In Vivo Polymer Mechanochemistry with Polynucleotides.

Polymer mechanochemistry utilizes mechanical force to activate latent functionalities in macromolecules and widely relies on ultrasonication techniques. Fundamental constraints of frequency and power intensity have prohibited the application of the polymer mechanochemistry principles in a biomedical context up to now, although medical ultrasound is a clinically established modality. Here, a universal polynucleotide framework is presented that allows the binding and release of therapeutic oligonucleotides, both DNA- and RNA-based, as cargo by biocompatible medical imaging ultrasound. It is shown that the high molar mass, colloidal assembly, and a distinct mechanochemical mechanism enable the force-induced release of cargo and subsequent activation of biological function in vitro and in vivo. Thereby, this work introduces a platform for the exploration of biological questions and therapeutics development steered by mechanical force.

Macrophage-like rapid uptake and toxicity of tattoo ink in human monocytes.

Macrophages play a critical role for the persistence of tattoo ink in human skin. However, a comparison to other skin-resident and blood circulating immune cells and a profound analysis of REACH-compliant tattoo ink are unmet medical needs. We hence characterized the size distribution of ink particles using physicochemical methods. We studied the uptake of tattoo ink by key human skin cells and blood-derived immune cells using optical and electron microscopy as well as flow cytometry. Scanning electron microscopy of ink revealed its crystalline structure, and a tendency towards aggregations was indicated by size changes upon diluting it. Flow cytometric analyses of skin and immune cells after incubation with tattoo ink demonstrated an increase in cellular granularity upon uptake and red ink additionally evoked fluorescent signals. Human macrophages were most potent in internalizing ink in full thickness 3D skin models. Macrophage cultures demonstrated that the ink did not lead to elevated inflammatory mediators, and showed no indications for toxicity, even after nice days. Strikingly, monocytes were most efficient in ink uptake, but displayed reduced viability, whereas granulocytes and lymphocytes showed only temporary ink uptake with flow cytometric signals declining after 1 day. Mechanistic studies on ink retention by corticosteroids or dexpanthenol in macrophage cultures demonstrated that these compounds do not lead to ink excretion, but even slightly increase the ink load in macrophages. The highly motile monocytes, precursors of macrophages, may play an underrated role for tattoo ink translocation from dermal blood vessels into internal organs.

Assessing the NLRP3 Inflammasome Activating Potential of a Large Panel of Micro- and Nanoplastics in THP-1 Cells.

Due to the ubiquity of environmental micro- and nanoplastics (MNPs), inhalation and ingestion by humans is very likely, but human health effects remain largely unknown. The NLRP3 inflammasome is a key player of the innate immune system and is involved in responses towards foreign particulate matter and the development of chronic intestinal and respiratory inflammatory diseases. We established NLRP3-proficient and -deficient THP-1 cells as an alternative in vitro screening tool to assess the potential of MNPs to activate the NLRP3 inflammasome. By investigating cytokine release (IL-1ß and IL-8) and cytotoxicity after treatment with engineered nanomaterials, this in vitro approach was compared to earlier published ex vivo murine bone marrow-derived macrophages and in vivo data. This approach showed a strong correlation with previously published data, verifying that THP-1 cells are a suitable model to investigate NLRP3 inflammasome activation. We then investigated the proinflammatory potential of eight MNPs of different size, shape, and chemical composition. Only amine-modified polystyrene (PS-NH2) acted as a direct NLRP3 activator. However, polyethylene terephthalate (PET), polyacrylonitrile (PAN), and nylon (PA6) induced a significant increase in IL-8 release in NLRP3-/- cells. Our results suggest that most MNPs are not direct activators of the NLRP3 inflammasome, but specific MNP types might still possess pro-inflammatory potential via other pathways.

Unraveling the Mechanism and Kinetics of Binding of an LCI-eGFP-Polymer for Antifouling Coatings.

