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Abstract: Lipid nanoparticles (LNPs) are central to nanomedicine, yet their clinical translation is limited by the difficulty of predicting structure-bioactivity relationships. Although the biomolecular corona is known to define the nanoparticle biological identity by modifying surface properties, its effect on internal nanoparticle organization remains largely unexplored. Since the internal lipid organization of LNPs governs key properties, including stability, cargo protection, internalization and intracellular trafficking, understanding this coupling is critical to correlate synthetic design to therapeutic outcome. Here, combining structural and mechanistic evidence, we show that plasma lipoproteins engage in molecular-scale lipid exchange with the LCNP membrane, rather than persisting as an adsorbed layer of intact particles, actively remodeling the internal nanoparticle structure. Using model lipid liquid-crystalline nanoparticles with well-defined cubic and inverse hexagonal phases, we systematically investigate how lipoproteins modulate LNP structure. Combining fluorescence nanoparticle tracking, synchrotron small-angle X-ray scattering, cryo-electron microscopy, and neutron reflectometry with isotopic contrast matching, we provide evidence of lipoprotein-driven lipid transfer and phase reorganization at the nanoscale. We observe a phase-selective response: inverse hexagonal LNPs remain structurally stable despite lipid exchange, whereas cubic LNPs undergo pronounced remodeling, including significant change in size and lattice ordering. These transformations correlate with distinct cellular uptake profiles. Our findings suggest that in soft lipid nanoparticles, the biological identity commonly described as a biomolecular corona is not merely a surface event but an interface-mediated process that reshapes the nanoparticle internal structure, with direct implications for next-generation nanomedicine design.

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Abstract: Colloidal quantum dots (QDs) represent a versatile class of luminescent nanomaterials whose physicochemical and interfacial properties can be engineered for advanced bio-related applications. Herein, the wet-precipitation synthesis and surface engineering of ultra-small fluorine-doped ZnO quantum dots (F/ZnO QDs) were proposed and their formulation into stable amphiphilic nanosystems using synthetic glycoglycerolipids. To control aggregation and interfacial behavior, the QDs were first capped with oleylamine and subsequently functionalized through an emulsion-based approach with mono-acyl or di-acyl glycoglycerolipids, yielding double-coated amphiphilic nanoformulations. The resulting materials were extensively characterized by TEM, DLS, zeta-potential measurements, XRD, FTIR/ATR, UV–Vis, and fluorescence spectroscopy, allowing to explore correlations between surface chemistry, colloidal stability, and optical properties. Glycoglycerolipid functionalization led to a marked improvement in aqueous dispersibility and long-term colloidal stability while preserving the enhanced fluorescence induced by fluorine doping. Biological assays confirmed the cytocompatibility of the coated QDs and supported their suitability for further biointerface studies. This work highlights glycoglycerolipid-based amphiphilic coatings as an effective strategy to tailor the surface and colloidal properties of ZnO-based QDs, enabling the development of stable luminescent nanomaterials as biocompatible nanoprobes and for bio-interfacial applications.

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Abstract: Self-assembling peptides (SAPs) provide a versatile, biocompatible platform for soft biomaterials, but their application in mechanically robust, processable polymers remains limited. We report a peptide–polyethylene glycol (PEG) multiblock copolymer (MBCP) using the amphipathic β-sheet-forming SAP K(FEFK)2K as a physical cross-linker. Synthesized via copper-free strain-promoted azide–alkyne cycloaddition (SPAAC), the MBCP was solution-cast from water into free-standing films whose properties were governed by the peptide’s ability to form stable β-sheet fibers and aggregates. Films were tough and plastic at room temperature, but elastomeric above PEG’s melting point (>60 °C). At high temperature, a micro- and nano-scale phase-separated morphology emerged, with peptide fiber-rich domains embedded in a soft, amorphous PEG matrix. At room temperature, only microphase separation persisted, while PEG crystallization produced a semicrystalline matrix in which peptide fibers restricted large crystal growth and were likely segregated at crystallite interfaces. Extensive mechanical testing revealed resilient films with shape-recovery behavior.

