A Critical Look at Multilayered Polymer Capsules in Biomedicine: Drug Carriers,Artificial Organelles,and Cell Mimics

This Feature Article discusses utility of multilayered polymer capsules in biomedicine, specifically in drug delivery and in design of artificial organelles and cells. We provide a critical view on recent successes and identified shortcomings of these capsules in delivery of therapeutic cargo and outline plausible further developments of capsules as candidate drug carriers. A special emphasis is placed on poly(methacrylic acid) hydrogel capsules as successful carriers used in delivery of anticancer drugs and protein and peptide vaccines. We further present a novel biomedical approach whereby the same vessel acts first as a microreactor and then as a carrier for de novo synthesized therapeutic cargo. Finally, utility of polymer capsules in design of cell mimics is discussed with an emphasis on assembly and performance of capsosomes, polymer capsules with liposomal subcompartments. This presentation of capsules in biomedicine aims to provide an overview of past achievements and existing challenges associated with these candidate vessels and to stimulate further research interest from a broad scientific audience.     

Biocatalytic Metal‐Organic Framework‐Based Artificial Cells

Artificial cells or cell mimics have drawn significant attention in cell biology and material science in the last decade and its development will provide a powerful toolbox for studying the origin of life and pave the way for novel biomedical applications. Artificial cells and their subcompartments are typically constructed from a semipermeable membrane composed of liposomes, polymersomes, hydrogels, or simply aqueous droplets enclosing bioactive molecules to perform cellular‐mimicking activities such as compartmentalization, communication, metabolism, or reproduction. Despite the rapid progress, concerns regarding their physical stability (e.g., thermal or mechanical) and tunability in membrane permeability have significantly hindered artificial cells systems in real‐life applications. In addition, developing a facile and versatile system that can mimic multiple cellular tasks is advantageous. Here, an ultrastable, multifunctional and stimulus‐responsive artificial cell system is reported. Constructed from metal‐phenolic network membranes enclosing enzyme‐containing metal‐organic frameworks as organelles, the bionic cell system can mimic multiple cellular tasks including molecular transport regulation, cell metabolism, communication and programmed degradation, and significantly extends its stability range across various chemical and physical conditions. It is believed that the development of such responsive cell mimics will have significant potentials for studying cellular reactions and have future applications in biosensing and drug delivery.     

Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

Nanomedicine is a promising approach for combination chemotherapy of triple‐negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli‐responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme‐cleavable polyethylene glycol (PEG) corona, a light‐responsive photosensitizer pheophorbide a (PPa), and a temperature‐sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl‐oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug‐loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa‐mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy.     

Multicompartment Polymer Vesicles with Artificial Organelles for Signal‐Triggered Cascade Reactions Including Cytoskeleton Formation

Organelles, i.e., internal subcompartments of cells, are fundamental to spatially separate cellular processes, while controlled intercompartment communication is essential for signal transduction. Furthermore, dynamic remodeling of the cytoskeleton provides the mechanical basis for cell shape transformations and mobility. In a quest to develop cell‐like smart synthetic materials, exhibiting functional flexibility, a self‐assembled vesicular multicompartment system, comprised of a polymeric membrane (giant unilamellar vesicle, GUV) enveloping polymeric artificial organelles (vesicles, nanoparticles), is herein presented. Such multicompartment assemblies respond to an external stimulus that is transduced through a precise sequence. Stimuli‐triggered communication between two types of internal artificial organelles induces and localizes an enzymatic reaction and allows ion‐channel mediated release from storage vacuoles. Moreover, cytoskeleton formation in the GUVs' lumen can be triggered by addition of ionophores and ions. An additional level of control is achieved by signal‐triggered ionophore translocation from organelles to the outer membrane, triggering cytoskeleton formation. This system is further used to study the diffusion of various cytoskeletal drugs across the synthetic outer membrane, demonstrating potential applicability, e.g., anticancer drug screening. Such multicompartment assemblies represent a robust system harboring many different functionalities and are a considerable leap in the application of cell logics to reactive and smart synthetic materials.     

