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Drug delivery with nanocarriers relies on the interaction of individual nanocarriers with the cell surface. For lipid-based NCs, this interaction uniquely involves a process of membrane fusion between the lipid bilayer that makes up the NC and the cell membrane. Cubosomes have emerged as promising fusogenic NCs, however their individual interactions had not yet been directly observed due to difficulties in achieving adequate resolution or disentangling multiple interactions with common characterization techniques. Moreover, many studies on these interactions have been performed under static conditions which may not mimic the actual transport of NCs. Herein we have observed fusion of lipid cubosome NCs with lipid bilayers under flow. Total internal reflection microscopy has allowed visualisation of the fusion event which was sensitive to the lipid compositions and rationalized by lipid diffusion. The fusion event in supported lipid bilayers has been compared with those in cells, revealing a distinct similarity in kinetics. Understanding the fusion of nanocarriers with cell membranes is important to the design of effective drug delivery methods. Here, the authors report on a study into the fusion of cubosomes with model cell membranes underflow conditions and report on the binding kinetics.

Non-lamellar lyotropic liquid crystalline (LLC) lipid nanoparticles contain internal multidimensional nanostructures such as the inverse bicontinuous cubic and the inverse hexagonal mesophases, which can respond to external stimuli and have the potential of controlling drug release. To date, the internal LLC mesophase responsiveness of these lipid nanoparticles is largely achieved by adding ionizable small molecules to the parent lipid such as monoolein (MO), the mixture of which is then dispersed into nanoparticle suspensions by commercially available poly(ethylene oxide)–poly(propylene oxide) block copolymers. In this study, the Reversible Addition-Fragmentation chain Transfer (RAFT) technique was used to synthesize a series of novel amphiphilic block copolymers (ABCs) containing a hydrophilic poly(ethylene glycol) (PEG) block, a hydrophobic block and one or two responsive blocks, i.e., poly(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) and/or poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA). High throughput small angle X-ray scattering studies demonstrated that the synthesized ABCs could simultaneously stabilize a range of LLC MO nanoparticles (vesicles, cubosomes, hexosomes, inverse micelles) and provide internal particle nanostructure responsiveness to changes of hydrogen peroxide (H2O2) concentrations, pH and temperature. It was found that the novel functional ABCs can substitute for the commercial polymer stabilizer and the ionizable additive in the formation of next generation non-lamellar lipid nanoparticles. These novel formulations have the potential to control drug release in the tumor microenvironment with endogenous H2O2 and acidic pH conditions.

Deep eutectic solvents are an exciting class of designer solvents that are increasingly gaining popularity. Deep eutectic solvents based on amino acids are particularly interesting for biomedical applications due to their potential low toxicity. However, very few have been reported to date, and only one of these has been comprehensively studied, made from a combination of proline and glycerol. Here, we report for the first time a systematic investigation into amino acid-based deep eutectic solvents, with a particular focus on the structural features of amino acids that promote eutectic formation and their influence on viscosity, refractive index, surface tension and thermal behavior. Of the 22 amino acids (and related compounds) examined, only 3 (lysine, arginine and, as previously reported, proline) formed stable homogenous liquids in combination with glycerol or ethylene glycol. For these mixtures, it was found that the second component (glycerol or ethylene glycol) had a much more significant influence on the physical properties than the identity of the amino acid. Most significantly, it was found that far fewer amino acids readily formed deep eutectic solvents than has been generally assumed. This is the first work to systematically characterize deep eutectic solvents based on amino acids and, as such, paves the way for future biomedical applications of these solvents.

pH-responsive nanoparticles enable the selective delivery of a chemotherapeutic agent to tumours while reducing adverse effects. Herein we synthesised four novel aminolipids and developed pH-responsive nanostructured lipid nanoparticles (LNP), which exhibited a slow-releasing hexagonal structure (H2) at physiological pH and quick release bicontinuous cubic phase (Q2) at the acidic tumour pH. The nanoparticles were used to encapsulate and control the release of the chemotherapeutic agent SN-38. High-throughput formulation techniques were employed to fabricate LNP by mixing various amounts of aminolipid with monoolein (MO). The effect of aminolipids on MO self-assembled structures was studied using small-angle X-ray scattering (SAXS) at various pH values. Out of the four studied aminolipid-MO LNP systems, the nanoparticles containing N-(Pyridin-4-ylmethyl) oleamide (OAPy-4) or N-(2(piperidin-1yl)ethyl) oleamide (OAPi-1) exhibited a pH-induced H2 to Q2 phase transition in a tumour-relevant pH range (pH 5.5–7.0). SN-38 is 1000 times more efficacious than the commercially available prodrug irinotecan. However, low solubility in water and instability at physiological pH makes it unsuitable for clinical use. SN-38 was loaded into LNP containing MO and aminolipid OAPy-4. The drug loading and entrapment efficiency were determined, and the results indicated that the aqueous solubility of SN-38 loaded in LNP dispersions was ~100 times higher compared to the solubility of the pure drug in aqueous solution. Furthermore, we demonstrated that the in vitro SN-38 release rate from LNPs was faster at lower pH (pH 5) than at neutral pH. Therefore, pH-responsive LNPs developed in this study can potentially be employed in delivering and controlling the release of the potent drug SN-38 to tumour sites.

