International Journal of Molecular Sciences Review Lipid Nanoparticle Technology for Delivering Biologically Active Fatty Acids and Monoglycerides Jia Ying Brenda Tan 1,2,†, Bo Kyeong Yoon 1,3,†, Nam-Joon Cho 2 , Jasmina Lovri´c 4, Mario Jug 4 and Joshua A. Jackman 1,* 1 School of Chemical Engineering and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Korea; [email protected] (J.Y.B.T.); [email protected] (B.K.Y.) 2 School of Materials Science and Engineering, Nanyang Technological University, Singapore 637553, Singapore; [email protected] 3 School of Healthcare and Biomedical Engineering, Chonnam National University, Yeosu 59626, Korea 4 Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; [email protected] (J.L.); [email protected] (M.J.) * Correspondence: [email protected]; Tel.: +82-31-290-7243 † These authors contributed equally to this work. Abstract: There is enormous interest in utilizing biologically active fatty acids and monoglycerides to treat phospholipid membrane-related medical diseases, especially with the global health importance of membrane-enveloped viruses and bacteria. However, it is difficult to practically deliver lipophilic fatty acids and monoglycerides for therapeutic applications, which has led to the emergence of lipid nanoparticle platforms that support molecular encapsulation and functional presentation. Herein, we introduce various classes of lipid nanoparticle technology and critically examine the latest progress in utilizing lipid nanoparticles to deliver fatty acids and monoglycerides in order to treat medical diseases related to infectious pathogens, cancer, and inflammation. Particular emphasis Citation: Tan, J.Y.B.; Yoon, B.K.; Cho, is placed on understanding how nanoparticle structure is related to biological function in terms N.-J.; Lovri´c,J.; Jug, M.; Jackman, J.A. of mechanism, potency, selectivity, and targeting. We also discuss translational opportunities and Lipid Nanoparticle Technology for regulatory needs for utilizing lipid nanoparticles to deliver fatty acids and monoglycerides, including Delivering Biologically Active Fatty unmet clinical opportunities. Acids and Monoglycerides. Int. J. Mol. Sci. 2021, 22, 9664. https://doi.org/ Keywords: fatty acid; monoglyceride; lipid nanoparticle; liposome; bicelle; solid lipid nanoparticle; 10.3390/ijms22189664 nanostructured lipid carrier; nanoemulsion; lipid nanocapsule; polymeric micelle Academic Editor: Elena Del Favero Received: 24 July 2021 Accepted: 5 September 2021 1. Introduction Published: 7 September 2021 Phospholipid membranes play integral roles in a number of medical diseases related to infectious pathogens [1,2], cancer [3,4], and inflammation [5,6] among various conditions. Publisher’s Note: MDPI stays neutral Global health challenges such as membrane-enveloped viruses with pandemic potential [7] with regard to jurisdictional claims in and the growing number of antibiotic-resistant bacteria [8] have heightened general in- published maps and institutional affil- terest in developing therapeutic strategies to modulate and/or disturb lipid membranes iations. surrounding cells and biological nanoparticles such as virus particles and exosomes [9,10]. Among various molecular drug options that interact with phospholipid membranes, natu- rally occurring fatty acids and monoglycerides have received extensive attention due to a wide range of molecule-specific biological activities, natural abundance, low cost, and Copyright: © 2021 by the authors. perceived safety for dietary consumption and medical use [11]. Licensee MDPI, Basel, Switzerland. Fatty acids and monoglycerides are single-chain lipid amphiphiles that possess a This article is an open access article hydrocarbon chain and a hydrophilic headgroup, and can intercalate into phospholipid distributed under the terms and membranes to trigger membrane disruptions such as solubilization, pore formation, or conditions of the Creative Commons shape remodeling depending on the context [12]. Such membrane-modulating activities Attribution (CC BY) license (https:// have proven useful for exploring fatty acids and monoglycerides, especially those with 6- creativecommons.org/licenses/by/ to 12-carbon long, saturated chains, as anti-infective agents to inhibit membrane-enveloped 4.0/). Int. J. Mol. Sci. 2021, 22, 9664. https://doi.org/10.3390/ijms22189664 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 26 Int. J. Mol. Sci. 2021, 22, 9664 2 of 27 to 12-carbon long, saturated chains, as anti-infective agents to inhibit membrane-envel- oped viruses and bacteriaviruses and[13,14], bacteria along [13 with,14], longer-chain, along with longer-chain, polyunsaturated polyunsaturated fatty acids fatty