Mimicking Cellular Signaling Pathways within Synthetic Multicompartment Vesicles with Triggered Enzyme Activity and Induced Ion Channel Recruitment

Subcellular compartmentalization of cells, a defining characteristic of eukaryotes, is fundamental for the fine tuning of internal processes and the responding to external stimuli. Reproducing and controlling such compartmentalized hierarchical organization, responsiveness, and communication is important toward understanding biological systems and applying them to smart materials. Herein, a cellular signal transduction strategy (triggered release from subcompartments) is leveraged to develop responsive, purely artificial, polymeric multicompartment assemblies. Incorporation of responsive nanoparticles—loaded with enzymatic substrate or ion channels—as subcompartments inside micrometer‐sized polymeric vesicles (polymersomes) allowed to conduct bioinspired signaling cascades. Response of these subcompartments to an externally added stimulus is achieved and studied by using confocal laser scanning microscopy (CLSM) coupled with in situ fluorescence correlation spectroscopy (FCS). Signal triggered activity of an enzymatic reaction is demonstrated in multicompartments through recombination of compartmentalized substrate and enzyme. In parallel, a two‐step signaling cascade is achieved by triggering the recruitment of ion channels from inner subcompartments to the vesicles' membrane, inducing ion permeability, mimicking endosome‐mediated insertion of internally stored channels. This design shows remarkable versatility, robustness, and controllability, demonstrating that multicompartment polymer‐based assemblies offer an ideal scaffold for the development of complex cell‐inspired responsive systems for applications in biosensing, catalysis, and medicine.     

Extracellular Microreactor for the Depletion of Phenylalanine Toward Phenylketonuria Treatment

Phenylketonuria (PKU) is a genetic enzyme defect affecting 1:10 000–20 000 newborn children every year. The amino acid phenylalanine (Phe) is not depleted but accumulates in tissues of several organs, which leads to severe medical conditions. A promising concept to restore the metabolism of the affected patients will be to orally administer the defective enzyme which will remove Phe in the intestine. Herein, capsosomes, a multicompartment carrier consisting of thousands of liposomes embedded within a polymeric carrier, are employed as encapsulation platform for this purpose. It is shown that the enzyme phenylalanine ammonia lyase can be entrapped within the liposomal compartments with preserved activity, demonstrated by the conversion of Phe into trans‐cinnamic acid (t‐ca). With the aim to mimic the dynamic environment in the intestine, the Phe conversion is performed in a microfluidic set up in the presence of human intestinal epithelial cells with applied intestinal flow and peristaltic motions. It is also shown that the microreactors are neither internalized by the cells nor exhibit inherent cytotoxicity while concurrently converting Phe into t‐ca. Taken together, the first active extracellular multicompartment microreactor is reported using the relevant enzymes and settings toward the treatment of the medical condition PKU.     

Cisplatin‐Prodrug‐Constructed Liposomes as a Versatile Theranostic Nanoplatform for Bimodal Imaging Guided Combination Cancer Therapy

Up to date, a large variety of liposomal nanodrugs have been explored for cancer nanomedicine, showing encouraging results in both preclinical animal experiments and clinical treatment of cancer patients. Herein, a phospholipid conjugated with a cisplatin prodrug is used as the major structure component of liposomes together with other commercial lipids via self‐assembling. By doping with 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindotricarbocyanine iodide (DiR), a lipophilic dye with strong near infrared (NIR) absorbance and fluorescence, the obtained DiR‐Pt(IV)‐liposome is found to be an effective probe for in vivo NIR fluorescence and photoacoustic bimodal imaging. Attributing to its intrinsically doped cis‐Pt(IV) prodrug, efficient photothermal conversion ability, and excellent tumor homing ability, DiR‐Pt(IV)‐liposome confers greatly enhanced therapeutic outcomes in the combined photothermal‐chemotherapy. Moreover, Pt(IV)‐liposome is also demonstrated to be an efficient carrier for both small hydrophilic molecules and proteins, which are encapsulated inside the water‐cavity of liposomes, further demonstrating the versatile functions of this nanoplatform. This study develops a unique type of liposomal nanomedicine with a prodrug conjugated phospholipid as the major structure component. Such Pt(IV)‐liposome is featured with advantages including precisely defined/easily tunable drug compositions, stealth‐like pharmacokinetics, efficient tumor passive uptake, and the capabilities to simultaneously load with various types of imaging or therapeutic agents.     

