However, Rg indicates both CC-LA and CC-OL exhibit a comparable degree of compactness (Fig. 2C), even though LA is slightly more water-exposed (Fig. 2D). To explore the aggregation mechanism [ 34 , 35 ], a number of contacts and hydrogen bond analyses were computed as shown in Fig. 3. A higher number of water contacts (Fig. 3B) and hydrogen bonds with water (Fig. 3C) in CC-LA confirm the more water exposure of a LA cluster, whilst OL molecules are found to be more buried due to lower number of water contacts and hydrogen bonds [ 36 ]. In case of CC, due to its location at the surface (Fig. 3A), CC in both LA and OL show similar degree of wettability and hydrogen bonds with water (Fig. 3D and 3E). CC appears to align on the oil surface in both cases resulting in a similar number of oil contacts (Fig. 3F). Nonetheless, CC in LA can form more hydrogen bonds (~ 2–4 CC-LA hydrogen bonds) than CC in OL (~ one CC-OL hydrogen bond) (Fig. 3G). Such higher number of CC-LA hydrogen bonds suggest the tighter binding of CC to LA. To better understand how CC interacts with OL and LA, the individual hydrogen bonds between CC and each oil were computed in Fig. 4 . The location of CC on a droplet surface is shown in Fig. 4 A. CC can interact with more LA than OL. Four LA molecules (LA-1: 41.87%, LA-4: 46.41%, LA-11: 43.97%, LA-15: 51%) are found to be in the close proximity to CC, whereas three OL molecules (OL-1: 44.14%, OL-8: 63.49%, OL-11: 53.66%) are sufficient to stabilise the CC binding (Fig. 4 B and 4 C). LA seems to completely hold the whole CC molecule, while, in CC-OL, the OL contacts were less evenly distributed (Fig. 4 C). The more balanced distribution of CC-LA contacts supports the more stable CC-LA packing. Based on these results, LA forms stronger and more consistent hydrogen bonds and close contacts with CC than OL. Such interactions improve the structural integrity and stability of the nanoemulsion [ 37 ], making LA the more suitable oil phase for the CC encapsulation. Furthermore, the principal moments of inertia and eccentricity were computed (Table 1 ) to provide insights into the molecular shape and mass distribution within the nanoemulsion aggregates [ 38 ]. For CC–OL, the ratios of I 1 : I 2 : I 3 is 1:1.6:1.8 and an eccentricity value of 0.18 suggest a moderately elongated but compact shape, with slight deviation from perfect sphericity. This is further supported by the low radius of sphere (R s ) of 0.17 nm, indicating a packed structure [ 39 ]. Similarly, the CC–LA system exhibits ratios of 1:1.5:1.8 with an eccentricity of 0.19 and R s of 0.16 nm, reflecting a slightly more compact structure compared to CC–OL. The close values of I 2 and I 3 in both systems imply that the aggregates maintain a generally ellipsoidal geometry rather than a spherical one. The slightly lower R s and similar eccentricity in CC–LA suggest better compactness and possibly stronger intermolecular interactions within the nanoemulsion [ 40 , 41 ], contributing to its structural stability. Based on these factors, LA derived from safflower oil shows higher CC-LA hydrogen bonding and provide a flexible micellar microenvironment. This suggests LA as a suitable candidate for the CC encapsulation. Table 1 Total moment of inertia (Itot) and the eccentricity (e) value of the CC-OL and CC-LA nanoemulsions. System I tot (10 5 au nm 2 ) I 1 (10 4 au nm 2 ) I 2 (10 4 au nm 2 ) I 3 (10 4 au nm 2 ) I 1 : I 2 : I 3 e Micelle Shape R s (nm) CC-OL 0.25 0.57 0.88 1.01 1:1.6:1.8 0.18 Slightly aspherical 0.17 CC-LA 0.21 0.48 0.74 0.84 1:1.5:1.8 0.19 Slightly aspherical 0.16 Nevertheless, despite successful encapsulation within safflower oil, CC is inherently hydrophobic and dispersion in aqueous systems is therefore less favourable. This feature emphasises the importance of surfactants, which not only lower the interfacial tension but also enable interaction between the hydrophobic oily core and the surrounding aqueous phase [ 42 , 43 ]. Consequently, the incorporation of surfactants is essential for reducing interfacial tension and facilitating interactions with water, thereby improving dispersion and potentially increasing delivery to the target site. MD simulation of the CC-LA-LC-T85 nanoemulsion Subsequent to the performance of CC-LA system, the newly formulated system of CC, LA, lecithin (LC) and Tween 85 (T85) was investigated through a 1000-ns MD simulation. This extended time scale allows the evaluation of aggregate stability, encapsulation efficiency and interfacial organization. The simulation illustrated that mini-droplets dispersed at the early moment (25 ns) increased and eventually coalesced into a large, stable aggregate at ~ 50 ns (Fig. 5 A). The spontaneous self-assembly is triggered by the CC-LA association at the centre, while LC and T85 are clustered before associating to CC-LA complex (Fig. 5 A). This mixed aggregation appears to be faster than CC-LA system. LC and T85 appear to promote the aggregation. LC, with its hydrophobic tails and polar phosphate head, was reported to facilitate the structuring of the oil-water phase, whereas T85 provided a steric stabilisation and an additional reduction in surface tension to prevent coalescence [ 44 , 45 ]. The synergistic activities of LA, LC and T85 ensured stable encapsulation of CC and robust oil-in-water (O/W) droplet formation. A RMSD analysis showed rapid structural adjustments within 50 ns, after which the system stabilised at ~ 0.31 ± 0.02 nm (Fig. 5 B). This plateau indicates that the aggregate maintained its conformational stability [ 46 ]. The radius of gyration (Rg) further confirms these findings, with an initial decrease followed by a stabilisation around 0.168 nm after ~ 100 ns (Fig. 5 C). This constant value reflects a compact, well-organised aggregate. The effective radius (Rs) estimated from Rg is 0.22 nm, consistent with a nearly spherical geometry and validating the compactness of the nanoemulsion droplet. Moreover, SASA analysis revealed a decrease in solvent exposure over time and stabilised at ~ 10.07 ± 0.05 nm² (Fig. 5 D). The hydrophobic contribution (3.36 ± 0.15 nm²) indicates efficient incorporation of LA and surfactant tails within the core, while the hydrophilic contribution (6.71 ± 0.31 nm²) reflects the outward orientation of the polar groups. This balanced distribution is characteristic of O/W nanoemulsions, supporting colloidal stability and favourable interactions with the aqueous environment [ 38 , 5 ]. In addition, the presence of LC and T85 appear to promote the tighter binding of CC to oil complex. Compared to CC-LA system, CC in CC-LA-LC-T85 can form more hydrogen bonds. (10.46 ± 2.45 hydrogen bonds), reflecting a robust network of intermolecular interactions (Fig. 5 E). Furthermore, the water contact analysis further confirms the hydration and surface exposure of the system [ 47 , 48 ]. A total of 5983.62 ± 342.28 water contacts is observed, with CC alone maintaining 147.09 ± 25.82 contacts (Fig. 5 F). Compared to CC-LA, the presence of LC and T85 induce the more buried CC (~ 200 CC-water contacts in CC-LA (Fig. 3D)). Besides, the system formed an average of 210.85 ± 7.34 hydrogen bonds with water (Fig. 5 G). This extensive hydration helps stabilise the interfaces, prevents aggregation and promotes long-term dispersion and bioavailability of the CC-loaded nanoemulsion. Next, CC is found to interact closely with three Tween 85 molecules (T85-2: 36.15%, T85-3: 38.00%, T85-5: 35.65%), one LC (LC-2: 36.15%) and four LA molecules (LA-21: 21.90%, LA-37: 22.54%, LA-39: 24.26%, LA-40: 16.36%) (Fig. 6 ). CC displays stronger associations with T85 and LC, which can be attributed to their polar head groups and chemical compatibility with CC. In contrast, LA, being purely hydrophobic, engaged mainly through transient hydrophobic associations rather than specific polar interactions. Overall, the preferential binding of CC to T85 and LC underlines their dual role as structural stabilizers and mediators of CC encapsulation and dispersion in the nanoemulsion. Furthermore, the morphological properties were investigated as seen in Table 2 , the inertia value ( I ) along the z-axis is higher than those along the x- and y-axes, suggesting a slight elongation of the aggregate along the z-axis. A perfectly spherical system would exhibit equal values along all three axes [ 13 ]. However, the observed ratio of 1.0:1.2:1.4 indicates a near-spherical morphology with minor deviations. The moment of inertia of the optimised CC-LA-LC-T85 system ( I = 1.24) was substantially higher than that of CC-LA alone ( I = 0.21), illustrating the more compact and organized aggregation achieved upon incorporation of LC and T85. Despite these differences, the system maintained a compact and energetically favourable structure, reflecting stable interactions among the components. Such a morphology minimises the risk of phase separation and is indicative of a uniform and stable nanoemulsion [ 49 , 50 ]. Table 2 Total moment of inertia (Itot) and the eccentricity (e) value of the CC-LA-LC-T85 nanoemulsion. System I tot (10 5 au nm 2 ) I 1 (10 4 au nm 2 ) I 2 (10 4 au nm 2 ) I 3 (10 4 au nm 2 ) I 1 : I 2 : I 3 e Micelle Shape R s (nm) CC-LA-LC-T85 1.24 3.46 4.24 4.71 1:1.2:1.4 0.13 Slightly aspherical 0.22 To further evaluate the shape of the aggregate, the eccentricity ( e ) was calculated. A perfect sphere has an eccentricity of zero, whereas the observed value of 0.13 indicates only a slight deviation from sphericity. This observation is consistent with the analysis of the principal moment of inertia and the visual inspection of the simulation snapshots, confirming a stable near-spherical geometry. Compared to the CC-LA system that had a more aspherical morphology, the CC-LA-LC-T85 system showed a more symmetrical and compact structure. Overall, these findings highlight the effective self-assembly of the CC-LA-LC-T85 nanoemulsion into a compact, stable morphology. Such structural features are critical to ensure long-term stability and provide a framework for surfactant and co-surfactant selection and formulation optimisation of curcumin-safflower oil nanoemulsion systems. Conclusion The comprehensive molecular