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Pluronic F127-stabilized non-lamellar liquid crystalline aqueous nanodispersions are promising injectable platforms for drug and contrast agent delivery. These nanodispersions, however, trigger complement activation in the human blood, where the extent of complement activation and opsonization processes may compromise their biological performance and safety. Here, we introduce a broad family of nanodispersions from glycerol monooleate (GMO) and oleic acid (OA) in different weight ratios, and stabilized with a plethora of nonionic methoxypoly(ethylene glycol) (mPEG)-lipids of different PEG chain length and variable lipid moiety (monounsaturated or saturated diglycerides or D-α-tocopheryl succinate). Through an integrated biophysical approach involving dynamic light scattering, synchrotron small-angle scattering, and cryo-transmission electron microscopy, we examine the impact of nonionic mPEG-lipid stabilization on size, internal self-assembled architecture, and gross morphological characteristics of nanodispersions. The results show how the nonionic mPEG-lipid type and concentration, and dependent on GMO/OA weight ratio, can variably modulate the internal architectures of nanoparticles. Assessment of complement profiling from selected nanodispersions with diverse structural heterogeneity further suggests a variable modulatory role for the lipid type of the nonionic mPEG-lipid in the extent of complement activation, which span from no activation to moderate to high levels. We comment on plausible mechanisms driving the observed complement activation variability and discuss the potential utility of these nanodispersions for future development of injectable nanopharmaceuticals.

Microfluidic platforms have become highly attractive tools for synthesis of nanoparticles, including lipid nano-self-assemblies, owing to unique features and at least three important aspects inherent to miniaturized micro-devices. Firstly, the fluids flow under controlled conditions in the microchannels, providing well-defined flow profiles and shorter diffusion lengths that play important roles in enhancing the continuous production of lipid and polymer nanoparticles with relatively narrow size distributions. Secondly, various geometries adapted to microfluidic device designs can be utilized for enhancing the colloidal stability of nanoparticles and improving their drug loading. Thirdly, microfluidic devices are usually compatible with in situ characterization methods for real-time monitoring of processes occurring inside the microchannels. This is unlike conventional nanoparticle synthesis methods, where a final solution or withdrawn aliquots are separately analysed. These features inherent to microfluidic devices provide a tool-set allowing not only precise nanoparticle size control, but also real-time analyses for process optimization. In this review, we focus on recent advances and developments in the use of microfluidic devices for synthesis of lipid nanoparticles. We present different designs based on hydrodynamic flow focusing, droplet-based methods and controlled microvortices, and discuss integration of microfluidic platforms with synchrotron small-angle X ray scattering (SAXS) for in situ structural characterization of lipid nano-self-assemblies under continuous flow conditions, along with major challenges and future directions in this research area., INP grant from the Danish Agency for Science and Higher Education [8073-00022B], AY and OYC acknowledge the INP grant (Ref. no.: 8073-00022B) from the Danish Agency for Science and Higher Education for initiating and exploring new networking and collaboration opportunities between Danish and Turkish research institutions.

The attractiveness of new omega-3 (ω-3) polyunsaturated fatty acid (PUFA) monoglycerides (MAGs) lies in the amphiphilic nature and the beneficial health effects as PUFA precursors in various disorders including cancer, pulmonary hypertension, and inflammatory diseases. For exploring the potential therapeutic applications of these new amphiphilic lipids, particularly as main lipid constituents in the development of nanocarriers for delivery of drugs and PUFAs, it is of paramount importance to gain insight into their self-assembly behavior on exposure to excess water. This work describes the structural characteristics of self-assemblies based on two newly synthesized MAGs, namely docosahexaenoic acid (MAG-DHA) and docosapentaenoic acid (MAG-DPA) monoglycerides, on exposure to excess water. We found that both lipids tend to form a dominant inverse hexagonal (H2) phase in excess water at 25 °C and a temperature-triggered structural transition to an inverse micellar solution (L2 phase) is detected similar to that recently reported (A. Yaghmur et al., Langmuir, 2017, 33, 14045-14057) for eicosapentaenoic acid monoglyceride (MAG-EPA). An experimental SAXS structural evaluation study on the temperature-dependent behavior of these new monoglycerides is provided, and the effects of unsaturation degree and fatty acyl chain length on the self-assembled structural features in excess water and on the H2-L2 phase transition temperature are discussed. In addition, hexosomes stabilized by using the triblock copolymer F127 and the food-grade emulsifier citrem were investigated to gain insights into the effects of stabilizer and temperature on the internal nanostructure. These nanoparticles are attractive for use in the development of nanocarriers for delivering drugs and/or nutritional compounds as the beneficial health effects of ω-3 PUFA monoglycerides can be combined with those of loaded therapeutic agents or nutraceuticals.