Transfer Printing of Cell Layers with an Anisotropic Extracellular Matrix Assembly using Cell‐Interactive and Thermosensitive Hydrogels

The structure of tissue plays a critical role in its function and therefore a great deal of attention has been focused on engineering native tissue‐like constructs for tissue engineering applications. Transfer printing of cell layers is a new technology that allows controlled transfer of cell layers cultured on smart substrates with defined shape and size onto tissue‐specific defect sites. Here, the temperature‐responsive swelling‐deswelling of the hydrogels with groove patterns and their versatile and simple use as a template to harvest cell layers with anisotropic extracellular matrix assembly is reported. The hydrogels with a cell‐interactive peptide and anisotropic groove patterns are obtained via enzymatic polymerization. The results show that the cell layer with patterns can be easily transferred to new substrates by lowering the temperature. In addition, multiple cell layers are stacked on the new substrate in a hierarchical manner and the cell layer is easily transplanted onto a subcutaneous region. These results indicate that the evaluated hydrogel can be used as a novel substrate for transfer printing of artificial tissue constructs with controlled structural integrity, which may hold potential to engineer tissue that can closely mimic native tissue architecture.     

Particulate Coatings with Optimized Haze Properties

The haze factor, which describes the fraction of light that is scattered when passing through a transparent material, is of general importance for any optical device, from milk glass shielding visibility while providing ambient lighting to solar cells that are optimized by sophisticated light management layers. Often, such active layers are fabricated from particulate materials that are deposited as thin films on a substrate. Here, the effect of structural arrangement, position, and orientation of particles on the resulting haze factor is investigated. A mathematical optimization model that iteratively alters the particle layer structure to maximize or minimize the haze factor for a range of optimization scenarios is designed. Colloidal self‐assembly techniques are then used to replicate typical particle structures found in the optimized designs and correlate the macroscopically measured haze values to the predictions of the optimization. The results indicate general design rules that control the haze value in particle layers. Non close‐packed structures with distributed scatterers and high degrees of order provide minimal haze values while chain‐like arrangements and small clusters maximize the haze of a particle layer. Finally, the findings are transferred to metal nanohole films as model transparent electrodes with controlled haze values.     

Enhancing Apoptosome Assembly via Mito-Biomimetic Lipid Nanocarrier for Cancer Therapy

Apoptosis is the natural programmed cell death process, which is responsible for abnormal cell clearance. However, many cancer cells develop various mechanisms to escape apoptosis through interrupting apoptosome assembly, which is a key step to initiate apoptosis. This promotes tumorigenesis and drug resistance, and thus, poses a great challenge in cancer treatment. Herein, a biomimetic lipid nanocarrier mimicking mitochondrial Cytochrome C (Cyt C) binding is developed. Cardiolipin, the major phospholipid of mitochondrial inner membrane, is introduced as the main component in biomimetic liposomal formulation. With the help of cardiolipin, Cyt C is sufficiently loaded in liposome based on electrostatic and hydrophobic interaction with cardiolipin. Lonidamine (LND) is added in hydrophobic phase of liposome to modulate the metabolic activity within cancer cells and sensitize the cells to Cyt C-induced apoptosis. The results suggest that LND reduces ATP level and creates favorable environment for Cyt C induced apoptosome assembly, exhibiting higher apoptosis level and anti-tumor efficacy in vitro and in vivo. The conjugation of a tumor-homing peptide, LinTT1, on the nanovesicle, increases the efficacy due to enhanced tumor accumulation. Overall, this biomimetic lipid nanocarrier proves to be an efficient delivery system with great potential of pro-apoptosis cancer therapy.     

A Multifunctional Nanoplatform against Multidrug Resistant Cancer: Merging the Best of Targeted Chemo/Gene/Photothermal Therapy

Synergistic therapy that combines chemo‐, gene‐, or photothermal means shows great potential for enhancing the therapeutic effects on cancers. Tumor‐targeted nanoparticles based on a doxorubicin (DOX)‐gated mesoporous silica nanocore (MSN) encapsulated with permeability glycoprotein (P‐gp) small interfering RNA (siRNA) and a polydopamine (PDA) outer layer for DOX loading and folic acid decoration are designed. The multifunctional nanoplatform tactfully integrates chemo‐ (DOX), gene‐ (P‐gp siRNA), and photothermal (PDA layer) substances in one system. In vitro results reveal that DOX release behaviors are both pH‐ and thermal‐responsive and the release of co‐delivered P‐gp siRNA is also pH‐dependent due to the pH‐cleavable DOX gatekeeper on MSN. In addition, due to the near‐infrared light‐responsive PDA outer layer and folic acid conjugation, the nanoparticles exhibit outstanding photothermal activity and selective cell targeting ability. Subsequently, in vitro and in vivo antitumor experiments both demonstrate the enhanced antitumor efficacy of the multifunctional nanoparticles, indicating the significance of synergistic therapy combining chemo‐, gene‐, and photothermal treatments in one system.     