Solvents that stabilize protein structures can improve and expand their biochemical applications, particularly with the growing interest in biocatalytic-based processes. Aiming to select novel solvents for protein stabilization, we explored the effect of alkylammonium nitrate protic ionic liquids (PILs)-water mixtures with increasing cation alkyl chain length on lysozyme conformational stability. Four PILs were studied, that is, ethylammonium nitrate (EAN), butylammonium nitrate (BAN), hexylammonium nitrate (HAN), and octylammonium nitrate (OAN). The surface tension, viscosity, and density of PIL-water mixtures at low to high concentrations were firstly determined, which showed that an increasing cation alkyl chain length caused a decrease in the surface tension and density as well as an increase in viscosity for all PIL solutions. Small-angle X-ray scattering (SAXS) was used to investigate the liquid nanostructure of the PIL solutions, as well as the overall size, conformational flexibility and changes to lysozyme structure. The concentrated PILs with longer alkyl chain lengths, i.e., over 10 mol% butyl-, 5 mol% hexyl- and 1 mol% octylammonium cations, possessed liquid nanostructures. This detrimentally interfered with solvent subtraction, and the more structured PIL solutions prevented quantitative SAXS analysis of lysozyme structure. The radius of gyration (Rg) of lysozyme in the less structured aqueous PIL solutions showed little change with up to 10 mol% of PIL. Kratky plots, SREFLEX models, and FTIR data showed that the protein conformation was maintained at a low PIL concentration of 1 mol% and lower when compared with the buffer solution. However, 50 mol% EAN and 5 mol% HAN significantly increased the Rg of lysozyme, indicating unfolding and aggregation of lysozyme. The hydrophobic interaction and liquid nanostructure resulting from the increased cation alkyl chain length in HAN likely becomes critical. The impact of HAN and OAN, particularly at high concentrations, on lysozyme structure was further revealed by FTIR. This work highlights the negative effect of a long alkyl chain length and high concentration of PILs on lysozyme structural stability.

Nanoparticle (NP)–hydrogel hybrid materials have emerged as promising platforms for controlled drug delivery, combining the tunable chemistry of NPs (e.g., liposomes, polymeric, and inorganic NPs) with the porous, biocompatible networks of hydrogels (e.g., alginate or poly(ethylene glycol)‐based systems). These composites can encapsulate a wide range of bioactive agents—small molecules, peptides, proteins, and nucleic acids—within hydrogel matrices, guided by molecular interactions such as electrostatic forces, hydrogen bonding, and hydrophobic/hydrophilic balance. Such interactions influence both the physicochemical stability and drug release profiles of the system. This review highlights recent advances in NP–hydrogel composites, emphasizing how molecular‐level interactions shape the nanostructure, drug encapsulation, and release behavior. The enhanced mechanical strength, stimuli responsiveness, pharmacokinetics, and biological performance of these materials are also discussed. Particular focus is placed on how improved mechanistic understanding can guide the design of next‐generation hybrid systems with tunable, predictable release for biomedical applications. This review provides a comprehensive overview of NP–hydrogel hybrid materials as versatile drug delivery systems and outlines future research directions for their use in personalized therapy, targeted treatment, and broader clinical translation. This review highlights recent advances in nanoparticle–hydrogel hybrid materials for controlled drug delivery. It explores diverse nanocarrier–hydrogel combinations, drug loading strategies, release mechanisms, and stimuli‐responsive behaviors. Emphasis is placed on the molecular interactions driving hybrid material performance, offering insights into rational design for applications in cancer therapy, wound healing, antimicrobial delivery, and gene‐based therapeutics

Cationic lipids are crucial in medical and biotechnological applications including cellular transfection and gene delivery. Ionizable cationic lipids are critical components of the mRNA‐based COVID vaccines while permanently charged cationic lipids have shown promise in cancer treatment. Despite significant research progress over the past few decades in designing improved, biocompatible cationic lipids, their transfection efficiency remains lower than that of viral vectors. Cationic lipids with additional functionalities like fusogenicity, stimuli‐responsiveness, targeting capabilities, and therapeutic activity have been engineered to improve their performance. This review highlights the importance of molecular hybridization toward the design of biocompatible cationic lipids having fusogenic, stimuli‐responsive, targeting, or therapeutic properties. This review mainly focuses on cationic lipids, having a permanent positive charge in the headgroup region, as these are typically employed to both increase cellular interactions and for improved loading, particularly for anionic nucleic acid‐based therapeutics and vaccines. Structure–activity relationships between the lipid chemical structure (headgroup, spacer, hydrocarbon chain) and, to a lesser extent, the self‐assembled nanostructure and the intrinsic biological activity of the multi‐functional cationic lipids are described. Finally, the challenges involved in developing smart lipids without affecting their inherent capacity to self‐assemble into structured nano‐carriers are discussed. In this review, the development of smart cationic lipids, typically formed via molecular hybridization of a lipid with a known bioactive moiety, is summarized. These multifunctional lipids may be considered as functional excipients, which may enhance the biological activity of certain drugs, and/or possess additional functionality such as fusogenic, targeting, or stimuli‐responsive properties.

