Some biologically active substances are unstable and poorly soluble in aqueous media, at the same time exhibiting low bioavailability. The incorporation of these biologically active compounds into the structure of a lipid-based lyotropic liquid crystalline phase or nanoparticles can increase or improve their stability and transport properties, subsequent bioavailability, and applicability in general. The aim of this short overview is (1) to clarify the principle of self-assembly of lipidic amphiphilic molecules in an aqueous environment and (2) to present lipidic bicontinuous cubic and hexagonal phases and their current biosensing (with a focus on electrochemical protocols) and biomedical applications.

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacky University Hnevotinska 3 775 15 Olomouc Czech Republic

Faculty of Chemistry University of Warsaw Pasteura 1 02 093 Warsaw Poland

Interfaces Team Department of Inorganic and Analytical Chemistry Faculty of Chemistry University of Lodz Tamka 12 91 403 Lodz Poland

Zobrazit více v PubMed

Kulkarni CV. Lipid crystallization: from self-assembly to hierarchical and biological ordering. Nanoscale. 2012;4(19):5779–5791. doi: 10.1039/C2NR31465G. PubMed DOI

Israelachvili JN, Mitchell DJ, Ninham BW. Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. J Chem Soc Faraday Trans. 1976;72:1525–1568. doi: 10.1039/f29767201525. DOI

Patra JK, Das G, Fraceto LF, Campos EVR, del Pilar R-T, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018;16(1):1–33. doi: 10.1186/s12951-018-0392-8. PubMed DOI PMC

Mitov M. Liquid-crystal science from 1888 to 1922: building a revolution. Chem Phys Chem. 2014;15(7):1245–1250. doi: 10.1002/cphc.201301064. PubMed DOI

Shanmugam T, Banerjee R. Nanostructured self assembled lipid materials for drug delivery and tissue engineering. Ther Deliv. 2011;2(11):1485–1516. doi: 10.4155/tde.11.105. PubMed DOI

Nazaruk E, Górecka E, Osornio YM, Landau EM, Bilewicz R. Charged additives modify drug release rates from lipidic cubic phase carriers by modulating electrostatic interactions. J Electroanal Chem. 2018;819:269–274. doi: 10.1016/j.jelechem.2017.10.057. DOI

Vacek J, Hrbac J. Sensors and microarrays in protein biomarker monitoring: an electrochemical perspective spots. Bioanalysis. 2020;12(18):1337–1345. doi: 10.4155/bio-2020-0166. PubMed DOI

Van Gool A, Corrales F, Čolović M, Krstić D, Oliver-Martos B, Martínez-Cáceres E, et al. Analytical techniques for multiplex analysis of protein biomarkers. Expert Rev Proteomics. 2020;17(4):257–273. doi: 10.1080/14789450.2020.1763174. PubMed DOI

Nikoleli G-P, Nikolelis DP, Siontorou CG, Nikolelis M-T, Karapetis S. The application of lipid membranes in biosensing. Membranes. 2018;8(4):108. doi: 10.3390/membranes8040108. PubMed DOI PMC

Nazaruk E, Bilewicz R, Lindblom G, Lindholm-Sethson B. Cubic phases in biosensing systems. Anal Bioanal Chem. 2008;391(5):1569. doi: 10.1007/s00216-008-2149-y. PubMed DOI

Vacek J, Zadny J, Storch J, Hrbac J. Chiral electrochemistry: anodic deposition of enantiopure helical molecules. ChemPlusChem. 2020;85(9):1954–1958. doi: 10.1002/cplu.202000389. PubMed DOI

Jakubec M, Novák D, Zatloukalová M, Císařová I, Cibulka R, Favereau L, et al. Flavin-helicene amphiphilic hybrids: synthesis, characterization, and preparation of surface-supported films. ChemPlusChem. 2021;86(7):982–990. doi: 10.1002/cplu.202100092. PubMed DOI