Controllable Stiffness Origami “Skeletons” for Lightweight and Multifunctional Artificial Muscles

Flexible, material‐based, artificial muscles enable compliant and safe technologies for human–machine interaction devices and adaptive soft robots, yet there remain long‐term challenges in the development of artificial muscles capable of mimicking flexible, controllable, and multifunctional human activity. Inspired by human limb's activity strategy, combining muscles' adjustable stiffness and joints' origami folding, controllable stiffness origami “skeletons,” which are created by laminar jamming and origami folding of multiple layers of flexible sandpaper, are embedded into a common monofunctional vacuumed‐powered cube‐shaped (CUBE) artificial muscle, thereby enabling the monofunctional CUBE artificial muscle to achieve lightweight and multifunctionality as well as controllable force/motion output without sacrificing its volume and shape. Successful demonstrations of arms self‐assembly and cooperatively gripping different objects and a “caterpillar” robot climbing different pipes illustrate high operational redundancy and high‐force output through “building blocks” assembly of multifunctional CUBE artificial muscles. Controllable stiffness origami “skeletons” offer a facile and low‐cost strategy to fabricate lightweight and multifunctional artificial muscles for numerous potential applications such as wearable assistant devices, miniature surgical instruments, and soft robots.     

Composite Living Fibers for Creating Tissue Constructs Using Textile Techniques

The fabrication of cell‐laden structures with anisotropic mechanical properties while having a precise control over the distribution of different cell types within the constructs is important for many tissue engineering applications. Automated textile technologies for making fabrics allow simultaneous control over the color pattern and directional mechanical properties. The use of textile techniques in tissue engineering, however, demands the presence of cell‐laden fibers that can withstand the mechanical stresses during the assembly process. Here, the concept of composite living fibers (CLFs) in which a core of load bearing synthetic polymer is coated by a hydrogel layer containing cells or microparticles is introduced. The core thread is drawn sequentially through reservoirs containing a cell‐laden prepolymer and a crosslinking reagent. The thickness of the hydrogel layer increases linearly with to the drawing speed and the prepolymer viscosity. CLFs are fabricated and assembled using regular textile processes including weaving, knitting, braiding, winding, and embroidering, to form cell‐laden structures. Cellular viability and metabolic activity are preserved during CLF fabrication and assembly, demonstrating the feasibility of using these processes for engineering functional 3D tissue constructs.     

In Situ Self‐Assembly of Coacervate Microdroplets into Viable Artificial Cell Wall with Heritability

Creating an intelligent artificial cell wall to endow fabricated cells with more advanced functionalities is highly desirable. Here, an efficient and cytocompatible approach to generate a type of viable artificial cell wall based on direct self‐assembly of coacervate microdroplets on individual cellular surface is developed, which can protect the fabricated cell against various external stresses and can then prolong the storage of the fabricated cells over two months. Moreover, as a type of viable artificial cell wall, it can not only help the fabricated cell sequester nutrients or functionalized substances such as catalase, or iron oxide nanoparticles actively from the solution which then makes the fabricated cell more versatile but also allows the fabricated cell proliferate. Significantly, the artificial cell wall also shows heritable behavior that can reserve its protection to as far as the third‐generation daughter cell. Undoubtedly, such an illustrated artificial cell wall provides a conceptually new and promising technique toward the cell‐based research as well as application of next generation.     

Suppression of the Keto‐Emission in Polyfluorene Light‐Emitting Diodes: Experiments and Models

The spectral characteristics of polyfluorene (PF)‐based light‐emitting diodes (LEDs) containing a defined low concentration of either keto‐defects or of the polymer poly(9,9‐octylfluorene‐co‐benzothiadiazole) (F8BT) are presented. Both types of blend layers were tested in different device configurations with respect to the relative and absolute intensities of green and blue emission components. It is shown that blending hole‐transporting molecules into the emission layer at low concentration or incorporation of a suitable hole‐transporting layer reduces the green emission contribution in the electroluminescence (EL) spectrum of the PF:F8BT blend, which is similar to what is observed for the keto‐containing PF layer. We conclude that the keto‐defects in PF homopolymer layers mainly constitute weakly emissive electron traps, in agreement with the results of quantum‐mechanical calculations.     