dynamics simulation study of nanoemulsions in this research has provided a detailed understanding of the self-assembly and potential for drug delivery applications. The comparison between CC-LA and CC-OL systems showed that CC-LA provided better stability. An extended study on the CC-LA-LC-T85 nanoemulsion reaffirmed its potential as a stable delivery agent. The CC-LA-LC-T85 nanoemulsion exhibited consistent RMSD values indicating structural stability, while its compactness as reflected by Rg and SASA suggest a minimal risk of phase separation. Morphological descriptors, including moments of inertia and eccentricity, confirmed a near-spherical morphology supporting aggregate stability. Importantly, these results are consistent with previous studies demonstrating that surfactant-assisted nanoemulsions improve structural integrity and encapsulation efficiency. However, they extend the understanding by demonstrating at the atomic level how LC and Tween 85 synergistically improve droplet organisation. By demonstrating denser packing and reduced solvent exposure compared to simpler CC-LA assemblies, this work highlights the importance of optimised surfactant selection in achieving durable nanoemulsion structures. Such insights not only reinforce current strategies for nanoemulsion design, but also provide a mechanistic framework for the rational development of drug delivery carriers with improved stability and biocompatibility. This compatibility study establishes a strong foundation for future research aimed at developing an effective nanoemulsion-based delivery system and a key step in ensuring that the final nanoemulsion is stable and suitable for its intended application. Abbreviations CC Curcumin OL Oleyl Laurate LA Linoleic Acid MD Molecular Dynamic PKOEs Palm Kernel Oil Esters SO Safflower Oil Declarations Ethics approval and consent to participate: Not applicable. This study did not involve human participants, animals or clinical data. Consent for publication: Not applicable. Availability of data and materials: All simulation data and analysis outputs generated during this study are available from the corresponding author upon reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: This research was supported by SATREPS program under JICA and Kasetsart University Research and Development Institute (KURDI) (Grant no: FF(KU)62.69). Authors' contributions: Aina Hazimah Bahaman: Conceptualization, methodology design, molecular dynamics simulations, data analysis, manuscript drafting. Prapasiri Pongprayoon: Co-supervision, guidance on computational protocols, manuscript review. Bimo Ario Tejo: Manuscript review Mohd Basyaruddin Abdul Rahman: Supervision, critical review, manuscript editing All authors read and approved the final manuscript. Acknowledgements: The authors acknowledge Universiti Putra Malaysia and the Institute for Medical Research (IMR), Ministry of Health Malaysia, for providing research facilities and Kasetsart University, Thailand, for the opportunity to develop expertise in bioinformatics. Authors' information: Dr. Aina Bahaman obtained her PhD in Chemistry (Computational and Theoretical Chemistry) from Universiti Putra Malaysia in June 2025. Her research focuses on molecular docking, molecular dynamics simulations, protein–ligand interactions, mutation analysis and the computational study of small molecules and nanoemulsion-based drug delivery systems. Data Availability Statement: The datasets and simulation trajectories generated during the current study are available from the corresponding author upon reasonable request. References McClements DJ (2018). Enhanced delivery of lipophilic bioactives using emulsions: a review of major factors affecting vitamin, nutraceutical, and lipid bioaccessibility. Food Funct. 9(1):22–41. 10.1039/c7fo01515a Franklyne JS, Gopinath PM, Mukherjee A, Chandrasekaran N (2021). Nanoemulsions: The rising star of antiviral therapeutics and nanodelivery system-current status and prospects. Curr Opin Colloid Interface Sci. 54:101458. 10.1016/j.cocis.2021.101458 Feng H-T, Lam JWY, Tang BZ (2020). Self-assembly of AIEgens. Coordination Chemistry Reviews. 406. 10.1016/j.ccr.2019.213142 Li S, Duan S, Zha Z, Pan J, Sun L, Liu M, Deng K, Xu X, Qiu X (2020). Structural Phase Transitions of Molecular Self-Assembly Driven by Nonbonded Metal Adatoms. ACS Nano. 14(5):6331–6338. 10.1021/acsnano.0c02995 Tayeb HH, Felimban R, Almaghrabi S, Hasaballah N (2021). Nanoemulsions: Formulation, characterization, biological fate, and potential role against COVID-19 and other viral outbreaks. Colloid Interface Sci Commun. 45:100533. 10.1016/j.colcom.2021.100533 Jennings MR, Parks RJ (2020). Curcumin as an Antiviral Agent. Viruses. 12(11). 10.3390/v12111242 Thimmulappa RK, Mudnakudu-Nagaraju KK, Shivamallu C, Subramaniam KJT, Radhakrishnan A, Bhojraj S, Kuppusamy G (2021). Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19. Heliyon. 7(2):e06350. 10.1016/j.heliyon.2021.e06350 Zhang L, Wang P, Yang Z, Du F, Li Z, Wu C, Fang A, Xu X, Zhou G (2020). Molecular dynamics simulation exploration of the interaction between curcumin and myosin combined with the results of spectroscopy techniques. Food Hydrocolloids. 101. 10.1016/j.foodhyd.2019.105455 Kaur K, Al-Khazaleh AK, Bhuyan DJ, Li F, Li CG (2024). A Review of Recent Curcumin Analogues and Their Antioxidant, Anti-Inflammatory, and Anticancer Activities. Antioxidants (Basel). 13(9). 10.3390/antiox13091092 Roshan Z, Haddadi-Asl V, Ahmadi H, Moussaei M (2024). Curcumin‐Encapsulated Poly(lactic‐co‐glycolic acid) Nanoparticles: A Comparison of Drug Release Kinetics from Particles Prepared via Electrospray and Nanoprecipitation. Macromolecular Materials and Engineering. 309(7). 10.1002/mame.202400040 Jafari M, Parastouei K, Abbaszadeh S (2024). Development of curcumin-loaded nanoemulsion stabilized with texturized whey protein concentrate: Characterization, stability and in vitro digestibility. Food Sci Nutr. 12(3):1655–1672. 10.1002/fsn3.3860 Almeida OP, de Freitas Marques MB, de Oliveira JP, da Costa JMG, Rodrigues AP, Yoshida MI, Mussel WDN, Carneiro G (2022). Encapsulation of safflower oil in nanostructured lipid carriers for food application. J Food Sci Technol. 59(2):805–814. 10.1007/s13197-021-05078-5 Faujan NH, Abedi Karjiban R, Kashaban I, Basri M, Basri H (2019). Computational simulation of palm kernel oil-based esters nano-emulsions aggregation as a potential parenteral drug delivery system. Arabian Journal of Chemistry. 12(8):2372–2383. 10.1016/j.arabjc.2015.03.003 Karjiban RA, Huan Q-Y, Abdul Rahman MB, Basri M, Tejo BA (2015). Self-assembly of Palm Kernel Oil Wax Esters in Aqueous Media: A Molecular Dynamics Study. International Journal of Chemistry. 7(1). 10.5539/ijc.v7n1p133 Asmawi AA, Salim N, Abdulmalek E, Abdul Rahman MB (2023). Size-Controlled Preparation of Docetaxel- and Curcumin-Loaded Nanoemulsions for Potential Pulmonary Delivery. Pharmaceutics. 15(2). 10.3390/pharmaceutics15020652 Salim N, Basri M, Rahman MB, Abdullah DK, Basri H (2012). Modification of palm kernel oil esters nanoemulsions with hydrocolloid gum for enhanced topical delivery of ibuprofen. Int J Nanomedicine. 7:4739–47. 10.2147/IJN.S34700 Rezaee M, Basri M, Rahman RN, Salleh AB, Chaibakhsh N, Karjiban RA (2014). Formulation development and optimization of palm kernel oil esters-based nanoemulsions containing sodium diclofenac. Int J Nanomedicine. 9:539–48. 10.2147/IJN.S49616 Sakeena MHF, Muthanna FA, Ghassan ZA, M. KM, M. ES, S. MA, N. AM (2010). Formulation and in vitro Evaluation of Ketoprofen in Palm Oil Esters Nanoemulsion for Topical Delivery. Journal of Oleo Science. 59 (4)(223–228). Esmari VJ, Plessis JD, Preez JLD, Shahzad Y, Gerber M (2022). Formulation and characterisation of artemether-loaded nano-emulsion for topical applications. Journal of Drug Delivery Science and Technology. 73(103449). https://doi.org/10.1016/j.jddst.2022.103449 Emami F, Vatanara A, Park EJ, Na DH (2018). Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals. Pharmaceutics. 10(3). 10.3390/pharmaceutics10030131 Efendy GD, Kadir SASH, Latip NA, Rahim AS, Mazlan M (2019). Palm Oil in Lipid-Based Formulations and Drug Delivery Systems. Biomolecules. 9(2). 10.3390/biom9020064 Sutradhar KB, Amin ML (2013). Nanoemulsions: increasing possibilities in drug delivery. European Journal of Nanomedicine. 5(2). 10.1515/ejnm-2013-0001 Öztürk D, Mihçiokur H (2022). Production of innovative magnetic adsorbent Fe3O4@PEI®Tween 85 and removal of oxytetracycline from aqueous media. Separation Science and Technology. 57(7):1030–1042. 10.1080/01496395.2021.1962911 Pantiora P, Furlan V, Matiadis D, Mavroidi B, Perperopoulou F, Papageorgiou AC, Sagnou M, Bren U, Pelecanou M, Labrou NE (2022). Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1. Antioxidants (Basel). 12(1). 10.3390/antiox12010063 Ibezim A, Madukaife MS, Osigwe SC, Engel N, Karuppasamy R, Ntie-Kang F (2022). Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIbeta ligands. BMC Chem. 16(1):19. 10.1186/s13065-022-00812-2 Toviwek B, Koonawootrittriron S, Suwanasopee T, Pongprayoon P (2022). Molecular insights into the binding of carnosine and anserine to human serum carnosinase 1 (CN1). PeerJ Physical Chemistry. 4. 10.7717/peerj-pchem.25 Kuntip N, Japrung D, Pongprayoon P (2021). How human serum albumin-selective DNA aptamer binds to bovine and canine serum albumins. Biopolymers. 112(3):e23421. 10.1002/bip.23421 Davidson RB, Hendrix J, Geiss BJ, McCullagh M (2018). Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations. PLoS Comput Biol. 14(4):e1006103. 10.1371/journal.pcbi.1006103 Phadungsombat J, Nakayama EE, Shioda T (2024). Unraveling Dengue Virus Diversity in Asia: An Epidemiological Study through Genetic Sequences and Phylogenetic Analysis. Viruses. 16(7). 10.3390/v16071046 Panman W, Japrung D, Pongprayoon P (2017). Exploring the interactions of a DNA aptamer with human serum albumins: simulation studies. J Biomol Struct Dyn. 35(11):2328–2336. 10.1080/07391102.2016.1224733 Arredondo-Ochoa T, Silva-Martínez GA (2022). Microemulsion Based Nanostructures for Drug Delivery. Frontiers in Nanotechnology. 3. 