Kulkarni CV, Wachter W, Iglesias-Salto G, Engelskirchen S, Ahualli S. Monoolein: a magic lipid? Phys Chem Chem Phys. 2011;13(8):3004–3021. doi: 10.1039/C0CP01539C. PubMed DOI

Zatloukalová M. 3D lipidic matrix for incorporation and stabilization of biologically active molecules. Chem Listy (in Czech) 2022;116(3):172–179. doi: 10.54779/chl20220172. DOI

Kulkarni CV. Lipid self-assemblies and nanostructured emulsions for cosmetic formulations. Cosmetics. 2016;3(4):37. doi: 10.3390/cosmetics3040037. DOI

Gaballa SA, El Garhy OH, Abdelkader H. Cubosomes: composition, preparation, and drug delivery applications. J Adv Biomed Pharm Sci. 2020;3(1):1–9. doi: 10.21608/jabps.2019.16887.1057. DOI

Qiu H, Caffrey M. The phase diagram of the monoolein/water system: metastability and equilibrium aspects. Biomaterials. 2000;21(3):223–234. doi: 10.1016/S0142-9612(99)00126-X. PubMed DOI

Barauskas J, Landh T. Phase behavior of the phytantriol/water system. Langmuir. 2003;19(23):9562–9565. doi: 10.1021/la0350812. DOI

Cytryniak A, Żelechowska-Matysiak K, Nazaruk E, Bilewicz R, Walczak R, Majka E, et al. Cubosomal lipid formulation for combination cancer treatment: delivery of a chemotherapeutic agent and complexed α-particle emitter 213Bi. Mol Pharm. 2022;19(8):2818–2831. doi: 10.1021/acs.molpharmaceut.2c00182. PubMed DOI PMC

Alvarez-Malmagro J, Matyszewska D, Nazaruk E, Szwedziak P, Bilewicz R. PM-IRRAS study on the effect of phytantriol-based cubosomes on DMPC bilayers as model lipid membranes. Langmuir. 2019;35(50):16650–16660. doi: 10.1021/acs.langmuir.9b02974. PubMed DOI

Nazaruk E, Majkowska-Pilip A, Bilewicz R. Lipidic cubic-phase nanoparticles—cubosomes for efficient drug delivery to cancer cells. ChemPlusChem. 2017;82(4):570–575. doi: 10.3390/nano10112272. PubMed DOI

Landau EM, Rosenbusch JP. Lipidic cubic phases: a novel concept for the crystallization of membrane proteins. Proc Natl Acad Sci USA. 1996;93(25):14532–14535. doi: 10.1073/pnas.93.25.14532. PubMed DOI PMC

Landau EM, Rummel G, Cowan-Jacob SW, Rosenbusch JP. Crystallization of a Polar Protein and Small Molecules from the Aqueous Compartment of Lipidic Cubic Phases. J Phys Chem. 1997;101(11):1935–1937. doi: 10.1021/jp963347q. DOI

Tan C, Hosseini SF, Jafari SM. Cubosomes and hexosomes as novel nanocarriers for bioactive compounds. J Agric Food Chem. 2022;70(5):1423–1437. doi: 10.1021/acs.jafc.1c06747. PubMed DOI

Li D, Caffrey M. Structure and Functional characterization of membrane integral proteins in the lipid cubic phase. J Mol Biol. 2020;432(18):5104–5123. doi: 10.1016/j.jmb.2020.02.024. PubMed DOI

Conn CE, Drummond CJ. Nanostructured bicontinuous cubic lipid self-assembly materials as matrices for protein encapsulation. Soft Matter. 2013;9(13):3449–3464. doi: 10.1039/C3SM27743G. DOI

Caffrey M. A comprehensive review of the lipid cubic phase or in meso method for crystallizing membrane and soluble proteins and complexes. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2015;71(1):3–18. doi: 10.1107/S2053230X14026843. PubMed DOI PMC

Tiefenbrunn T, Liu W, Chen Y, Katritch V, Stout CD, Fee JA, et al. High resolution structure of the ba3 cytochrome c oxidase from Thermus thermophilus in a lipidic environment. PloS One. 2011;6(7):e22348. doi: 10.1371/journal.pone.0022348. PubMed DOI PMC