The ability of proteins to adsorb irreversibly onto surfaces opens new possibilities to functionalize biological interfaces. Herein, the mechanism and kinetics of adsorption of protein-polymer macromolecules with the ability to equip surfaces with antifouling properties are investigated. These macromolecules consist of the liquid chromatography peak I peptide from which antifouling polymer brushes are grafted using single electron transfer-living radical polymerization. Surface plasmon resonance spectroscopy reveals an adsorption mechanism that follows a Langmuir-type of binding with a strong binding affinity to gold. X-ray reflectivity supports this by proving that the binding occurs exclusively by the peptide. However, the lateral organization at the surface is directed by the cylindrical eGFP. The antifouling functionality of the unimolecular coatings is confirmed by contact with blood plasma. All coatings reduce the fouling from blood plasma by 8894% with only minor effect of the degree of polymerization for the studied range (DP between 101 and 932). The excellent antifouling properties, combined with the ease of polymerization and the straightforward coating procedure make this a very promising antifouling concept for a multiplicity of applications.

Low-Temperature Synthesis of Titanium Oxynitride Nanoparticles.

The synthesis of transition metal oxynitrides is complicated by extreme reaction conditions such as high temperatures and/or high pressures. Here, we show an unprecedented solution-based synthesis of narrowly dispersed titanium oxynitride nanoparticles of cubic shape and average size of 65 nm. Their synthesis is performed by using titanium tetrafluoride and lithium nitride as precursors alongside trioctylphosphine oxide (TOPO) and cetrimonium bromide (CTAB) as stabilizers at temperatures as low as 250 °C. The obtained nanoparticles are characterized in terms of their shape and optical properties, as well as their crystalline rock-salt structure, as confirmed by XRD and HRTEM analysis. We also determine the composition and nitrogen content of the synthesized particles using XPS and EELS. Finally, we investigate the applicability of our titanium oxynitride nanoparticles by compounding them into carbon fiber electrodes to showcase their applicability in energy storage devices. Electrodes with titanium oxynitride nanoparticles exhibit increased capacity compared to the pure carbon material.

Enhanced Concanavalin†A Binding to Preorganized Mannose Nanoarrays in Glycodendrimersomes Revealed Multivalent Interactions.

The effect of the two-dimensional glycan display on glycan-lectin recognition remains poorly understood despite the importance of these interactions in a plethora of cellular processes, in (patho)physiology, as well as its potential for advanced therapeutics. Faced with this challenge we utilized glycodendrimersomes, a type of synthetic vesicles whose membrane mimics the surface of a cell and offers a means to probe the carbohydrate biological activity. These single-component vesicles were formed by the self-assembly of sequence-defined mannose-Janus dendrimers, which serve as surrogates for glycolipids. Using atomic force microscopy and molecular modeling we demonstrated that even mannose, a monosaccharide, was capable of organizing the sugar moieties into periodic nanoarrays without the need of the formation of liquid-ordered phases as assumed necessary for rafts. Kinetics studies of Concanavalin A binding revealed that those nanoarrays resulted in a new effective ligand yielding a ten-fold increase in the kinetic and thermodynamic constant of association.

Unraveling topology-induced shape transformations in dendrimersomes.

The vital functions of cell membranes require their ability to quickly change shape to perform complex tasks such as motion, division, endocytosis, and apoptosis. Membrane curvature in cells is modulated by very complex processes such as changes in lipid composition, the oligomerization of curvature-scaffolding proteins, and the reversible insertion of protein regions that act like wedges in the membrane. But, could much simpler mechanisms support membrane shape transformation? In this work, we demonstrate how the change of amphiphile topology in the bilayer can drive shape transformations of cell membrane models. To tackle this, we have designed and synthesized new types of amphiphiles-Janus dendrimers-that self-assemble into uni-, multilamellar, or smectic-ordered vesicles, named dendrimersomes. We synthesized Janus dendrimers containing a photo-labile bond that upon UV-Vis irradiation cleavage lose a part of the hydrophilic dendron. This leads to a change from a cylindrically to a wedge-shaped amphiphile. The high mobility of these dendrimers allows for the concentration of the wedge-shaped amphiphiles and the generation of transmembrane asymmetries. The concentration of the wedges and their rate of segregation allowed control of the budding and generation of structures such as tubules and high genus vesicles.

Stimuli-Responsive Zwitterionic Core-Shell Microgels for Antifouling Surface Coatings.