10.3389/fnano.2021.753947 Shaker DS, Ishak RAH, Ghoneim A, Elhuoni MA (2019). Nanoemulsion: A Review on Mechanisms for the Transdermal Delivery of Hydrophobic and Hydrophilic Drugs. Scientia Pharmaceutica. 87(3). 10.3390/scipharm87030017 Rangubpit W, Suwan E, Sangthong D, Wongpanit K, Stich RW, Pongprayoon P, Jittapalapong S (2022). Observing How Glutathione and S-Hexyl Glutathione Bind to Glutathione S-Transferase from Rhipicephalus (Boophilus) microplus. Int J Mol Sci. 23(21). 10.3390/ijms232112775 Adhav VA, Saikrishnan K (2023). The Realm of Unconventional Noncovalent Interactions in Proteins: Their Significance in Structure and Function. ACS Omega. 8(25):22268–22284. 10.1021/acsomega.3c00205 Anindita PD, Halbeisen M, Reha D, Tuma R, Franta Z (2022). Mechanistic insight into the RNA-stimulated ATPase activity of tick-borne encephalitis virus helicase. J Biol Chem. 298(10):102383. 10.1016/j.jbc.2022.102383 Liu S, Zhang H, Yuan S (2022). Hydrophilic Silica Nanoparticles in O/W Emulsion: Insights from Molecular Dynamics Simulation. Molecules. 27(23). 10.3390/molecules27238407 Altamimi MA, Hussain A, Alshehri S, Imam SS, Alnemer UA (2021). Development and Evaluations of Transdermally Delivered Luteolin Loaded Cationic Nanoemulsion: In Vitro and Ex Vivo Evaluations. Pharmaceutics. 13:1218. Hakim L, Mardiana D, Rokhiyah U, Lestari MLAD, Ningsih Z (2021). Structure and Dynamics of Curcumin Encapsulated Lecithin Micelles: A Molecular Dynamics Simulation Study. Science and Technology Indonesia. 6(3):113–120. 10.26554/sti.2021.6.3.113-120 Umar AK, Zothantluanga JH, Aswin K, Maulana S, Sulaiman Zubair M, Lalhlenmawia H, Rudrapal M, Chetia D (2022). Antiviral phytocompounds "ellagic acid" and "(+)-sesamin" of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction. Struct Chem. 33(5):1445–1465. 10.1007/s11224-022-01959-3 Mishra N, Kaushik N, Sharma PK, Alam MA (2023). Nano Emulsion Drug Delivery System: A Review. Current Nanomedicine. 13(1):2–16. 10.2174/2468187313666230213121011 Moghaddasi F, Housaindokht MR, Darroudi M, Bozorgmehr MR, Sadeghi A (2018). Soybean oil-based nanoemulsion systems in absence and presence of curcumin: Molecular dynamics simulation approach. Journal of Molecular Liquids. 264:242–252. 10.1016/j.molliq.2018.05.066 Donthi MR, Munnangi SR, Krishna KV, Saha RN, Singhvi G, Dubey SK (2023). Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery. Pharmaceutics. 15(1). 10.3390/pharmaceutics15010164 Raya SA, Saaid IM, Mohd Aji AQ, AA AR (2022). Investigation of the synergistic effect of nonionic surfactants on emulsion resolution using response surface methodology. RSC Adv. 12(48):30952–30961. 10.1039/d2ra04816g Sharma S, Awad IE, Yadav A, Poirier RA (2020). Molecular level investigation of curcumin self-assembly induced by trigonelline and nanoparticle formation. Appl Nanosci. 10(11):3987–3998. 10.1007/s13204-020-01526-4 Singh Y, Meher JG, Raval K, Khan FA, Chaurasia M, Jain NK, Chourasia MK (2017). Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release. 252:28–49. 10.1016/j.jconrel.2017.03.008 Tanbin S, Ahmad Fuad FA, Abdul Hamid AA (2020). Virtual Screening for Potential Inhibitors of Human Hexokinase II for the Development of Anti-Dengue Therapeutics. BioTech (Basel). 10(1). 10.3390/biotech10010001 Hensel JK, Carpenter AP, Ciszewski RK, Schabes BK, Kittredge CT, Moore FG, Richmond GL (2017). Molecular characterization of water and surfactant AOT at nanoemulsion surfaces. Proc Natl Acad Sci U S A. 114(51):13351–13356. 10.1073/pnas.1700099114 Shi P, Luo H, Tan X, Lu Y, Zhang H, Yang X (2022). Molecular dynamics simulation study of adsorption of anionic-nonionic surfactants at oil/water interfaces. RSC Adv. 12(42):27330–27343. 10.1039/d2ra04772a Kozuch DJ, Ristroph K, Prud'homme RK, Debenedetti PG (2020). Insights into Hydrophobic Ion Pairing from Molecular Simulation and Experiment. ACS Nano. 14(5):6097–6106. 10.1021/acsnano.0c01835 Siraj A, Naqash F, Shah MA, Fayaz S, Majid D, Dar BN (2021). Nanoemulsions: formation, stability and an account of dietary polyphenol encapsulation. International Journal of Food Science & Technology. 56(9):4193–4205. 10.1111/ijfs.15228 Additional Declarations No competing interests reported. Supplementary Files GA.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8023845","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":541520907,"identity":"29d66e5c-f1ce-4749-bcc7-1cc38039a3b7","order_by":0,"name":"Aina Hazimah Bahaman","email":"","orcid":"","institution":"Universiti Putra Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Aina","middleName":"Hazimah","lastName":"Bahaman","suffix":""},{"id":541520908,"identity":"0f1476e3-00da-41f6-af4a-42d966bf93a3","order_by":1,"name":"Prapasiri Pongprayoon","email":"","orcid":"","institution":"Kasetsart University","correspondingAuthor":false,"prefix":"","firstName":"Prapasiri","middleName":"","lastName":"Pongprayoon","suffix":""},{"id":541520911,"identity":"6769f2d4-697b-4a44-a44a-ca65ca5e85cf","order_by":2,"name":"Bimo Ario Tejo","email":"","orcid":"","institution":"Universiti Putra Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Bimo","middleName":"Ario","lastName":"Tejo","suffix":""},{"id":541520912,"identity":"ec774c34-ae17-412d-8e60-b5c61a36202f","order_by":3,"name":"Mohd Basyaruddin Abdul Rahman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYBACAzBZAeFIkKDlDMlaGNtI0WLOfvyZxM95h/N0G5gP3uZh2JbYQEiLZU+OmWTvtsPFZgfYkq15GG4T1mJwIIdNgnfb4cRtB3jMpInTcv75M8m/c0Ba+L8RqeVGgpk0bwPYFjbitFjOeGNsLXMsvdjsMJux5RyD28YEtZjzpz+8+abGOs/sePPDG28qbssS1AIELKDoSGBgBruTwZEYLcwfwFqgwJ4IHaNgFIyCUTDCAAD4DT/FSdxCwAAAAABJRU5ErkJggg==","orcid":"","institution":"Universiti Putra Malaysia","correspondingAuthor":true,"prefix":"","firstName":"Mohd","middleName":"Basyaruddin Abdul","lastName":"Rahman","suffix":""}],"badges":[],"createdAt":"2025-11-04 03:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8023845/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8023845/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97161566,"identity":"ea521766-7978-478b-9a23-2ee0d7fb4cb0","added_by":"auto","created_at":"2025-12-01 12:41:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":278976,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Chemical structures of curcumin (CC), linoleic acid (LA) (from safflower oil), oleyl laurate (OL) (from PKOEs), lecithin (LC) and Tween 85 (T85). Initial molecular arrangements of (B) CC-LA, (C) CC-OL and (D) CC-LA-LC-T85 at t = 0 ns, used to evaluate compatibility and formulation preference.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/70398d2827549f5133bc31b8.jpg"},{"id":97249790,"identity":"7b05afda-f701-4dc3-9101-d37477a17027","added_by":"auto","created_at":"2025-12-02 13:13:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":295561,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Snapshots of CC-LA and CC-OL aggregation as a function of time. (B) Root mean square deviations (RMSDs), radius of gyration (Rg), and\u003cstrong\u003e \u003c/strong\u003esolvent accessible surface area (SASA) are shown in (B), (C), and (D), respectively.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/0d945b79fc6540b9e5cfeca8.jpg"},{"id":97161564,"identity":"35b48aa7-3e1c-49e5-9a17-1afe076fee56","added_by":"auto","created_at":"2025-12-01 12:41:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":354054,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Final snapshots of CC-LA and CC-OL nanoemulsion droplets. (B), (D), and (F) are number of OL-water, LA-water, CC(OL)-water, CC(LA)-water, CC-OL, and CC-LA contacts where their hydrogen bonds are shown in (C), (E), and (G), respectively.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/e5cf2ed581e5da3e7ac003a4.jpg"},{"id":97161570,"identity":"17972e1c-cdf6-42eb-bcdf-69dc649613ef","added_by":"auto","created_at":"2025-12-01 12:41:35","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":255915,"visible":true,"origin":"","legend":"\u003cp\u003e(A)\u003cstrong\u003e \u003c/strong\u003eLocation of CC in both CC-LA and CC-OL systems.\u003cstrong\u003e \u003c/strong\u003e(B) Percentages of individual oil contacts with CC where their locations can be seen in (C).\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/5647d316ed67525b72c65b5e.jpg"},{"id":97249902,"identity":"0e708840-3952-4017-9429-5e05d14001ec","added_by":"auto","created_at":"2025-12-02 13:13:36","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":311969,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003eA) Snapshots of CC-LA-LC-T85 aggregation as a function of time. Root mean squared deviation (RMSD) and radius of gyration (Rg), solvent accessible surface area (SASA) are shown in (B) (C), and (D), respectively. The CC-LA-LC-T85 contacts with water is shown in (F). A number of self-hydrogen bonds and CC-LA-LC-T85 hydrogen bonds with water are displayed in (E) and (G).\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/deafc5db6738771612ba7177.jpg"},{"id":97161568,"identity":"db4da66d-f0a9-437c-b480-b82ea0b9b244","added_by":"auto","created_at":"2025-12-01 12:41:35","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":94502,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Percentages of CC contacts with other components where their location can be seen in (B).\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/c725ad2251f0ce6143c00873.jpg"},{"id":100910149,"identity":"fb8a62a0-5b66-4795-9b4c-43068abbbef3","added_by":"auto","created_at":"2026-01-22 16:42:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2261004,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/99312377-3418-4e0b-9af5-9350dcffcb57.pdf"},{"id":97249868,"identity":"0f3c01fb-2214-48ad-92ee-5308690f6a72","added_by":"auto","created_at":"2025-12-02 13:13:33","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":195793,"visible":true,"origin":"","legend":"","description":"","filename":"GA.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8023845/v1/baf0997d600dc833fb3f17a0.