This journal is © The Royal Society of Chemistry 2022 J. Mater. Chem. B Cite this: DOI: 10.1039/d2tb00031h Cubosomes as an emerging platform for drug delivery: a review of the state of the art Mohammed A.S. Abourehab,* ab Mohammad Javed Ansari, c Anshul Singh, d Ahmed Hassan, e Mohamed A. Abdelgawad, f Prachi Shrivastav, gh Bassam M. Abualsoud, i Larissa Souza Amaral jk and Sheersha Pramanik * l Lipid-based drug-delivery nanoparticles, including non-lamellar-type, mesophasic nanostructured materials of lyotropic liquid crystals (LLCs), have been a topic of interest for researchers for their applications in the encapsulation of biopharmaceutical drugs as well as their controlled and targeted release. Cubosomes, derived from LLCs, are self-assembled cubic-phase bicontinuous crystalline nanoparticulate colloidal dispersions. Their lipid bilayers are arranged in 3D space such that they have an uninterrupted, regular cubic symmetrical surface, separated by two interconnected aqueous channels. Thus, they have a large surface area involving numerous internal segments, giving them a definitive advantage over lamellar liposomes in facilitating the efficient entrapment and sustained release of active therapeutic substances. This Review focuses on the unique properties of cubosomes, such as their ability to encapsulate hydrophobic, hydrophilic, and amphiphilic bioactive substances, which make them attractive for the encapsulation and release of therapeutic molecules, including large biomolecules. Controlled drug release via functionalization has demonstrated cubosomes as a potential vehicle for various administration routes. Their self-assembling properties make their production uncomplicated, with two major manufacturing methods: the top-down and bottom-up methods. Cubosomes are formed when amphiphilic lipids, such as monoolein, monolinolein, phytantriol, etc., self-assemble into non-lamellar bicontinuous cubic phases in excess water. In this Review, we have endeavored to outline the composition, preparation techniques, drug-encapsulation approaches, and drug-loading and -release mechanisms of cubosomes. Furthermore, the prospective routes for cubosomes, their challenges, and future potentialities are addressed. 1. Introduction A typical drug-delivery system (DDS) may be described as a device that releases a pharmacological substance at a specified site in the body at a programmed rate to establish an effective concentration at the drug’s site of action. Sustained release over an extended period may lessen the need for multiple dosages, resulting in lower costs and better patient compliance. 1–5 DDSs are intended to enhance the pharmacokinetic parameters and biological dis- tribution of the agents to which they are attached, to act as reservoirs for the drug substances (i.e., sustained-release systems), or to do both. 6 To this end, the DDSs, involving the use of nanoparticle-based carriers, could improve many of the pharma- cological features of traditional drugs because they offer protec- tion for the actives against premature degradation while also enhancing filtration in the intracellular system. Nanocarriers produced using biologically compatible materials show differen- tial uptake into the targeted cells/tissues, rendering them useful for various drug targeting strategies. 7,8 Over the past few years we have seen an exponential growth in research for the development of new medicine-delivery a Department of Pharmaceutics, College of Pharmacy, Umm Al Qura University, Makkah 21955, Saudi Arabia. E-mail: maabourehab@uqu.edu.sa b Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia 11566, Egypt c Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia d Department of Chemistry, Baba Mastnath University, Rohtak-124021, India e Department of Clinical Pharmacy, Faculty of Pharmacy, University of Sadat City (USC), Sadat City, Menoufia, 32897, Egypt f Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf 72341, Saudi Arabia g Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Mohali, Punjab 160 062, India h Bombay College of Pharmacy, Kolivery Village, Mathuradas Colony, Kalina, Vakola, Santacruz East, Mumbai, Maharashtra 400 098, India i Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Al-Ahliyya Amman University, Amman, 19328, Jordan j Department of Bioengineering, University of Sa ˜o Paulo (USP), Av. Trabalhador Sa ˜o Carlense, 400, 13566590, Sa ˜o Carlos (SP), Brazil k Minas Gerais State University (UEMG), Av. Esco´cia, 1000, 38202436 Frutal (MG), Brazil l Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai-600036, Tamil Nadu, India. E-mail: sheershopramanik24@gmail.com, bt19d601@smail.iitm.ac.in Received 6th January 2022, Accepted 2nd March 2022 DOI: 10.1039/d2tb00031h rsc.li/materials-b Journal of Materials Chemistry B REVIEW Published on 02 March 2022. Downloaded on 3/22/2022 3:12:09 PM. View Article Online View Journal