Fouling on filtration membranes is induced by the nonspecific interactions between the membrane surface and the foulants, and effectively hinders their efficient use in various applications. Here, we established a facile method for the coating of membrane surface with a dual stimuli-responsive antifouling microgel system enriched with a high polyzwitterion content. Different poly(sulfobetaine) (PSB) zwitterionic polymers with defined molecular weights and narrow dispersities were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and integrated onto poly(N-vinylcaprolactam) (PVCL) microgels via a controlled dosage of a cross-linker, adapting a precipitation polymerization technique to obtain a core-shell microstructure. Increasing the PSB macro-RAFT concentration resulted in a shift of both upper critical solution temperature and lower critical solution temperature toward higher temperatures. Cryogenic transmission electron microscopy at different temperatures suggested the formation of a core-shell morphology with a PVCL-rich core and a PSB-rich shell. On the other hand, the significant variations of different characteristic proton signals and reversible phase transitions of the microgel constituents were confirmed by temperature-dependent 1H NMR studies. Utilizing a quartz crystal microbalance with dissipation monitoring, we have been able to observe and quantitatively describe the antipolyelectrolyte behavior of the zwitterionic microgels. The oscillation frequency of the sensor proved to change reversibly according to the variations of the NaCl concentration, showing, in fact, the effect of the interaction between the salt and the opposite charges present in the microgel deposited on the sensor. Poly(ethersulfone) membranes, chosen as the model surface, when functionalized with zwitterionic microgel coatings, displayed protein-repelling property, stimulated by different transition temperatures, and showed even better performances at increasing NaCl concentration. These kinds of stimuli-responsive zwitterionic microgel can act as temperature-triggered drug delivery systems and as potential coating materials to prevent bioadhesion and biofouling as well.

Dual-Degradable Biohybrid Microgels by Direct Cross-Linking of Chitosan and Dextran Using Azide-Alkyne Cycloaddition.

In this work, biocompatible and degradable biohybrid microgels based on chitosan and dextran were synthesized for drug delivery applications. Two kinds of bio-based building blocks, alkyne-modified chitosan and azide-modified dextran, were used to fabricate microgels via single-step cross-linking in water-in-oil emulsions. The cross-linking was initiated in the presence of copper(II) without the use of any extra cross-linkers. A series of pH-responsive and degradable microgels were successfully synthesized by varying the degree of cross-links. The microgels were characterized using 1H NMR and FTIR spectroscopy which proved the successful cross-linking of alkyne-modified chitosan and azide-modified dextran by copper(II)-mediated click reaction. The obtained microgels exhibit polyampholyte character and can carry positive or negative charges in aqueous solutions at different pH values. Biodegradability of microgels was shown at pH 9 or in the presence of Dextranase due to the hydrolysis of carbonate esters in the microgels or 1,6-α-glucosidic linkages in dextran structure, respectively. Furthermore, the microgels could encapsulate vancomycin hydrochloride (VM), an antibiotic, with a high loading of approximately 93.67% via electrostatic interactions. The payload could be released in the presence of Dextranase or under an alkaline environment, making the microgels potential candidates for drug delivery, such as colon-specific drug release.

Nanovesicles displaying functional linear and branched oligomannose self-assembled from sequence-defined Janus glycodendrimers.

Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus glycodendrimers containing more complex linear and branched glycans has so far prevented access to more realistic cell mimics. However, the present work reports the use of an isothiocyanate-amine "click"-like reaction between isothiocyanate-containing sequence-defined amphiphilic Janus dendrimers and either linear or branched oligosaccharides containing up to six monosaccharide units attached to a hydrophobic amino-pentyl linker, a construct not expected to assemble into glycodendrimersomes. Unexpectedly, these oligoMan-containing dendrimers, which have their hydrophobic linker connected via a thiourea group to the amphiphilic part of Janus glycodendrimers, self-organize into nanoscale glycodendrimersomes. Specifically, the mannose-binding lectins that best agglutinate glycodendrimersomes are those displaying hexamannose. Lamellar "raft-like" nanomorphologies on the surface of glycodendrimersomes, self-organized from these sequence-defined glycans, endow these membrane mimics with high biological activity.

Direct Visualization of Vesicle Disassembly and Reassembly Using Photocleavable Dendrimers Elucidates Cargo Release Mechanisms.