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Optimizing oil selection for curcumin-based nanoemulsions formulation through molecular self-assembly","fulltext":[{"header":"Introduction","content":"\u003cp\u003eConventional emulsions are often used for the delivery of lipophilic molecules which are prone to phase separation, coalescence and low bioavailability [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Nanoemulsions as colloidal dispersions with droplet sizes (\u0026gt;\u0026thinsp;200 nm) offer higher kinetic stability and better encapsulation efficiency [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Their formation and long-term stability are strictly controlled by molecular self-assembly, a fundamental process driven by non-covalent interactions that allow molecules to spontaneously organize into stable, structured arrangements [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This process provides a comprehensive framework for understanding the formation and stabilization of nanoemulsions [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], which are promising drug delivery systems for bioactive compounds [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] including curcumin. Curcumin (CC), the principal curcuminoid extracted from the rhizome of \u003cem\u003eCurcuma longa\u003c/em\u003e, has emerged as a highly potential therapeutic molecule with its potent antioxidant, anti-inflammatory, antimicrobial, antiviral and anticancer activities [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Interestingly, curcumin also shows inhibition effects against dengue virus, influenza A, HIV and SARS‐CoV‐2 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, several key obstacles limit its effectiveness as a therapeutic agent. Curcumin shows poor water solubility (\u0026lt;\u0026thinsp;8 \u0026micro;g/mL), poor bioavailability and rapid metabolism [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Thus, many studies have been attempted to search for suitable methods to enhance curcumin\u0026rsquo;s effectiveness [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. One potential strategy is the use of nanoemulsions, which offer the potential to enhance absorption, protect active compounds from degradation and facilitate controlled release [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo obtain an effective nanoemulsion, suitable oils and surfactant is required for optimizing nanoemulsion formulations [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Oils like safflower oil (SO) or palm kernel oil esters (PKOEs) emerged as promising oil-based components for curcumin nanoemulsion formulations due to their good solubilizing capacity, improved oxidative stability and biocompatibility proven applications in drug delivery [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Moreover, SO and PKOEs were found to improve droplet size distribution and exhibit sustained release and high encapsulation efficiency [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. PKOEs were reported to act as potential oil phase in drug nanoemulsions such as ibuprofen [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], diclofenac [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], ketoprofen [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], whereas SO was widely used in food, cosmetic nanoemulsion formulations [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Moreover, SO and PKOEs were widely studied as curcumin nanoemulsion [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In a previous work, CC-loaded SO core nanoemulsions was found to form stable droplets with sustained release and high encapsulation efficiency for pulmonary delivery [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Also, with good viscosity and osmolality attributes, CC-loaded SO and PKOE nanoemulsions have been suggested to be a promising therapeutic candidate for pulmonary application [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Linoleic acid (LA) is the main component in SO, while oleyl laurate (OL) serves as the major compound in PKOEs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). LA-based nanoemulsions were found to improve CC stability and antioxidant activity under physiological conditions [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], whereas OL helps to stabilize the oil-water interface [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Both LA and OL appear to facilitate the formation of nanoemulsion. Nonetheless, no molecular information on such nanoemulsion formation is available. In addition, there is no comparative study explain the advantages and disadvantages of using SO and PKOEs for curcumin nanoemulsion in a molecular level.\u003c/p\u003e\u003cp\u003eThus, in this work, the formation of curcumin-loaded nanoemulsion using SO and PKOEs was studied in comparison. Molecular Dynamics (MD) simulations were performed to obtain a molecular detail. LA (a major components in SO) and OL (a main component in PKOEs) were used as SO and OL representatives. Herein, the molecular mechanisms of CC-loaded nanoemulsion using LA and OL are revealed. The advantages and disadvantages of LA and OL for CC nanoemulsion are also extracted. Our primary results reported that LA acts as more promising oil-phase candidate, therefore further simulations were performed on CC-loaded LA system. Further MD simulation on the assembly of CC, LA, lecithin (LC) and tween 85 (T85) was performed to investigate the mechanism of nanoemulsion formation. LC and T85 were included here to mimic a real nanoemulsion condition. LC and T85 are common chemicals used to enhance stability and encapsulation efficiency. LC acts as both stabilizer and emulsifier [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], while T85 reduces interfacial tension to support droplet formation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The insights obtained here will be useful for future design of effective CC-loaded nanoemulsion formulations in food and nutraceutical applications.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Materials and method","content":"\u003cp\u003eThe three-dimensional (3D) structures of CC, LA, OL, LC and T85 were build using Avogadro software [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The structurers were optimized by Automated Topology Builder (ATB) and Repository version 3.0 server [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The topologies were generated using ACPYPE [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The RESP charges of each ligand were obtained from quantum calculation with a HF/6-31G(d) basis set. At the beginning, two systems which are CC-LA and CC-OL were set. CC was placed in a cubic box with a dimension of 10 x 10 x 10 \u0026Aring;\u003csup\u003e3\u003c/sup\u003e. 20 molecules of LA were randomly added into a CC-LA box, while 13 molecules of OL were added in CC-OL box. Each oil was placed at least 10 \u0026Aring; away from each other. A number of LA and OL used in this work are obtained from a previous experimental work [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Then, CC-LA and CC-OL were solvated by TIP3P water models and neutralized by counterions. In case of CC-LA in LC and T85, CC was placed in a cubic box with a dimension of 10 x 10 x 10 \u0026Aring;\u003csup\u003e3\u003c/sup\u003e. 20 molecules of LA, 7 molecules of LC and 7 molecules of T85 were randomly added into a CC-LA-LC-T85 box with a distance of at least 10 \u0026Aring; away from each other. The quantities of LA, LC and T85 used in this study were based on a previous experimental work. The CC-LA-LC-T85 system was then solvated using the TIP3P water model and neutralized with counterions.\u003c/p\u003e\u003cp\u003eAll the molecular dynamics simulations were carried out using GROMACS version 2022.1 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.gromacs.org\" target=\"_blank\"\u003ewww.gromacs.org\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.gromacs.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) using the AMBER99SB force field [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Each of the systems was placed in a simulation box of cubic shape and solvated with TIP3P water molecules and counterions added to make the system neutral. To resolve steric clashes during system setup, energy minimization was achieved using the steepest descent algorithm for a maximum of 1000 steps. Long-range electrostatic interactions were treated with Particle Mesh Ewald (PME) and a 1.0 nm short-range cutoff, Fourier grid spacing of 0.12 nm and fourth-order spline interpolation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Simulations were conducted in the NPT ensemble at constant number of particles, pressure, and temperature. Temperature coupling was done separately for the ions, solvent, and protein with the velocity-rescale thermostat at 300 K and a coupling parameter of 0.1 ps [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Pressure was maintained at 1 bar using the Berendsen barostat and a coupling parameter of 1 ps. The time step of integration was 2 fs, and coordinates were stored at every 2 ps for analysis. All the systems were given a 10 ns equilibration time, following which production runs were taken for 1000 ns, and this was done for reproducibility. Results presented are the average of two independent simulations. The data analysis was carried out using GROMACS tools and homemade scripts. Molecular graphics were generated using PyMOL, VMD, and Discovery Studio 2021. The analysis included observing the evolution of mean square displacement (MSD), principal moments of inertia and eccentricity of each component in order to enable evaluation of nanoemulsion size, shape, diffusion nature and self-assembly dynamics. Structural evolution and stability were monitored at equal intervals during simulations.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eThe assembly of CC-LA and CC-OL nanoemulsion\u003c/h2\u003e\u003cp\u003eThe results in Fig.\u0026nbsp;2A illustrates the spontaneous self-assembly of the CC-LA and CC-OL systems, in which droplet formation occurs within 500 ns. In both systems, the hydrophobic tails of LA and OL cluster together with curcumin and shield it from the aqueous phase, while the hydrophilic moieties orient outward to stabilise the micelle-like structure [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Remarkably, curcumin tends to align with the droplet surface and appear pinched between the oil molecules (Fig.