Santos JS, Asmar-Rovira GA, Han GW, Liu W, Syeda R, Cherezov V, et al. Crystal structure of a voltage-gated K+ channel pore module in a closed state in lipid membranes. J Biol Chem. 2012;287(51):43063–43070. doi: 10.1074/jbc.M112.415091. PubMed DOI PMC

Zabara A, Chong JTY, Martiel I, Stark L, Cromer BA, Speziale C, et al. Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains. Nat Commun. 2018;9(1):1–9. doi: 10.1038/s41467-018-02996-5. PubMed DOI PMC

Li D, Caffrey M. Lipid cubic phase as a membrane mimetic for integral membrane protein enzymes. Proc Natl Acad Sci USA. 2011;108(21):8639–8644. doi: 10.1073/pnas.1101815108. PubMed DOI PMC

Cherezov V, Yamashita E, Liu W, Zhalnina M, Cramer WA, Caffrey M. In meso structure of the cobalamin transporter, BtuB, at 19.5 Å resolution. J Mol Biol. 2006;364(4):716–34. doi: 10.1016/j.jmb.2006.09.022. PubMed DOI PMC

Rasmussen SGF, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, et al. Crystal structure of the β 2 adrenergic receptor–Gs protein complex. Nature. 2011;477(7366):549–555. doi: 10.1038/nature10361. PubMed DOI PMC

Kang Y, Gao X, Zhou XE, He Y, Melcher K, Xu HE. A structural snapshot of the rhodopsin–arrestin complex. FEBS J. 2016;283(5):816–821. doi: 10.1111/febs.13561. PubMed DOI PMC

Sęk S, Vacek J, Dorčák V. Electrochemistry of peptides. Curr Opin. Electrochem. 2019;14:166–172. doi: 10.1016/j.coelec.2019.03.002. DOI

Vacek J, Zatloukalova M, Novak D. Electrochemistry of membrane proteins and protein–lipid assemblies. Curr Opin Electrochem. 2018;12:73–80. doi: 10.1016/j.coelec.2018.04.012. DOI

Qutub Y, Reviakine I, Maxwell C, Navarro J, Landau EM, Vekilov PG. Crystallization of transmembrane proteins in cubo: mechanisms of crystal growth and defect formation. J Mol Biol. 2004;343(5):1243–1254. doi: 10.1016/j.jmb.2004.09.022. PubMed DOI

Chiu ML, Nollert P, MeC L, Belrhali H, Pebay-Peyroula E, Rosenbusch JP, et al. Crystallization in cubo: general applicability to membrane proteins. Acta Crystallogr D. 2000;56(6):781–784. doi: 10.1107/s0907444900004716. PubMed DOI

Cherezov V. Lipidic cubic phase technologies for membrane protein structural studies. Curr Opin Struct Biol. 2011;21(4):559–566. doi: 10.1016/j.sbi.2011.06.007. PubMed DOI PMC

Ma P, Weichert D, Aleksandrov LA, Jensen TJ, Riordan JR, Liu X, et al. The cubicon method for concentrating membrane proteins in the cubic mesophase. Nat Protoc. 2017;12(9):1745–1762. doi: 10.1038/nprot.2017.057. PubMed DOI

Belrhali H, Nollert P, Royant A, Menzel C, Rosenbusch JP, Landau EM, et al. Protein, lipid and water organization in bacteriorhodopsin crystals: a molecular view of the purple membrane at 1.9 Å resolution. Structure. 1999;7(8):909–17. doi: 10.1016/s0969-2126(99)80118-x. PubMed DOI

Vacek J, Zatloukalova M, Geleticova J, Kubala M, Modriansky M, Fekete L, et al. Electrochemical platform for the detection of transmembrane proteins reconstituted into liposomes. Anal Chem. 2016;88(8):4548–4556. doi: 10.1021/acs.analchem.6b00618. PubMed DOI