Gold(I)‐thiolate complexes have served as primary building blocks for diverse Au nanostructure synthesis strategies. A delicate approach to characterize and control Au(I)‐thiolate motif formation and assembly on the surface is needed as it can potentially solve challenges associated with utilizing gold nanomaterials in many applications. Here, the controllable generation of flower‐shaped surface gold nanostructures (FSGNs) is demonstrated by manipulating the formation‐assembly process of Au(I)‐dodecanethiolate motifs within nanoscale surface droplets. The morphology and structure of the resulting Au nanostructures are governed by internal convection flows and interfacial energy, modulated by the nanodroplet composition and substrate wettability. The obtained FSGNs are proven to act as versatile scaffolds for the selective generation of Au spiky nanostars. These FSGNs can also be utilized to functionalize nanodroplet‐based reactors, boosting the fluorescent intensity of Nile red (NR) fluorophores and decomposing NR via catalytic reaction. Remarkably, with FSGN functionalized droplets smaller than a radius of 500 nm, the decomposition rate of NR can reach ≈0.01 s−1. These results highlight a miniaturized, controllable, and automated method for the in situ production of 3D gold nanostructures on substrates, offering prospects for fast surface nanostructure fabrication and efficient environmental pollutant treatment. Surface‐bound flower‐shaped gold nanostructures (FSGNs) are generated through confined formation and assembly of Au(I)‐dodecanethiolate in surface nanodroplets. The shapes and structures of these nanostructures are modulated by droplet composition and substrate characteristics. The resulting FSGNs efficiently serve as adaptable scaffolds for growing anisotropic Au spiky nanostars and as nanoreactors for amplified fluorescence and accelerated catalytic reactions.

Antimicrobial resistance (AMR) poses a global health crisis demanding innovative solutions. Traditional antibiotics, though pivotal over the past century in combating bacterial infections, face diminished efficacy against evolving bacterial defense mechanisms, especially in Gram‐negative strains. This study explores self‐assembled ionizable lipid nanoparticles (LNPs) with the incorporation of two ionizable lipid components (one cationic, one anionic) in nanocarriers for advanced antimicrobial drug delivery of the broad‐spectrum antibiotic Piperacillin (Pip). Incorporating cationic ionizable lipid ALC‐0315, recognized as a functional lipid in the Pfizer‐BioNTech mRNA‐based SARS‐CoV‐2 vaccine, into LNPs allowed mesophase transition, pH responsiveness, and ionization behavior in acidic environments found in sites of bacterial infections, to be studied using synchrotron small angle X‐ray scattering, dynamic light scattering, and a 2‐(p‐toluidino)‐6‐naphthalene sulfonic acid assay. Incorporating another anionic ionizable lipid, oleic acid not only modulates the LNPs’ physicochemical properties, such as size, internal phase nanostructure, and surface charge but also synergistically enhances the antimicrobial potency together with ALC‐0315 with a benefit enhancing permeability and fusion with bacterial membranes. This study introduces a strategy for tailoring ionizable lipid compositions in LNPs, providing a new approach to antimicrobial treatment contributing to the fight against AMR. Lipid cubosomes comprising monoolein, ionizable cationic lipid ALC‐0315, and ionizable anionic oleic acid are developed as an antimicrobial drug delivery system. The synergistic effect of the internal inverse cubic structure and the ionic lipid molecular interactions significantly enhances the membrane permeability of piperacillin‐loaded particles, leading to increased Gram‐negative bacteria growth inhibition.

Oleogels based on three different oils (sunflower oil, solid coconut oil and liquid coconut oil) were formulated using β-sitosterol. In general, an observed increase in crystallinity was correlated with an increase in the gel storage modulus and hardness. Addition of lecithin promoted the formation of needle-like crystals of β-sitosterol with a corresponding increase in strain tolerance and oil-trapping capacity for oleogels produced with liquid oils. However, the incorporation of β-sitosterol crystals with or without lecithin into oleogels containing solid coconut oil reduced its strain tolerance by interrupting the formation of continual radiolitic crystal structures. The use of sunflower oil (long chain fatty acids) was more favourable to the packing and growth of gelator crystals and the formation of an elastic gel, in comparison to liquid coconut oil (short chain fatty acids). Overall, the type and physical state of oil influence the formation of oil crystal network, thus affecting its gel properties. These findings allow the better understanding of β-sitosterol-based oleogels, providing opportunity to design for the application as a fat-replacer and lowering solid fat content.