Release of cargo molecules from cell-like nanocarriers can be achieved by chemical perturbations, including changes to pH and redox state and via optical modulation of membrane properties. However, little is known about the kinetics or products of vesicle breakdown due to limitations in real-time imaging at nanometer length scales. Using a library of 12 single-single type photocleavable amphiphilic Janus dendrimers, we developed a self-assembling light-responsive dendrimersome vesicle platform. A photocleavable ortho-nitrobenzyl inserted between the hydrophobic and hydrophilic dendrons of amphiphilic Janus dendrimers allowed for photocleavage and disassembly of their supramolecular assemblies. Distinct methods used to self-assemble amphiphilic Janus dendrimers produced either nanometer size small unilamellar vesicles or micron size giant multilamellar and onion-like dendrimersomes. In situ observation of giant photosensitive dendrimersomes via confocal microscopy elucidated rapid morphological transitions that accompany vesicle breakdown upon 405 nm laser illumination. Giant dendrimersomes displayed light-induced cleavage, disassembling and reassembling into much smaller vesicles at millisecond time scales. Additionally, photocleavable vesicles demonstrated rapid release of molecular and macromolecular cargos. These results guided our design of multilamellar particles to photorelease surface-attached proteins, photoinduce cargo recruitment, and photoconvert vesicle morphology. Real-time characterization of the breakdown and reassembly of lamellar structures provides insights on partial cargo retention and informs the design of versatile, optically regulated carriers for applications in nanoscience and synthetic biology.

Electroactive and degradable supramolecular microgels.

In this work, we synthesized electroactive and degradable microgels based on biomacromolecular building blocks, which enable the controlled release of therapeutic drugs. Functional chitosan-poly(hydroquinone) (Ch:PHQ) microgels exhibiting redox-active and pH-sensitive properties were synthesized by an oxidative polymerization in an inverse miniemulsion system. Physically crosslinked microgels were formed by polymerization of hydroquinone in the presence of chitosan through the formation of hydrogen bonds between PHQ and Ch. A series of microgel samples with variable Ch : PHQ ratios were synthesized. These obtained microgels exhibit pH-responsive properties due to the protonation/deprotonation of amino-groups of chitosan in the microgel system. Poly(hydroquinone) is a redox-active polymer exhibiting a two-electron/proton-transfer behavior and conveys this property to the microgels as confirmed by cyclic voltammetry. In addition, the microgels can be switched by electrochemical means: they swell in the oxidized state or shrink in the reduced state. In the presence of urea or lysozyme, the microgels undergo a fast degradation due to the disruption of hydrogen bonds acting as physical crosslinks in the microgel networks or due to the cleavage of glucosidic linkages of the incorporated chitosan scaffold, respectively. Doxorubicin (DOX), an anticancer drug, could be effectively encapsulated into the microgels and released in the presence of an enzyme, indicating that these biodegradable microgels could be used as drug delivery vehicles for tumor cells.

Encapsulation of hydrophobic components in dendrimersomes and decoration of their surface with proteins and nucleic acids.

Reconstructing the functions of living cells using nonnatural components is one of the great challenges of natural sciences. Compartmentalization, encapsulation, and surface decoration of globular assemblies, known as vesicles, represent key early steps in the reconstitution of synthetic cells. Here we report that vesicles self-assembled from amphiphilic Janus dendrimers, called dendrimersomes, encapsulate high concentrations of hydrophobic components and do so more efficiently than commercially available stealth liposomes assembled from phospholipid components. Multilayer onion-like dendrimersomes demonstrate a particularly high capacity for loading low-molecular weight compounds and even folded proteins. Coassembly of amphiphilic Janus dendrimers with metal-chelating ligands conjugated to amphiphilic Janus dendrimers generates dendrimersomes that selectively display folded proteins on their periphery in an oriented manner. A modular strategy for tethering nucleic acids to the surface of dendrimersomes is also demonstrated. These findings augment the functional capabilities of dendrimersomes to serve as versatile biological membrane mimics.

Membrane-Mimetic Dendrimersomes Engulf Living Bacteria via Endocytosis.