Rowiński P, Korytkowska A, Bilewicz R. Diffusion of hydrophilic probes in bicontinuous lipidic cubic phase. Chem Phys Lipids. 2003;124(2):147–156. doi: 10.1016/s0009-3084(03)00051-3. PubMed DOI

Nazaruk E, Górecka E, Bilewicz R. Enzymes and mediators hosted together in lipidic mesophases for the construction of biodevices. J Colloid Interface Sci. 2012;385(1):130–136. doi: 10.1016/j.jcis.2012.06.087. PubMed DOI

Nazaruk E, Landau EM, Bilewicz R. Membrane bound enzyme hosted in liquid crystalline cubic phase for sensing and fuel cells. Electrochim Acta. 2014;140:96–100. doi: 10.1016/j.electacta.2014.05.130. DOI

Sun W, Vallooran JJ, Fong W-K, Mezzenga R. Lyotropic liquid crystalline cubic phases as versatile host matrices for membrane-bound enzymes. J Phys Chem Lett. 2016;7(8):1507–1512. doi: 10.1021/acs.jpclett.6b00416. PubMed DOI

Zatloukalová M, Nazaruk E, Novak D, Vacek J, Bilewicz R. Lipidic liquid crystalline cubic phases for preparation of ATP-hydrolysing enzyme electrodes. Biosens Bioelectron. 2018;100:437–444. doi: 10.1016/j.bios.2017.09.036. PubMed DOI

Speziale C, Salvati Manni L, Manatschal C, Landau EM, Mezzenga R. A macroscopic H+ and Cl− ions pump via reconstitution of EcClC membrane proteins in lipidic cubic mesophases. Proc Natl Acad Sci USA. 2016;113(27):7491–7496. doi: 10.1073/pnas.1603965113. PubMed DOI PMC

Miszta P, Nazaruk E, Nieciecka D, Możajew M, Krysiński P, Bilewicz R, et al. The EcCLC antiporter embedded in lipidic liquid crystalline films–molecular dynamics simulations and electrochemical methods. Phys Chem Chem Phys. 2022;24(5):3066–3077. doi: 10.1039/D1CP03992J. PubMed DOI

Speziale C, Zabara AF, Drummond CJ, Mezzenga R. Active gating, molecular pumping, and turnover determination in biomimetic lipidic cubic mesophases with reconstituted membrane proteins. ACS Nano. 2017;11(11):11687–11693. doi: 10.1021/acsnano.7b06838. PubMed DOI

Angelova A, Ollivon M, Campitelli A, Bourgaux C. Lipid cubic phases as stable nanochannel network structures for protein biochip development: X-ray diffraction study. Langmuir. 2003;19(17):6928–6935. doi: 10.1021/la0345284. DOI

Razumas V, Kanapienien JJ, Nylander T, Engström S, Larsson K. Electrochemical biosensors for glucose, lactate, urea, and creatinine based on enzymes entrapped in a cubic liquid crystalline phase. Anal Chim Acta. 1994;289:155–162. doi: 10.1016/0003-2670(94)80098-7. DOI

Nylander T, Mattisson C, Razumas V, Miezis Y, Håkansson B. A study of entrapped enzyme stability and substrate diffusion in a monoglyceride-based cubic liquid crystalline phase. Colloids Surf. 1996;114:311–320. doi: 10.1016/0927-7757(96)03563-7. DOI

Gao F, Yao Z, Huang Q, Chen X, Guo X, Ye Q, et al. A hydrogen peroxide biosensor based on the direct electron transfer of hemoglobin encapsulated in liquid-crystalline cubic phase on electrode. Colloids Surf. 2011;82(2):359–364. doi: 10.1016/j.colsurfb.2010.09.009. PubMed DOI

Nazaruk E, Bilewicz R. Catalytic activity of oxidases hosted in lipidic cubic phases on electrodes. Bioelectrochemistry. 2007;71:8–14. doi: 10.1016/j.bioelechem.2006.12.007. PubMed DOI