for acids for cardiovascular andcardiovascular immune health and [15]. immune An overview health [15]. of An the overview molecular of thestructures molecular of structuresbio- of logically active fattybiologically acids and active monoglycerides fatty acids and is monoglycerides presented in Figure is presented 1 and in there Figure are1 and var- there are ious classes dependingvarious on classes the headgroup depending on properties, the headgroup chain properties, length, chain and length, prevalence and prevalence and and number of double bonds in the chain. number of double bonds in the chain. Figure 1. Molecular structures of biologically active fatty acids and monoglycerides that have been utilized with lipid nanoparticleFigure technologies.1. Molecular structures of biologically active fatty acids and monoglycerides that have been utilized with lipid nanoparticle technologies. However, despite the useful biological activities of fatty acids and monoglycerides, However, despitecritical the hurdles useful to biological translational activities applications of fatty must acids be overcome. and monoglycerides, Indeed, fatty acids and critical hurdles to monoglyceridestranslational applications are rather poorly must soluble be overcome. and require Indeed, supramolecular fatty acids organization and to be biologically active in many cases. Hence, practically realizing therapeutic delivery of fatty monoglycerides areacids rather and poorly monoglycerides soluble callsand for require the development supramolecular of effective organization pharmacological to be strategies biologically active into encapsulatemany cases. fatty Hence, acids practically and monoglycerides realizing intherapeutic configurations delivery that not of onlyfatty support acids and monoglycerideshigh loading calls capacity for the butdevelopment also permit of retention, effective or pharmacological even enhancement, strate- of membrane- gies to encapsulatemodulating fatty acids biological and monoglycerides activities. These in design configurations requirements that have not led only to the support development of high loading capacitynumerous, but also increasingly permit retent sophisticatedion, or even nano-carriers enhancement, to encapsulate of membrane-mod- and deliver fatty acids and monoglycerides [16,17], a topic of nanomedicine that is experiencing a renaissance ulating biological activities. These design requirements have led to the development of in general due to the widespread implementation of lipid nanoparticle technology for numerous, increasinglyvaccine sophisticated delivery applications nano-carriers [18] and to the encapsulate broader translational and deliver possibilities fatty acids that such and monoglyceridesdevelopments [16,17], a topic inspire. of nanomedicine that is experiencing a renaissance in general due to the widespreadHerein, we implementation cover the latest progress of lipid in nanoparticle developing lipid technology nanoparticle for technology vac- to cine delivery applicationsdeliver biologically [18] and the active broader fatty acids translational and monoglycerides possibilities across that applications such devel- spanning opments inspire. infectious diseases, cancer, and inflammation as well as for small-molecule drug delivery enhancement. We first introduce the basic design principles of various lipid nanoparticle Herein, we cover the latest progress in developing lipid nanoparticle technology to technologies and related nano-carriers involving other lipid-like building blocks, all of deliver biologicallywhich active have fatty been acids used and to encapsulate monoglycerides fatty acids across and monoglycerides, applications spanning and then provide infectious diseases,application cancer, and examples. inflammation Lastly, we as criticallywell as for discuss small-molecule some of the biggest drug needsdelivery and unmet enhancement. We firstopportunities introduce in the field,basic including design principles areas where of we various see high lipid translational nanoparticle potential and technologies and relatedpossible nano-carriers steps to reach these involv goals.ing other lipid-like building blocks, all of which have been used to encapsulate fatty acids and monoglycerides, and then provide application examples. Lastly, we critically discuss some of the biggest needs and unmet opportunities in the field, including areas where we see high translational potential and possible steps to reach these goals. 2. Why Nano? While fatty acids and monoglycerides can have important biological activities, it is challenging to utilize these molecules as therapeutic drugs because they are mainly active Int. J. Mol. Sci. 2021, 22,