\u0026nbsp;2A and 3A). The stability of these assemblies was assessed through RMSD and radius of gyration (Rg) analyses (Figs.\u0026nbsp;2B and 2C). It can be seen that the aggregation of both CC-LA and CC-OL is fast and spontaneous. Both CC-LA and CC-OL are clustered within ~\u0026thinsp;50 ns where CC-OL shows lightly higher RMSD (0.251\u0026thinsp;\u0026plusmn;\u0026thinsp;0.029 nm for CC-OL and 0.224\u0026thinsp;\u0026plusmn;\u0026thinsp;0.020 nm for CC-LA) (Fig.\u0026nbsp;2A and 2B). The lower RMSD of CC-LA suggests slightly more rigid CC-LA molecules [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, Rg indicates both CC-LA and CC-OL exhibit a comparable degree of compactness (Fig.\u0026nbsp;2C), even though LA is slightly more water-exposed (Fig.\u0026nbsp;2D).\u003c/p\u003e\u003cp\u003eTo explore the aggregation mechanism [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], a number of contacts and hydrogen bond analyses were computed as shown in Fig.\u0026nbsp;3. A higher number of water contacts (Fig.\u0026nbsp;3B) and hydrogen bonds with water (Fig.\u0026nbsp;3C) in CC-LA confirm the more water exposure of a LA cluster, whilst OL molecules are found to be more buried due to lower number of water contacts and hydrogen bonds [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In case of CC, due to its location at the surface (Fig.\u0026nbsp;3A), CC in both LA and OL show similar degree of wettability and hydrogen bonds with water (Fig.\u0026nbsp;3D and 3E). CC appears to align on the oil surface in both cases resulting in a similar number of oil contacts (Fig.\u0026nbsp;3F). Nonetheless, CC in LA can form more hydrogen bonds (~\u0026thinsp;2\u0026ndash;4 CC-LA hydrogen bonds) than CC in OL (~\u0026thinsp;one CC-OL hydrogen bond) (Fig.\u0026nbsp;3G). Such higher number of CC-LA hydrogen bonds suggest the tighter binding of CC to LA.\u003c/p\u003e\u003cp\u003eTo better understand how CC interacts with OL and LA, the individual hydrogen bonds between CC and each oil were computed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The location of CC on a droplet surface is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003eA. CC can interact with more LA than OL. Four LA molecules (LA-1: 41.87%, LA-4: 46.41%, LA-11: 43.97%, LA-15: 51%) are found to be in the close proximity to CC, whereas three OL molecules (OL-1: 44.14%, OL-8: 63.49%, OL-11: 53.66%) are sufficient to stabilise the CC binding (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003eB and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). LA seems to completely hold the whole CC molecule, while, in CC-OL, the OL contacts were less evenly distributed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). The more balanced distribution of CC-LA contacts supports the more stable CC-LA packing. Based on these results, LA forms stronger and more consistent hydrogen bonds and close contacts with CC than OL. Such interactions improve the structural integrity and stability of the nanoemulsion [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], making LA the more suitable oil phase for the CC encapsulation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurthermore, the principal moments of inertia and eccentricity were computed (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) to provide insights into the molecular shape and mass distribution within the nanoemulsion aggregates [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. For CC\u0026ndash;OL, the ratios of I\u003csub\u003e1\u003c/sub\u003e: I\u003csub\u003e2\u003c/sub\u003e: I\u003csub\u003e3\u003c/sub\u003e is 1:1.6:1.8 and an eccentricity value of 0.18 suggest a moderately elongated but compact shape, with slight deviation from perfect sphericity. This is further supported by the low radius of sphere (R\u003csub\u003es\u003c/sub\u003e) of 0.17 nm, indicating a packed structure [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Similarly, the CC\u0026ndash;LA system exhibits ratios of 1:1.5:1.8 with an eccentricity of 0.19 and R\u003csub\u003es\u003c/sub\u003e of 0.16 nm, reflecting a slightly more compact structure compared to CC\u0026ndash;OL. The close values of I\u003csub\u003e2\u003c/sub\u003e and I\u003csub\u003e3\u003c/sub\u003e in both systems imply that the aggregates maintain a generally ellipsoidal geometry rather than a spherical one. The slightly lower R\u003csub\u003es\u003c/sub\u003e and similar eccentricity in CC\u0026ndash;LA suggest better compactness and possibly stronger intermolecular interactions within the nanoemulsion [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], contributing to its structural stability. Based on these factors, LA derived from safflower oil shows higher CC-LA hydrogen bonding and provide a flexible micellar microenvironment. This suggests LA as a suitable candidate for the CC encapsulation.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e Total moment of inertia (Itot) and the eccentricity (e) value of the CC-OL and CC-LA nanoemulsions.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystem\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003etot\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e5\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e4\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e4\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e4\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e: \u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e: \u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003ee\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMicelle Shape\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eR\u003csub\u003es\u003c/sub\u003e (nm)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCC-OL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1:1.6:1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSlightly aspherical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCC-LA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1:1.5:1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSlightly aspherical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eNevertheless, despite successful encapsulation within safflower oil, CC is inherently hydrophobic and dispersion in aqueous systems is therefore less favourable. This feature emphasises the importance of surfactants, which not only lower the interfacial tension but also enable interaction between the hydrophobic oily core and the surrounding aqueous phase [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Consequently, the incorporation of surfactants is essential for reducing interfacial tension and facilitating interactions with water, thereby improving dispersion and potentially increasing delivery to the target site.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMD simulation of the CC-LA-LC-T85 nanoemulsion\u003c/h3\u003e\n\u003cp\u003eSubsequent to the performance of CC-LA system, the newly formulated system of CC, LA, lecithin (LC) and Tween 85 (T85) was investigated through a 1000-ns MD simulation. This extended time scale allows the evaluation of aggregate stability, encapsulation efficiency and interfacial organization. The simulation illustrated that mini-droplets dispersed at the early moment (25 ns) increased and eventually coalesced into a large, stable aggregate at ~\u0026thinsp;50 ns (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). The spontaneous self-assembly is triggered by the CC-LA association at the centre, while LC and T85 are clustered before associating to CC-LA complex (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). This mixed aggregation appears to be faster than CC-LA system. LC and T85 appear to promote the aggregation. LC, with its hydrophobic tails and polar phosphate head, was reported to facilitate the structuring of the oil-water phase, whereas T85 provided a steric stabilisation and an additional reduction in surface tension to prevent coalescence [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The synergistic activities of LA, LC and T85 ensured stable encapsulation of CC and robust oil-in-water (O/W) droplet formation. A RMSD analysis showed rapid structural adjustments within 50 ns, after which the system stabilised at ~\u0026thinsp;0.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 nm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eB). This plateau indicates that the aggregate maintained its conformational stability [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. The radius of gyration (Rg) further confirms these findings, with an initial decrease followed by a stabilisation around 0.168 nm after ~\u0026thinsp;100 ns (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eC). This constant value reflects a compact, well-organised aggregate. The effective radius (Rs) estimated from Rg is 0.22 nm, consistent with a nearly spherical geometry and validating the compactness of the nanoemulsion droplet. Moreover, SASA analysis revealed a decrease in solvent exposure over time and stabilised at ~\u0026thinsp;10.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 nm\u0026sup2; (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eD). The hydrophobic contribution (3.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15 nm\u0026sup2;) indicates efficient incorporation of LA and surfactant tails within the core, while the hydrophilic contribution (6.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31 nm\u0026sup2;) reflects the outward orientation of the polar groups. This balanced distribution is characteristic of O/W nanoemulsions, supporting colloidal stability and favourable interactions with the aqueous environment [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn addition, the presence of LC and T85 appear to promote the tighter binding of CC to oil complex. Compared to CC-LA system, CC in CC-LA-LC-T85 can form more hydrogen bonds. (10.