Aghbolagh MS, Khani Meynaq MY, Shimizu K, Lindholm-Sethson B. Aspects on mediated glucose oxidation at a supported cubic phase. Bioelectrochemistry. 2017;118:8–13. doi: 10.1016/j.bioelechem.2017.06.010. PubMed DOI

Wu G, Yao Z, Fei B, Gao F. An enzymatic ethanol biosensor and ethanol/air biofuel cell using liquid-crystalline cubic phases as hosting matrices to co-entrap enzymes and mediators. J Electrochem Soc. 2017;164(7):G82. doi: 10.1149/2.0791707jes. DOI

Liu Y, Qu X, Guo H, Chen H, Liu B, Dong S. Facile preparation of amperometric laccase biosensor with multifunction based on the matrix of carbon nanotubes–chitosan composite. Biosens Bioelectron. 2006;21(12):2195–2201. doi: 10.1016/j.bios.2005.11.014. PubMed DOI

Grippo V, Ma S, Ludwig R, Gorton L, Bilewicz R. Cellobiose dehydrogenase hosted in lipidic cubic phase to improve catalytic activity and stability. Bioelectrochemistry. 2019;125:134–141. doi: 10.1016/j.bioelechem.2017.10.003. PubMed DOI

Ropers M-H, Bilewicz R, Stébé M-J, Hamidi A, Miclo A, Rogalska E. Fluorinated and hydrogenated cubic phases as matrices for immobilisation of cholesterol oxidase on electrodes. Phys Chem Chem Phys. 2001;3(2):240–245. doi: 10.1039/B007718F. DOI

Rowinski P, Kang C, Shin H, Heller A. Mechanical and chemical protection of a wired enzyme oxygen cathode by a cubic phase lyotropic liquid crystal. Anal Chem. 2007;79(3):1173–1180. doi: 10.1021/ac061325m. PubMed DOI

Ericsson B, Larsson K, Fontell K. A cubic protein-monoolein-water phase. Biochim Biophys Acta. 1983;729(1):23–27. doi: 10.1016/0005-2736(83)90451-0. PubMed DOI

Razumas V, Talaikyté Z, Barauskas J, Miezis Y, Nylander T. An FT-IR study of the effects of distearoylphosphatidylglycerol and cytochrome c on the molecular organization of the monoolein-water cubic liquid-crystalline phase. Vib Spectrosc. 1997;15(1):91–101. doi: 10.1016/S0924-2031(97)00021-0. DOI

Razumas V, Larsson K, Miezis Y, Nylander T. A cubic monoolein− cytochrome c− water phase: X-ray diffraction, ft-ir, differential scanning calorimetric, and electrochemical studies. J Phys Chem A. 1996;100(28):11766–11774. doi: 10.1021/jp952613h. DOI

Kraineva J, Narayanan RA, Kondrashkina E, Thiyagarajan P, Winter R. Kinetics of lamellar-to-cubic and intercubic phase transitions of pure and cytochrome c containing monoolein dispersions monitored by time-resolved small-angle X-ray diffraction. Langmuir. 2005;21(8):3559–3571. doi: 10.1021/la046873e. PubMed DOI

Barauskas J, Razumas V, Talaikyt Z, Bulovas A, Nylander T, Taurait D, et al. Towards redox active liquid crystalline phases of lipids: a monoolein/water system with entrapped derivatives of ferrocene. Chem Phys Lipids. 2003;123(1):87–97. doi: 10.1016/S0009-3084(02)00170-6. PubMed DOI

Kostela J, Elmgren M, Kadi M, Almgren M. Redox activity and diffusion of hydrophilic, hydrophobic, and amphiphilic redox active molecules in a bicontinuous cubic phase. J Phys Chem B. 2005;109(11):5073–5078. doi: 10.1021/jp048088g. PubMed DOI

Kumar PS, Lakshminarayanan V. Electron-transfer studies in a lyotropic columnar hexagonal liquid crystalline medium. Langmuir. 2007;23(3):1548–1554. doi: 10.1021/la0625244. PubMed DOI