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Abstract: Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes and obesity. Despite its clinical efficacy, oral administration remains challenging because of its limited gastrointestinal stability, poor epithelial permeability, and low affinity for lipid-based delivery systems. In the present study, a combined hydrophobic ion pairing (HIP) and solid lipid nanoparticle (SLN) approach was explored to improve semaglutide incorporation and delivery-related properties. Semaglutide was complexed with the cationic lipid DOTAP at different molar ratios (1:0–1:18) and subsequently incorporated into cetyl palmitate-based SLNs produced by microfluidic mixing using a herringbone device. The resulting formulations were characterized in terms of particle size, ζ-potential, encapsulation efficiency, morphology, solid-state organization, colloidal stability, release behavior, mucus interaction, cytocompatibility, and epithelial permeability. Among the various formulations prepared, the one prepared with a molar ratio semaglutide: DOTAP of 1:18 and a peptide concentration of 10% (w/w) (F10) showed the best results, combining particle sizes of less than 300 nm with almost complete encapsulation efficiency and a highly positive ζ-potential. FTIR, DSC, TGA and SAXS analyses confirmed the correct formation of the complex and its incorporation into the lipid matrix. The F10 formulation demonstrated good stability under simulated gastrointestinal conditions and a sustained-release profile. The formulation also exhibited strong interactions with mucus, whilst retaining the ability to diffuse through the mucin network. Cytocompatibility studies demonstrated acceptable cell viability at relevant concentrations, whilst permeability experiments through Caco-2 monolayers revealed an approximately 6-fold increase in apparent permeability compared to free semaglutide. Therefore, these findings indicate that the combination of DOTAP-mediated hydrophobic ion pairing and microfluidic-assisted SLN production represents a potentially promising strategy for improving semaglutide encapsulation, gastrointestinal stability, and epithelial transport, while maintaining a favorable balance between mucus interaction and mucodiffusion.

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Abstract: Amphiphilic copolymers have emerged as powerful, detergent-free tools for solubilizing biological membranes, enabling the extraction and stabilization of membrane proteins within native-like lipid environments. We report a comprehensive, multi-technique elucidation of how polymer:lipid stoichiometry governs the formation, size, and stability of styrene-maleic acid lipid particles (SMALPs). Using commercial SMA2000, a styrene-maleic acid copolymer made using free radical polymerization and 1,2-ditetradecanoyl-sn-glycero-3-phosphocholine (DMPC) as a model phospholipid, we prepared SMALPs across a wide range of polymer-to-lipid weight ratios and employed an integrated suite of orthogonal characterization methods, including size exclusion chromatography (SEC), dynamic light scattering (DLS), flow-induced dispersion analysis (FIDA), mass photometry, ensemble and time-resolved Förster resonance energy transfer (FRET), and small-angle X-ray scattering (SAXS), to establish the structural consequences of varying polymer content. Our data reveal that efficient lipid solubilization into nanodiscs requires a minimum amount of polymer. Above ~1% (w/v) SMA2000: 1% DMPC, well-defined nanodiscs of ~10 nm diameter are formed that, on average, exhibit a consistent stoichiometry of ~130 lipids encircled by ~11 polymer chains. Through a new molecularly-constrained SAXS model, we show that these nanodiscs possess a stable bilayer height across variations in polymer to lipid ratio and a narrow polymer belt, and that their structural parameters remain invariant once excess polymer is used. In contrast, insufficient polymer (<1% w/v) generates bimodal populations including substantially larger discs. Notably, nanodiscs formed at optimal polymer:lipid ratios remain structurally stable for at least two months. Together, these results provide a rigorous quantification of SMALP composition and preferred size, enhancing our understanding of polymer-lipid nanodisc formation and offering critical design rules for detergent-free membrane protein extraction.