Highly Scalable,Closed‐Loop Synthesis of Drug‐Loaded,Layer‐by‐Layer Nanoparticles

Layer‐by‐layer (LbL) self‐assembly is a versatile technique from which multi­component and stimuli‐responsive nanoscale drug‐carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, a generalizable method for increasing throughput with LbL assembly is described by using highly scalable, closed‐loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid‐polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. The cytotoxicity, shelf life, and long‐term storage of LbL nanoparticles produced using this approach are explored. It is found that LbL coated systems can be reliably and rapidly produced: specifically, LbL‐modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug‐carriers that show low toxicity and are amenable to clinically relevant storage conditions.     

Screening of Zwitterionic Liposomes with Red Blood Cell-Hitchhiking and Tumor Cell-Active Transporting Capability for Efficient Tumor Entrance

The active transport of nanoparticles into the solid tumor through cell transcytosis has shown great promise in cancer nanomedicine, but it is challenging to develop efficient active transporting nanomedicines with the potential for clinical translation. Here, a type of tertiary amine oxide (TAO)-containing zwitterionic liposomal nanocarriers is developed that can hitchhike red blood cells (RBCs) to tumor blood vessels and enter solid tumors through transcytosis. To boost the active-transporting capability, a library of the TAO liposomes (TAOLs) with different chemical structures and particle sizes is constructed and screened by their stability and active transporting capability. Two types of TAOLs are identified that can induce efficient tumor cell transcytosis through rapid macropinocytosis and endoplasmic reticulum/Golgi-involved exocytosis. It is found that these zwitterionic TAOLs can hitchhike RBCs to gain long blood circulation, get off the cell at the tumor site, effectively enter the tumor through transcytosis, and infiltrate the whole tumor. The chemotherapeutic drug-loaded liposomes can stop the tumor progression of mice bearing human hepatocellular carcinoma HepG2 cells, exhibiting superior antitumor activity compared to the traditional liposomal drug. This study demonstrates a strategy to construct effective active transporting liposomal nanomedicines for efficient tumor entrance.     

Enhancement of n‐Type Organic Field‐Effect Transistor Performances through Surface Doping with Aminosilanes

Dopants, i.e., electronically active impurities, are added to organic semiconductor materials to control the material's Fermi level and conductivity, to improve injection at the device contacts, or to fill trap states in the active device layers and interfaces. In contrast to bulk doping as achieved by blending or co‐deposition of dopant and semiconductor, surface doping has a lower propensity to introduce additional traps or scattering centers or to even alter the layer morphology relative to the undoped active material layers. In this study, the electrical effects of a very simple, post‐device‐fabrication surface doping process involving various amine group–containing alkoxysilanes on the performance of organic field‐effect transistors (OFETs) made from the well‐known n‐type materials PTCDI‐C8 and N2200 are researched. It is demonstrated that OFETs doped in such a way generally show enhanced characteristics (up to 10 times mobility increase and a significant reduction in threshold voltage) without any adverse effects on the devices' on/off ratio. It is also shown that the efficiency of the doping process is linked to the number of amine groups.     

The Development of a Generic Bioanalytical Matrix Using Polydiacetylenes

In order to develop more user‐viable formats for polydiacetylene (PDA) biosensors, it is necessary to control the biochemical and physical properties of the PDA matrix. In this study, we prepare polydiacetylene liposomes from controlled mixtures of 10,12‐pentacosadiynoic acid (PCDA) and PCDA–MI, a PCDA derivative with a maleimide headgroup. Both the chemical and physical properties of the liposome are easily manipulated by controlling the molar ratio of PCDA to PCDA–MI during liposome preparation. After preparing the liposomes, the activity of the maleimide headgroups increases linearly with the PCDA–MI content for concentrations in the range of 0–30 %. As a result, the antibody‐binding characteristics of the PDA liposomes increase with PCDA–MI content. It is also possible to modulate the physical properties of the liposome. Differential scanning calorimetry measurements show that the phase organization of the liposome is progressively lost with increasing PCDA–MI content. Furthermore, the liposomes show an increased color change in response to temperature that is also dependent on PCDA–MI content, indicating increased membrane fluidity. When PCDA:PCDA–MI liposomes are conjugated with a cell‐specific antibody the response to the antigen induces a color change that is dependent on the PCDA–MI content. Consequently, it is deduced that the increased sensitivity of the liposomes containing higher PCDA‐MI content is due to increased antibody binding and membrane fluidity. From these experiments, we identify the factors controlling the colorimetric properties of the PDA matrix and demonstrate that it is possible to modulate the sensitivity and stability of PDA biosensors by controlling the ratio of constituent monomers.     

Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.