Nazaruk E, Miszta P, Filipek S, Gorecka E, Landau EM, Bilewicz R. Lyotropic cubic phases for drug delivery: diffusion and sustained release from the mesophase evaluated by electrochemical methods. Langmuir. 2015;31(46):12753–12761. doi: 10.1021/acs.langmuir.5b03247. PubMed DOI

Antognini LM, Assenza S, Speziale C, Mezzenga R. Quantifying the transport properties of lipid mesophases by theoretical modelling of diffusion experiments. J Chem Phys. 2016;145(8):084903. doi: 10.1063/1.4961224. PubMed DOI

Esposito E, Ravani L, Mariani P, Contado C, Drechsler M, Puglia C, et al. Curcumin containing monoolein aqueous dispersions: a preformulative study. Mater Sci Eng C. 2013;33(8):4923–4934. doi: 10.1016/j.msec.2013.08.017. PubMed DOI

Linkevičiūtė A, Misiūnas A, Naujalis E, Barauskas J. Preparation and characterization of quercetin-loaded lipid liquid crystalline systems. Colloids Surf B. 2015;128:296–303. doi: 10.1016/j.colsurfb.2015.02.001. PubMed DOI

Yaghmur A, Mu H. Recent advances in drug delivery applications of cubosomes, hexosomes, and solid lipid nanoparticles. Acta Pharm Sin B. 2021;11:871–885. doi: 10.1016/j.apsb.2021.02.013. PubMed DOI PMC

Larsson K. Cubic lipid-water phases: structures and biomembrane aspects. J Phys Chem. 1989;93(21):7304–7314. doi: 10.1021/j100358a010. DOI

Karami Z, Hamidi M. Cubosomes: remarkable drug delivery potential. Drug Discov Today. 2016;21(5):789–801. doi: 10.1016/j.drudis.2016.01.004. PubMed DOI

Spicer PT, Hayden KL, Lynch ML, Ofori-Boateng A, Burns JL. Novel process for producing cubic liquid crystalline nanoparticles (cubosomes) Langmuir. 2001;17(19):5748–5756. doi: 10.1021/la010161w. DOI

Mezzenga R, Meyer C, Servais C, Romoscanu AI, Sagalowicz L, Hayward RC. Shear rheology of lyotropic liquid crystals: a case study. Langmuir. 2005;21(8):3322–3333. doi: 10.1021/la046964b. PubMed DOI

Hirlekar R, Jain S, Patel M, Garse H, Kadam V. Hexosomes: a novel drug delivery system. Curr Drug Deliv. 2010;7(1):28–35. doi: 10.2174/156720110790396526. PubMed DOI

Angelova A, Garamus VM, Angelov B, Tian Z, Li Y, Zou A. Advances in structural design of lipid-based nanoparticle carriers for delivery of macromolecular drugs, phytochemicals and anti-tumor agents. Adv Colloid Interface Sci. 2017;249:331–345. doi: 10.1016/j.cis.2017.04.006. PubMed DOI

Murgia S, Biffi S, Mezzenga R. Recent advances of non-lamellar lyotropic liquid crystalline nanoparticles in nanomedicine. Curr Opin Colloid Interface Sci. 2020;48:28–39. doi: 10.1016/j.cocis.2020.03.006. DOI

Tenchov R, Bird R, Curtze AE, Zhou Q. Lipid Nanoparticles─ From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement. ACS Nano. 2021;15(11):16982–17015. doi: 10.1021/acsnano.1c04996. PubMed DOI

Tilley AJ, Drummond CJ, Boyd BJ. Disposition and association of the steric stabilizer Pluronic® F127 in lyotropic liquid crystalline nanostructured particle dispersions. J Colloid Interface Sci. 2013;392:288–296. doi: 10.1016/j.jcis.2012.09.051. PubMed DOI

Murgia S, Falchi AM, Mano M, Lampis S, Angius R, Carnerup AM, et al. Nanoparticles from lipid-based liquid crystals: emulsifier influence on morphology and cytotoxicity. J Phys Chem B. 2010;114(10):3518–3525. doi: 10.1021/jp9098655. PubMed DOI