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45 hydrogen bonds), reflecting a robust network of intermolecular interactions (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eE). Furthermore, the water contact analysis further confirms the hydration and surface exposure of the system [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. A total of 5983.62\u0026thinsp;\u0026plusmn;\u0026thinsp;342.28 water contacts is observed, with CC alone maintaining 147.09\u0026thinsp;\u0026plusmn;\u0026thinsp;25.82 contacts (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eF). Compared to CC-LA, the presence of LC and T85 induce the more buried CC (~\u0026thinsp;200 CC-water contacts in CC-LA (Fig.\u0026nbsp;3D)). Besides, the system formed an average of 210.85\u0026thinsp;\u0026plusmn;\u0026thinsp;7.34 hydrogen bonds with water (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e5\u003c/span\u003eG). This extensive hydration helps stabilise the interfaces, prevents aggregation and promotes long-term dispersion and bioavailability of the CC-loaded nanoemulsion.\u003c/p\u003e\u003cp\u003eNext, CC is found to interact closely with three Tween 85 molecules (T85-2: 36.15%, T85-3: 38.00%, T85-5: 35.65%), one LC (LC-2: 36.15%) and four LA molecules (LA-21: 21.90%, LA-37: 22.54%, LA-39: 24.26%, LA-40: 16.36%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e6\u003c/span\u003e). CC displays stronger associations with T85 and LC, which can be attributed to their polar head groups and chemical compatibility with CC. In contrast, LA, being purely hydrophobic, engaged mainly through transient hydrophobic associations rather than specific polar interactions. Overall, the preferential binding of CC to T85 and LC underlines their dual role as structural stabilizers and mediators of CC encapsulation and dispersion in the nanoemulsion.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurthermore, the morphological properties were investigated as seen in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the inertia value (\u003cem\u003eI\u003c/em\u003e) along the z-axis is higher than those along the x- and y-axes, suggesting a slight elongation of the aggregate along the z-axis. A perfectly spherical system would exhibit equal values along all three axes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, the observed ratio of 1.0:1.2:1.4 indicates a near-spherical morphology with minor deviations. The moment of inertia of the optimised CC-LA-LC-T85 system (\u003cem\u003eI\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.24) was substantially higher than that of CC-LA alone (\u003cem\u003eI\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.21), illustrating the more compact and organized aggregation achieved upon incorporation of LC and T85. Despite these differences, the system maintained a compact and energetically favourable structure, reflecting stable interactions among the components. Such a morphology minimises the risk of phase separation and is indicative of a uniform and stable nanoemulsion [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e Total moment of inertia (Itot) and the eccentricity (e) value of the CC-LA-LC-T85 nanoemulsion.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystem\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003etot\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e5\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e4\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e4\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sub\u003e (10\u003csup\u003e4\u003c/sup\u003e au nm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e: \u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e: \u003cem\u003eI\u003c/em\u003e\u003csub\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sub\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003ee\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMicelle Shape\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eR\u003csub\u003es\u003c/sub\u003e (nm)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCC-LA-LC-T85\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1:1.2:1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSlightly aspherical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTo further evaluate the shape of the aggregate, the eccentricity (\u003cem\u003ee\u003c/em\u003e) was calculated. A perfect sphere has an eccentricity of zero, whereas the observed value of 0.13 indicates only a slight deviation from sphericity. This observation is consistent with the analysis of the principal moment of inertia and the visual inspection of the simulation snapshots, confirming a stable near-spherical geometry. Compared to the CC-LA system that had a more aspherical morphology, the CC-LA-LC-T85 system showed a more symmetrical and compact structure. Overall, these findings highlight the effective self-assembly of the CC-LA-LC-T85 nanoemulsion into a compact, stable morphology. Such structural features are critical to ensure long-term stability and provide a framework for surfactant and co-surfactant selection and formulation optimisation of curcumin-safflower oil nanoemulsion systems.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe comprehensive molecular dynamics simulation study of nanoemulsions in this research has provided a detailed understanding of the self-assembly and potential for drug delivery applications. The comparison between CC-LA and CC-OL systems showed that CC-LA provided better stability. An extended study on the CC-LA-LC-T85 nanoemulsion reaffirmed its potential as a stable delivery agent. The CC-LA-LC-T85 nanoemulsion exhibited consistent RMSD values indicating structural stability, while its compactness as reflected by Rg and SASA suggest a minimal risk of phase separation. Morphological descriptors, including moments of inertia and eccentricity, confirmed a near-spherical morphology supporting aggregate stability. Importantly, these results are consistent with previous studies demonstrating that surfactant-assisted nanoemulsions improve structural integrity and encapsulation efficiency. However, they extend the understanding by demonstrating at the atomic level how LC and Tween 85 synergistically improve droplet organisation. By demonstrating denser packing and reduced solvent exposure compared to simpler CC-LA assemblies, this work highlights the importance of optimised surfactant selection in achieving durable nanoemulsion structures. Such insights not only reinforce current strategies for nanoemulsion design, but also provide a mechanistic framework for the rational development of drug delivery carriers with improved stability and biocompatibility. This compatibility study establishes a strong foundation for future research aimed at developing an effective nanoemulsion-based delivery system and a key step in ensuring that the final nanoemulsion is stable and suitable for its intended application.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Curcumin\u003c/p\u003e\n\u003cp\u003eOL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Oleyl Laurate\u003c/p\u003e\n\u003cp\u003eLA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Linoleic Acid\u003c/p\u003e\n\u003cp\u003eMD \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Molecular Dynamic\u003c/p\u003e\n\u003cp\u003ePKOEs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Palm Kernel Oil Esters\u003c/p\u003e\n\u003cp\u003eSO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Safflower Oil\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not applicable. This study did not involve human participants, animals or clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e All simulation data and analysis outputs generated during this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was supported by SATREPS program under JICA and Kasetsart University Research and Development Institute (KURDI) (Grant no: FF(KU)62.69).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAina Hazimah Bahaman: Conceptualization, methodology design, molecular dynamics simulations, data analysis, manuscript drafting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrapasiri Pongprayoon: Co-supervision, guidance on computational protocols, manuscript review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBimo Ario Tejo: Manuscript review\u003c/p\u003e\n\u003cp\u003eMohd Basyaruddin Abdul Rahman: Supervision, critical review, manuscript editing\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors acknowledge Universiti Putra Malaysia and the Institute for Medical Research (IMR), Ministry of Health Malaysia, for providing research facilities and Kasetsart University, Thailand, for the opportunity to develop expertise in bioinformatics. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information:\u003c/strong\u003e Dr. Aina Bahaman obtained her PhD in Chemistry (Computational and Theoretical Chemistry) from Universiti Putra Malaysia in June 2025. Her research focuses on molecular docking, molecular dynamics simulations, protein\u0026ndash;ligand interactions, mutation analysis and the computational study of small molecules and nanoemulsion-based drug delivery systems.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe datasets and simulation trajectories generated during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcClements DJ (2018). Enhanced delivery of lipophilic bioactives using emulsions: a review of major factors affecting vitamin, nutraceutical, and lipid bioaccessibility. Food Funct. 9(1):22\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1039/c7fo01515a\u003c/span\u003e\u003cspan address=\"10.1039/c7fo01515a\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFranklyne JS, Gopinath PM, Mukherjee A, Chandrasekaran N (2021). Nanoemulsions: The rising star of antiviral therapeutics and nanodelivery system-current status and prospects. Curr Opin Colloid Interface Sci. 54:101458. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cocis.2021.101458\u003c/span\u003e\u003cspan address=\"10.1016/j.cocis.2021.101458\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeng H-T, Lam JWY, Tang BZ (2020). Self-assembly of AIEgens. Coordination Chemistry Reviews. 406. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ccr.2019.213142\u003c/span\u003e\u003cspan address=\"10.1016/j.ccr.2019.213142\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi S, Duan S, Zha Z, Pan J, Sun L, Liu M, Deng K, Xu X, Qiu X (2020). Structural Phase Transitions of Molecular Self-Assembly Driven by Nonbonded Metal Adatoms. ACS Nano. 14(5):6331\u0026ndash;6338. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/acsnano.0c02995\u003c/span\u003e\u003cspan address=\"10.1021/acsnano.0c02995\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTayeb HH, Felimban R, Almaghrabi S, Hasaballah N (2021). Nanoemulsions: Formulation, characterization, biological fate, and potential role against COVID-19 and other viral outbreaks. Colloid Interface Sci Commun. 45:100533. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.colcom.2021.100533\u003c/span\u003e\u003cspan address=\"10.1016/j.colcom.2021.100533\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJennings MR, Parks RJ (2020). Curcumin as an Antiviral Agent. Viruses. 12(11). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/v12111242\u003c/span\u003e\u003cspan address=\"10.3390/v12111242\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThimmulappa RK, Mudnakudu-Nagaraju KK, Shivamallu C, Subramaniam KJT, Radhakrishnan A, Bhojraj S, Kuppusamy G (2021). Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19. Heliyon. 7(2):e06350. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.heliyon.2021.e06350\u003c/span\u003e\u003cspan address=\"10.1016/j.heliyon.2021.e06350\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang L, Wang P, Yang Z, Du F, Li Z, Wu C, Fang A, Xu X, Zhou G (2020). Molecular dynamics simulation exploration of the interaction between curcumin and myosin combined with the results of spectroscopy techniques. Food Hydrocolloids. 101. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.foodhyd.2019.105455\u003c/span\u003e\u003cspan address=\"10.1016/j.foodhyd.2019.105455\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaur K, Al-Khazaleh AK, Bhuyan DJ, Li F, Li CG (2024). A Review of Recent Curcumin Analogues and Their Antioxidant, Anti-Inflammatory, and Anticancer Activities. Antioxidants (Basel). 13(9). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/antiox13091092\u003c/span\u003e\u003cspan address=\"10.3390/antiox13091092\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoshan Z, Haddadi-Asl V, Ahmadi H, Moussaei M (2024). Curcumin‐Encapsulated Poly(lactic‐co‐glycolic acid) Nanoparticles: A Comparison of Drug Release Kinetics from Particles Prepared via Electrospray and Nanoprecipitation. Macromolecular Materials and Engineering. 309(7). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/mame.202400040\u003c/span\u003e\u003cspan address=\"10.1002/mame.202400040\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJafari M, Parastouei K, Abbaszadeh S (2024). Development of curcumin-loaded nanoemulsion stabilized with texturized whey protein concentrate: Characterization, stability and in vitro digestibility. Food Sci Nutr. 12(3):1655\u0026ndash;1672. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/fsn3.3860\u003c/span\u003e\u003cspan address=\"10.1002/fsn3.3860\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlmeida OP, de Freitas Marques MB, de Oliveira JP, da Costa JMG, Rodrigues AP, Yoshida MI, Mussel WDN, Carneiro G (2022). Encapsulation of safflower oil in nanostructured lipid carriers for food application. J Food Sci Technol. 59(2):805\u0026ndash;814. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13197-021-05078-5\u003c/span\u003e\u003cspan address=\"10.1007/s13197-021-05078-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFaujan NH, Abedi Karjiban R, Kashaban I, Basri M, Basri H (2019). Computational simulation of palm kernel oil-based esters nano-emulsions aggregation as a potential parenteral drug delivery system. Arabian Journal of Chemistry. 12(8):2372\u0026ndash;2383. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.arabjc.2015.03.003\u003c/span\u003e\u003cspan address=\"10.1016/j.arabjc.2015.03.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKarjiban RA, Huan Q-Y, Abdul Rahman MB, Basri M, Tejo BA (2015). Self-assembly of Palm Kernel Oil Wax Esters in Aqueous Media: A Molecular Dynamics Study. International Journal of Chemistry. 7(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5539/ijc.v7n1p133\u003c/span\u003e\u003cspan address=\"10.5539/ijc.v7n1p133\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAsmawi AA, Salim N, Abdulmalek E, Abdul Rahman MB (2023). Size-Controlled Preparation of Docetaxel- and Curcumin-Loaded Nanoemulsions for Potential Pulmonary Delivery. Pharmaceutics. 15(2). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/pharmaceutics15020652\u003c/span\u003e\u003cspan address=\"10.3390/pharmaceutics15020652\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSalim N, Basri M, Rahman MB, Abdullah DK, Basri H (2012). Modification of palm kernel oil esters nanoemulsions with hydrocolloid gum for enhanced topical delivery of ibuprofen. Int J Nanomedicine. 7:4739\u0026ndash;47. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/IJN.S34700\u003c/span\u003e\u003cspan address=\"10.2147/IJN.S34700\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRezaee M, Basri M, Rahman RN, Salleh AB, Chaibakhsh N, Karjiban RA (2014). Formulation development and optimization of palm kernel oil esters-based nanoemulsions containing sodium diclofenac. Int J Nanomedicine. 9:539\u0026ndash;48. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/IJN.S49616\u003c/span\u003e\u003cspan address=\"10.2147/IJN.S49616\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSakeena MHF, Muthanna FA, Ghassan ZA, M. KM, M. ES, S. MA, N. AM (2010). Formulation and \u003cem\u003ein vitro\u003c/em\u003e Evaluation of Ketoprofen in Palm Oil Esters Nanoemulsion for Topical Delivery. Journal of Oleo Science. 59 (4)(223\u0026ndash;228).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEsmari VJ, Plessis JD, Preez JLD, Shahzad Y, Gerber M (2022). Formulation and characterisation of artemether-loaded nano-emulsion for topical applications. Journal of Drug Delivery Science and Technology. 73(103449). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jddst.2022.103449\u003c/span\u003e\u003cspan address=\"10.1016/j.jddst.2022.103449\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEmami F, Vatanara A, Park EJ, Na DH (2018). Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals. Pharmaceutics. 10(3). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/pharmaceutics10030131\u003c/span\u003e\u003cspan address=\"10.3390/pharmaceutics10030131\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEfendy GD, Kadir SASH, Latip NA, Rahim AS, Mazlan M (2019). Palm Oil in Lipid-Based Formulations and Drug Delivery Systems. Biomolecules. 9(2). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/biom9020064\u003c/span\u003e\u003cspan address=\"10.3390/biom9020064\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSutradhar KB, Amin ML (2013). Nanoemulsions: increasing possibilities in drug delivery. European Journal of Nanomedicine. 5(2). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1515/ejnm-2013-0001\u003c/span\u003e\u003cspan address=\"10.1515/ejnm-2013-0001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e\u0026Ouml;zt\u0026uuml;rk D, Mih\u0026ccedil;iokur H (2022). Production of innovative magnetic adsorbent Fe3O4@PEI\u0026reg;Tween 85 and removal of oxytetracycline from aqueous media. Separation Science and Technology. 57(7):1030\u0026ndash;1042. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/01496395.2021.1962911\u003c/span\u003e\u003cspan address=\"10.1080/01496395.2021.1962911\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePantiora P, Furlan V, Matiadis D, Mavroidi B, Perperopoulou F, Papageorgiou AC, Sagnou M, Bren U, Pelecanou M, Labrou NE (2022). Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1. Antioxidants (Basel). 12(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/antiox12010063\u003c/span\u003e\u003cspan address=\"10.3390/antiox12010063\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIbezim A, Madukaife MS, Osigwe SC, Engel N, Karuppasamy R, Ntie-Kang F (2022). Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIbeta ligands. BMC Chem. 16(1):19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13065-022-00812-2\u003c/span\u003e\u003cspan address=\"10.1186/s13065-022-00812-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eToviwek B, Koonawootrittriron S, Suwanasopee T, Pongprayoon P (2022). Molecular insights into the binding of carnosine and anserine to human serum carnosinase 1 (CN1). PeerJ Physical Chemistry. 4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7717/peerj-pchem.25\u003c/span\u003e\u003cspan address=\"10.7717/peerj-pchem.25\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKuntip N, Japrung D, Pongprayoon P (2021). How human serum albumin-selective DNA aptamer binds to bovine and canine serum albumins. Biopolymers. 112(3):e23421. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/bip.23421\u003c/span\u003e\u003cspan address=\"10.1002/bip.23421\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavidson RB, Hendrix J, Geiss BJ, McCullagh M (2018). Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations. PLoS Comput Biol. 14(4):e1006103. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pcbi.1006103\u003c/span\u003e\u003cspan address=\"10.1371/journal.pcbi.1006103\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePhadungsombat J, Nakayama EE, Shioda T (2024). Unraveling Dengue Virus Diversity in Asia: An Epidemiological Study through Genetic Sequences and Phylogenetic Analysis. Viruses. 16(7). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/v16071046\u003c/span\u003e\u003cspan address=\"10.3390/v16071046\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePanman W, Japrung D, Pongprayoon P (2017). Exploring the interactions of a DNA aptamer with human serum albumins: simulation studies. J Biomol Struct Dyn. 35(11):2328\u0026ndash;2336. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/07391102.2016.1224733\u003c/span\u003e\u003cspan address=\"10.1080/07391102.2016.1224733\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArredondo-Ochoa T, Silva-Mart\u0026iacute;nez GA (2022). Microemulsion Based Nanostructures for Drug Delivery. Frontiers in Nanotechnology. 3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fnano.2021.753947\u003c/span\u003e\u003cspan address=\"10.3389/fnano.2021.753947\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShaker DS, Ishak RAH, Ghoneim A, Elhuoni MA (2019). Nanoemulsion: A Review on Mechanisms for the Transdermal Delivery of Hydrophobic and Hydrophilic Drugs. Scientia Pharmaceutica. 87(3). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/scipharm87030017\u003c/span\u003e\u003cspan address=\"10.3390/scipharm87030017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRangubpit W, Suwan E, Sangthong D, Wongpanit K, Stich RW, Pongprayoon P, Jittapalapong S (2022). Observing How Glutathione and S-Hexyl Glutathione Bind to Glutathione S-Transferase from Rhipicephalus (Boophilus) microplus. Int J Mol Sci. 23(21). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijms232112775\u003c/span\u003e\u003cspan address=\"10.3390/ijms232112775\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdhav VA, Saikrishnan K (2023). The Realm of Unconventional Noncovalent Interactions in Proteins: Their Significance in Structure and Function. ACS Omega. 8(25):22268\u0026ndash;22284. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/acsomega.3c00205\u003c/span\u003e\u003cspan address=\"10.1021/acsomega.3c00205\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnindita PD, Halbeisen M, Reha D, Tuma R, Franta Z (2022). Mechanistic insight into the RNA-stimulated ATPase activity of tick-borne encephalitis virus helicase. J Biol Chem. 298(10):102383. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jbc.2022.102383\u003c/span\u003e\u003cspan address=\"10.1016/j.jbc.2022.102383\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu S, Zhang H, Yuan S (2022). Hydrophilic Silica Nanoparticles in O/W Emulsion: Insights from Molecular Dynamics Simulation. Molecules. 27(23). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/molecules27238407\u003c/span\u003e\u003cspan address=\"10.3390/molecules27238407\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAltamimi MA, Hussain A, Alshehri S, Imam SS, Alnemer UA (2021). Development and Evaluations of Transdermally Delivered Luteolin Loaded Cationic Nanoemulsion: In Vitro and Ex Vivo Evaluations. Pharmaceutics. 13:1218.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHakim L, Mardiana D, Rokhiyah U, Lestari MLAD, Ningsih Z (2021). Structure and Dynamics of Curcumin Encapsulated Lecithin Micelles: A Molecular Dynamics Simulation Study. Science and Technology Indonesia. 6(3):113\u0026ndash;120. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.26554/sti.2021.6.3.113-120\u003c/span\u003e\u003cspan address=\"10.26554/sti.2021.6.3.113-120\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUmar AK, Zothantluanga JH, Aswin K, Maulana S, Sulaiman Zubair M, Lalhlenmawia H, Rudrapal M, Chetia D (2022). Antiviral phytocompounds \"ellagic acid\" and \"(+)-sesamin\" of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction. Struct Chem. 33(5):1445\u0026ndash;1465. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11224-022-01959-3\u003c/span\u003e\u003cspan address=\"10.1007/s11224-022-01959-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMishra N, Kaushik N, Sharma PK, Alam MA (2023). Nano Emulsion Drug Delivery System: A Review. Current Nanomedicine. 13(1):2\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/2468187313666230213121011\u003c/span\u003e\u003cspan address=\"10.2174/2468187313666230213121011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoghaddasi F, Housaindokht MR, Darroudi M, Bozorgmehr MR, Sadeghi A (2018). Soybean oil-based nanoemulsion systems in absence and presence of curcumin: Molecular dynamics simulation approach. Journal of Molecular Liquids. 264:242\u0026ndash;252. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.molliq.2018.05.066\u003c/span\u003e\u003cspan address=\"10.1016/j.molliq.2018.05.066\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDonthi MR, Munnangi SR, Krishna KV, Saha RN, Singhvi G, Dubey SK (2023). Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery. Pharmaceutics. 15(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/pharmaceutics15010164\u003c/span\u003e\u003cspan address=\"10.3390/pharmaceutics15010164\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaya SA, Saaid IM, Mohd Aji AQ, AA AR (2022). Investigation of the synergistic effect of nonionic surfactants on emulsion resolution using response surface methodology. RSC Adv. 12(48):30952\u0026ndash;30961. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1039/d2ra04816g\u003c/span\u003e\u003cspan address=\"10.1039/d2ra04816g\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharma S, Awad IE, Yadav A, Poirier RA (2020). Molecular level investigation of curcumin self-assembly induced by trigonelline and nanoparticle formation. Appl Nanosci. 10(11):3987\u0026ndash;3998. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13204-020-01526-4\u003c/span\u003e\u003cspan address=\"10.1007/s13204-020-01526-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh Y, Meher JG, Raval K, Khan FA, Chaurasia M, Jain NK, Chourasia MK (2017). Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release. 252:28\u0026ndash;49. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jconrel.2017.03.008\u003c/span\u003e\u003cspan address=\"10.1016/j.jconrel.2017.03.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTanbin S, Ahmad Fuad FA, Abdul Hamid AA (2020). Virtual Screening for Potential Inhibitors of Human Hexokinase II for the Development of Anti-Dengue Therapeutics. BioTech (Basel). 10(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/biotech10010001\u003c/span\u003e\u003cspan address=\"10.3390/biotech10010001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHensel JK, Carpenter AP, Ciszewski RK, Schabes BK, Kittredge CT, Moore FG, Richmond GL (2017). Molecular characterization of water and surfactant AOT at nanoemulsion surfaces. Proc Natl Acad Sci U S A. 114(51):13351\u0026ndash;13356. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1073/pnas.1700099114\u003c/span\u003e\u003cspan address=\"10.1073/pnas.1700099114\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShi P, Luo H, Tan X, Lu Y, Zhang H, Yang X (2022). Molecular dynamics simulation study of adsorption of anionic-nonionic surfactants at oil/water interfaces. RSC Adv. 12(42):27330\u0026ndash;27343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1039/d2ra04772a\u003c/span\u003e\u003cspan address=\"10.1039/d2ra04772a\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKozuch DJ, Ristroph K, Prud'homme RK, Debenedetti PG (2020). Insights into Hydrophobic Ion Pairing from Molecular Simulation and Experiment. ACS Nano. 14(5):6097\u0026ndash;6106. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/acsnano.0c01835\u003c/span\u003e\u003cspan address=\"10.1021/acsnano.0c01835\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSiraj A, Naqash F, Shah MA, Fayaz S, Majid D, Dar BN (2021). Nanoemulsions: formation, stability and an account of dietary polyphenol encapsulation. International Journal of Food Science \u0026amp; Technology. 56(9):4193\u0026ndash;4205. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ijfs.15228\u003c/span\u003e\u003cspan address=\"10.1111/ijfs.15228\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Curcumin, Safflower Oil, PKOEs, Nanoemulsion, Molecular Dynamics Simulation","lastPublishedDoi":"10.21203/rs.3.rs-8023845/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8023845/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCurcumin is a bioactive compound with anti-inflammatory and anticancer activity, which is poorly water solubility and stability that limiting its therapeutic potential. Curcumin delivery can be improved by oil-in-water nanoemulsions by providing a hydrophobic core, but it is challenging to develop stable systems due to oil-drug compatibility. Molecular dynamics simulations were used to compare two oil cores of linoleic acid (LA) from safflower oil and oleyl laurate (OL) from palm kernel oil esters for curcumin nanoemulsions. The LA structure exhibited smaller structural movements, reduced radius of gyration (Rg) and more persistent intermolecular hydrogen bonds than the OL system. The higher number of CC-LA hydrogen bonds suggest the curcumin molecules become more densely packed with LA to form a tightly ordered hydrophobic core with its amphiphilic character enables a closely packed self-assembly with curcumin. Based on these findings, an optimized nanoemulsion was formulated by adding lecithin (LC) and Tween 85 (T85) into CC-LA (CC-LA-LC-T85), with LC and T85 appearing to enhance the aggregation rate. In simulations, self-association of surfactants occurred at the droplet interface with exposed polar head groups, a uniform shell around a CC-LA core. The ultimate aggregate was near-spherical and structurally hard, as shown by a stable Rg and minimal molecular diffusion. The dense hydrophobic core formed by LA, stabilized by persistent interactions with LC and T85, demonstrated a compact and organised self-assembled structure. These intermolecular interactions collectively ensured effective encapsulation and well-defined nanoemulsion, rendering its potential suitability as a carrier for future curcumin encapsulation in drug delivery applications.\u003c/p\u003e","manuscriptTitle":"Optimizing oil selection for curcumin-based nanoemulsions formulation through molecular self-assembly","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 12:41:31","doi":"10.21203/rs.3.rs-8023845/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6318442b-7e67-4e9d-a887-1230f275c8d2","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-22T16:41:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 12:41:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8023845","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8023845","identity":"rs-8023845","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}