There is much interest in developing vesicular microcompartments from natural and synthetic amphiphiles, enabling programmable interactions with living matter. Of particular interest is the development of vesicles capable of endocytosis of living bacteria. Despite the complexity of this process, theoretical studies predict that the endocytosis of prolate micro-objects is possible without the need of active cell machinery if the energy released upon bacterial adhesion to the membrane surpasses the energy required to bend the membrane. Nonetheless, natural liposomes and synthetic polymersomes fail to sufficiently recapitulate membrane properties to perform this advanced function. Here we report the engulfment of living bacteria into endosomes by cell-like dendrimersomes assembled from Janus dendrimers. Full engulfment occurred in less than a minute after contact. The process is driven by the adhesion of the bacterium to the dendrimersome's membrane by ultraweak interactions, comparable to those utilized by nature. The key to success relies on the combination of high flexibility and stability of the dendrimersomes. The key properties of the dendrimersomes are programmed into the molecular structures of their building blocks. The ability to support endocytosis highlights opportunities for the design and programming of dendrimersomes in biomedical research.

Encoding biological recognition in a bicomponent cell-membrane mimic.

Self-assembling dendrimers have facilitated the discovery of periodic and quasiperiodic arrays of supramolecular architectures and the diverse functions derived from them. Examples are liquid quasicrystals and their approximants plus helical columns and spheres, including some that disregard chirality. The same periodic and quasiperiodic arrays were subsequently found in block copolymers, surfactants, lipids, glycolipids, and other complex molecules. Here we report the discovery of lamellar and hexagonal periodic arrays on the surface of vesicles generated from sequence-defined bicomponent monodisperse oligomers containing lipid and glycolipid mimics. These vesicles, known as glycodendrimersomes, act as cell-membrane mimics with hierarchical morphologies resembling bicomponent rafts. These nanosegregated morphologies diminish sugar-sugar interactions enabling stronger binding to sugar-binding proteins than densely packed arrangements of sugars. Importantly, this provides a mechanism to encode the reactivity of sugars via their interaction with sugar-binding proteins. The observed sugar phase-separated hierarchical arrays with lamellar and hexagonal morphologies that encode biological recognition are among the most complex architectures yet discovered in soft matter. The enhanced reactivity of the sugar displays likely has applications in material science and nanomedicine, with potential to evolve into related technologies.

Design-functionality relationships for adhesion/growth-regulatory galectins.

Glycan-lectin recognition is assumed to elicit its broad range of (patho)physiological functions via a combination of specific contact formation with generation of complexes of distinct signal-triggering topology on biomembranes. Faced with the challenge to understand why evolution has led to three particular modes of modular architecture for adhesion/growth-regulatory galectins in vertebrates, here we introduce protein engineering to enable design switches. The impact of changes is measured in assays on cell growth and on bridging fully synthetic nanovesicles (glycodendrimersomes) with a chemically programmable surface. Using the example of homodimeric galectin-1 and monomeric galectin-3, the mutual design conversion caused qualitative differences, i.e., from bridging effector to antagonist/from antagonist to growth inhibitor and vice versa. In addition to attaining proof-of-principle evidence for the hypothesis that chimera-type galectin-3 design makes functional antagonism possible, we underscore the value of versatile surface programming with a derivative of the pan-galectin ligand lactose. Aggregation assays with N,N'-diacetyllactosamine establishing a parasite-like surface signature revealed marked selectivity among the family of galectins and bridging potency of homodimers. These findings provide fundamental insights into design-functionality relationships of galectins. Moreover, our strategy generates the tools to identify biofunctional lattice formation on biomembranes and galectin-reagents with therapeutic potential.

Solvent-Induced Nanotopographies of Single Microfibers Regulate Cell Mechanotransduction.

The extracellular matrix (ECM) is a dynamic three-dimensional (3D) fibrous network, surrounding all cells in vivo. Fiber manufacturing techniques are employed to mimic the ECM but still lack the knowledge and methodology to produce single fibers approximating cell size with different surface topographies to study cell-material interactions. Using solvent-assisted spinning (SAS), the potential to continuously produce single microscale fibers with unlimited length, precise diameter, and specific surface topographies was demonstrated. By applying solvents with different solubilities and volatilities, fibers with smooth, grooved, and porous surface morphologies are produced. Due to their hierarchical structures, the porous fibers are the most hydrophobic, followed by the grooved and the smooth fibers. The fiber diameter is increased by increasing the polymer concentration or decreasing the collector rotational speed. Moreover, SAS offers the advantage to control the interfiber distance and angle to fabricate multilayered 3D constructs. This report shows for the first time that the micro- and nanoscale topographies of single fibers mechanically regulate cell behavior. Fibroblasts, grown on fibers with grooved topographical features, stretch and elongate more compared to smooth and porous fibers, whereas both porous and grooved fibers induce nuclear translocation of yes-associated protein. The presented technique, therefore, provides a unique platform to study the interaction between cells and single ECM-like fibers in a precise and reproducible manner, which is of great importance for new material developments in the field of tissue engineering.