Chong JY, Mulet X, Waddington LJ, Boyd BJ, Drummond CJ. Steric stabilisation of self-assembled cubic lyotropic liquid crystalline nanoparticles: high throughput evaluation of triblock polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers. Soft Matter. 2011;7(10):4768–4777. doi: 10.1039/C1SM05181D. DOI

Yaghmur A, Glatter O. Characterization and potential applications of nanostructured aqueous dispersions. Adv Colloid Interface Sci. 2009;147:333–342. doi: 10.1016/j.cis.2008.07.007. PubMed DOI

Zhai J, Waddington L, Wooster TJ, Aguilar M-I, Boyd BJ. Revisiting β-Casein as a stabilizer for lipid liquid crystalline nanostructured particles. Langmuir. 2011;27(24):14757–14766. doi: 10.1021/la203061f. PubMed DOI

Nilsson C, Østergaard J, Larsen SW, Larsen C, Urtti A, Yaghmur A. PEGylation of phytantriol-based lyotropic liquid crystalline particles the effect of lipid composition, PEG chain length, and temperature on the internal nanostructure. Langmuir. 2014;30(22):6398–6407. doi: 10.1021/la501411w. PubMed DOI

Angelova A, Angelov B, Garamus VM, Couvreur P, Lesieur S. Small-angle X-ray scattering investigations of biomolecular confinement, loading, and release from liquid-crystalline nanochannel assemblies. J Phys Chem Lett. 2012;3(3):445–457. doi: 10.1021/jz2014727. PubMed DOI

Helvig S, Azmi ID, Moghimi SM, Yaghmur A. Recent advances in cryo-TEM imaging of soft lipid nanoparticles. AIMS Biophys. 2015;2(2):116–130. doi: 10.3934/biophy.2015.2.116. DOI

Neto C, Aloisi G, Baglioni P, Larsson K. Imaging soft matter with the atomic force microscope: cubosomes and hexosomes. J Phys Chem B. 1999;103(19):3896–3899. doi: 10.1021/jp984551b. DOI

Fraser SJ, Mulet X, Martin L, Praporski S, Mechler A, Hartley PG, et al. Surface immobilization of bio-functionalized cubosomes: sensing of proteins by quartz crystal microbalance. Langmuir. 2012;28(1):620–627. doi: 10.1021/la2032994. PubMed DOI

Barriga HM, Holme MN, Stevens MM. Cubosomes: the next generation of smart lipid nanoparticles? Angew Chem Int Ed. 2019;58(10):2958–2978. doi: 10.1002/anie.201804067. PubMed DOI PMC

Ryan S, Shortall K, Dully M, Djehedar A, Murray D, Butler J, et al. Long acting injectables for therapeutic proteins. Colloid Surf B-Biointerfaces. 2022;217:112644. doi: 10.1016/j.colsurfb.2022.112644. PubMed DOI

Nazaruk E, Szlęzak M, Górecka E, Bilewicz R, Osornio YM, Uebelhart P, et al. Design and assembly of pH-sensitive lipidic cubic phase matrices for drug release. Langmuir. 2014;30(5):1383–1390. doi: 10.1021/la403694e. PubMed DOI

Falchi AM, Rosa A, Atzeri A, Incani A, Lampis S, Meli V, et al. Effects of monoolein-based cubosome formulations on lipid droplets and mitochondria of HeLa cells. Toxicol Res. 2015;4(4):1025–1036. doi: 10.1039/C5TX00078E. DOI

Tudose A, Celia C, Belu I, Borisova S, Paolino D. Effect of three monoglyceride based cubosomes systems on the viability of human keratinocytes. Farmacia. 2014;62(4):777–790.