Zwitterionic Functionalizable Scaffolds with Gyroid Pore Architecture for Tissue Engineering.

Stereolithography-assisted fabrication of hydrogels of carboxybetaine methacrylamide (CBMAA) and a α,ω-methacrylate poly(d,l-lactide-block-ethylene glycol-block- d,l-lactide) (MA-PDLLA-PEG-PDLLA-MA) telechelic triblock macromer is presented. This technique allows printing complex structures with gyroid interconnected porosity possessing extremely high specific area. Hydrogels are characterized by infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and laser scanning confocal microscopy (LSCM). The copolymerization with zwitterionic comonomer leads hydrogels with high equilibrium water content (EWC), up to 700% while maintaining mechanical robustness. The introduction of carboxybetaine yields excellent resistance to nonspecific protein adsorption while providing a facile way for specific biofunctionalization with a model protein, fluorescein isothiocyanate labeled bovine serum albumin (BSA). The homogeneous protein immobilization across the hydrogel pores prove the accessibility to the innermost pore volumes. The remarkably low protein adsorption combined with the interconnected nature of the porosity allowing fast diffusion of nutrient and waste product and the mimicry of bone trabecular, makes the hydrogels presented here highly attractive for tissue engineering.

Antifouling Microparticles To Scavenge Lipopolysaccharide from Human Blood Plasma.

Currently, one of the most promising treatments of lipopolysaccharides (LPS)-induced sepsis is based on hemofiltration. Nevertheless, proteins rapidly adsorbed on the artificial surface of membranes which leads to activation of coagulation impairing effective scavenging of the endotoxins. To overcome this challenge, we designed polymer-brush-coated microparticles displaying antifouling properties and functionalized them with polymyxin B (PMB) to specifically scavenge LPS the most common endotoxin. Poly[( N-(2-hydroxypropyl) methacrylamide)- co-(carboxybetaine methacrylamide)] brushes were grafted from poly(glycidyl methacrylate) microparticles using photoinduced single-electron transfer living radical polymerization (SET-LRP). Notably, only parts-per-million of copper catalyst were necessary to achieve brushes able to repel adsorption of proteins from blood plasma. The open porosity of the particles, accessible to polymerization, enabled us to immobilize sufficient PMB to selectively scavenge LPS from blood plasma.

Screening Libraries of Amphiphilic Janus Dendrimers Based on Natural Phenolic Acids to Discover Monodisperse Unilamellar Dendrimersomes.

Natural, including plant, and synthetic phenolic acids are employed as building blocks for the synthesis of constitutional isomeric libraries of self-assembling dendrons and dendrimers that are the simplest examples of programmed synthetic macromolecules. Amphiphilic Janus dendrimers are synthesized from a diversity of building blocks including natural phenolic acids. They self-assemble in water or buffer into vesicular dendrimersomes employed as biological membrane mimics, hybrid and synthetic cells. These dendrimersomes are predominantly uni- or multilamellar vesicles with size and polydispersity that is predicted by their primary structure. However, in numerous cases, unilamellar dendrimersomes completely free of multilamellar assemblies are desirable. Here, we report the synthesis and structural analysis of a library containing 13 amphiphilic Janus dendrimers containing linear and branched alkyl chains on their hydrophobic part. They were prepared by an optimized iterative modular synthesis starting from natural phenolic acids. Monodisperse dendrimersomes were prepared by injection and giant polydisperse by hydration. Both were structurally characterized to select the molecular design principles that provide unilamellar dendrimersomes in higher yields and shorter reaction times than under previously used reaction conditions. These dendrimersomes are expected to provide important tools for synthetic cell biology, encapsulation, and delivery.