Caltagirone C, Arca M, Falchi AM, Lippolis V, Meli V, Monduzzi M, et al. Solvatochromic fluorescent BODIPY derivative as imaging agent in camptothecin loaded hexosomes for possible theranostic applications. RSC Adv. 2015;5(30):23443–23449. doi: 10.1039/C5RA01025J. DOI

Cytryniak A, Nazaruk E, Bilewicz R, Górzyńska E, Żelechowska-Matysiak K, Walczak R, et al. Lipidic cubic-phase nanoparticles (cubosomes) loaded with doxorubicin and labeled with 177Lu as a potential tool for combined chemo and internal radiotherapy for cancers. Nanomaterials. 2020;10(11):2272. doi: 10.3390/nano10112272. PubMed DOI PMC

Mat Azmi ID, Wu L, Wibroe PP, Nilsson C, Østergaard J, Sturup S, et al. Modulatory effect of human plasma on the internal nanostructure and size characteristics of liquid-crystalline nanocarriers. Langmuir. 2015;31(18):5042–5049. doi: 10.1021/acs.langmuir.5b00830. PubMed DOI

Nielsen LS, Schubert L, Hansen J. Bioadhesive drug delivery systems: I. characterisation of mucoadhesive properties of systems based on glyceryl mono-oleate and glyceryl monolinoleate. Eur J Pharm Sci. 1998;6(3):231–9. doi: 10.1016/s0928-0987(97)10004-5. PubMed DOI

Souza C, Watanabe E, Borgheti-Cardoso LN, Fantini MCDA, Lara MG. Mucoadhesive system formed by liquid crystals for buccal administration of poly (hexamethylene biguanide) hydrochloride. J Pharm Sci. 2014;103(12):3914–3923. doi: 10.1002/jps.24198. PubMed DOI

Dully M, Brasnett C, Djeghader A, Seddon A, Neilan J, Murray D, et al. Modulating the release of pharmaceuticals from lipid cubic phases using a lipase inhibitor. J Colloid Interface Sci. 2020;573:176–192. doi: 10.1016/j.jcis.2020.04.015. PubMed DOI

Zatloukalová M, Jedinák L, Riman D, Franková J, Novák D, Cytryniak A, et al. Cubosomal lipid formulation of nitroalkene fatty acids: preparation, stability and biological effects. Redox Biol. 2021;46:102097. doi: 10.1016/j.redox.2021.102097. PubMed DOI PMC

Akbar S, Anwar A, Ayish A, Elliott JM, Squires AM. Phytantriol based smart nano-carriers for drug delivery applications. Eur J Pharm Sci. 2017;101:31–42. doi: 10.1016/j.ejps.2017.01.035. PubMed DOI

Sobczak K, Rudnicki K, Jedinak L, Zatloukalova M, Vacek J, Poltorak L. Oleic and nitro-oleic acid behavior at an electrified water-1, 2-dichloroethane interface. J Mol Liq. 2022;365:120110. doi: 10.1016/j.molliq.2022.120110. DOI

Laborda E, Molina A, Espín VF, Martínez-Ortiz F, Garcia de la Torre J, Compton RG. Single fusion events at polarized liquid–liquid interfaces. Angew Chem Int Ed. 2017;129(3):800–803. doi: 10.1002/anie.201610185. PubMed DOI

Laborda E, Molina A. Impact experiments at the interface between two immiscible electrolyte solutions (ITIES) Curr Opin Electrochem. 2021;26:100664. doi: 10.1016/j.coelec.2020.100664. DOI

Trojánek A, Samec Z. Study of the emulsion droplet collisions with the polarizable water/1, 2-dichloroethane interface by the open circuit potential measurements. Electrochim Acta. 2019;299:875–885. doi: 10.1016/j.electacta.2019.01.041. DOI

Trojánek A, Mareček V, Samec Z. Open circuit potential transients associated with single emulsion droplet collisions at an interface between two immiscible electrolyte solutions. Electrochem Commun. 2018;86:113–116. doi: 10.1016/j.elecom.2017.11.026. DOI

Santos HA, García-Morales V, Pereira CM. Electrochemical properties of phospholipid monolayers at liquid–liquid interfaces. ChemPhysChem. 2010;11(1):28–41. doi: 10.1002/cphc.200900609. PubMed DOI