Precisely controlled spatial distributions of artificial light-harvesting systems in aqueous media are of significant importance for mimicking natural light-harvesting systems; however, they are often restrained by the solubility and the aggregation-caused quenching effect of the hydrophobic chromophores. Herein, we report one highly efficient artificial light-harvesting system based on peptoid nanotubes that mimic the hierarchical cylindrical structure of natural systems. The high crystallinity of these nanotubes enabled the organization of arrays of donor chromophores with precisely controlled spatial distributions, favoring an efficient Förster resonance energy transfer (FRET) process in aqueous media. This FRET system exhibits an extremely high efficiency of 98.6% with a fluorescence quantum yield of 40% and an antenna effect of 29.9. We further demonstrated the use of this artificial light-harvesting system for quantifying miR-210 within cancer cells. The fluorescence intensity ratio of donor to acceptor is linearly related to the concentration of intercellular miR-210 in the range of 3.3–156 copies/cell. Such high sensitivity in intracellular detection of miR-210 using this artificial light-harvesting system offers a great opportunity and pathways for biological imaging and detection, and for the further creation of microRNA (miRNA) toolbox for quantitative epigenetics and personalized medicine.

Near-infrared (NIR) laser-induced phototherapy through NIR agents has demonstrated the great potential for cancer therapy. However, insufficient tumor killing due to the nonuniform heat or cytotoxic singlet oxygen ( 1 O 2 ) distribution over tumors from phototherapy results in tumor recurrence and inferior outcomes. To achieve high tumor killing efficacy, one of the solutions is to employ the combinational treatment of phototherapy with other modalities, especially with chemotherapeutic agents. In this paper, a simple and effective multimodal therapeutic system was designed via combining chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) to achieve the polytherapy of malignant glioma which is one of the most aggressive tumors in the brain. IR-780 (IR780) dye-labeled tube-forming peptoids (PepIR) were synthesized and self-assembled into crystalline nanotubes (PepIR nanotubes). These PepIR nanotubes showed an excellent efficacy for PDT/PTT because the IR780 photosensitizers were effectively packed and separated from each other within crystalline nanotubes by tuning IR780 density; thus, a self-quenching of these IR780 molecules was significantly reduced. Moreover, the efficient DOX loading achieved due to the nanotube large surface area contributed to an efficient and synergistic chemotherapy against glioma cells. Given the unique properties of peptoids and peptoid nanotubes, we believe that the developed multimodal DOX-loaded PepIR nanotubes in this work offer great promises for future glioma therapy in clinic.

Inspired by the formation of hierarchically structured natural biominerals (e.g., bone and tooth), various sequence-defined polymers have been synthesized and exploited for design and synthesis of functional hybrid materials. Here, we synthesized a series of organic-inorganic hybrid peptoids by using polyhedral oligomeric silsesquioxane (POSS) nanoclusters as side chains at a variety of backbone locations. We further demonstrated the use of these hybrid peptoids as sequence-defined building blocks to assemble a new class of programmable two-dimensional (2D) nanocrystals. They are highly stable and exhibit an enhanced mechanical property and electron scattering due to the incorporated POSS nanoclusters. By varying peptoid side-chain chemistry, we further demonstrated the precise displacement of a large variety of function groups within these 2D nanocrystals and developed a highly efficient aqueous light-harvesting system for live cell imaging. Because these 2D nanocrystals are biocompatible and highly programmable, we expect that they offer unique opportunities for applications.

Free-standing two-dimensional (2D) organic nanomaterials are highly attractive for biological applications because of their unique structural properties and high biocompatibility. Herein, we designed and synthesized a new class of highly bright and photostable membrane-mimetic 2D nanosheets from sequence-defined peptoids. These nanosheets exhibited high quantum yield and photostability as a result of the precise placement and ordering of dansyl dye molecules within crystalline nanosheets. We further showed the use of these nanosheets as biocompatible and programmable probes for live cell imaging and cell labeling. By programing these nanosheets with different surface charges, we achieved the enhanced lysosome escape of these nanosheets, showing their great potential as nanocarriers for the efficient intracellular delivery of macromolecular drugs.

During the past few decades, a variety of two-dimensional (2D) nanomaterials have been developed through molecular self-assembly. Among them, those assembled from sequence-defined polymers have received particular attention because they enable a programmable display of functional groups, including fluorescent dyes, on their surfaces for applications. On the other hand, due to fluorescence self-quenching, synthesis of 2D nanomaterials exhibiting high fluorescence quantum yields is a significant challenge. Herein, we design and synthesize peptoid-based crystalline 2D nanomembranes (2DNMs) as a biocompatible and programmable sensor for selectively and sensitively detecting H2S in live cells. This 2DNM sensor is assembled from peptoids covalently attached with H2S-responsive molecular probes. Compared with its amorphous controls, this crystalline 2DNM sensor exhibits a significantly stronger fluorescence intensity and a higher sensitivity as a result of long-range structural ordering and alignment of H2S-responsive molecular probes. By sonication-cutting these 2DNM sensors into a colloidal form in an aqueous solution, we further demonstrated the use of colloidal 2DNMs for detecting exogenous and endogenous H2S inside cells and targeted cell organelles. Because peptoids are biocompatible and peptoid-based 2DNMs are programmable, we expect that this class of 2DNM sensors offer great potential for detecting H2S in live cells and for investigating H2S-related diseases.

In article number 1902485, Chun-Long Chen, Yuehe Lin, and co-workers design and synthesize two types of peptoid nanotubes with precisely controlled functional groups for targeted tumor cell imaging and chem-photodynamic therapy by co-assembling ligand-tagged peptoid oligomers. These nanotubes are highly robust and show a high killing efficiency toward cancer cells by combining chemotherapy and photodynamic therapy.

Substantial progress has been made in applying nanotubes in biomedical applications such as bioimaging and drug delivery due to their unique architecture, characterized by very large internal surface areas and high aspect ratios. However, the biomedical applications of organic nanotubes, especially for those assembled from sequence-defined molecules, are very uncommon. In this paper, the synthesis of two new peptoid nanotubes (PepTs1 and PepTs2) is reported by using sequence-defined and ligand-tagged peptoids as building blocks. These nanotubes are highly robust due to sharing a similar structure to those of nontagged ones, and offer great potential to hold guest molecules for biomedical applications. The findings indicate that peptoid nanotubes loaded with doxorubicin drugs are promising candidates for targeted tumor cell imaging and chemo-photodynamic therapy.

Despite recent advances in the assembly of organic nanotubes, conferral of sequence-defined engineering and dynamic response characteristics to the tubules remains a challenge. Here we report a new family of highly designable and dynamic nanotubes assembled from sequence-defined peptoids through a unique “rolling-up and closure of nanosheet” mechanism. During the assembly process, amorphous spherical particles of amphiphilic peptoid oligomers crystallize to form well-defined nanosheets before folding to form single-walled nanotubes. These nanotubes undergo a pH-triggered, reversible contraction–expansion motion. By varying the number of hydrophobic residues of peptoids, we demonstrate tuning of nanotube wall thickness, diameter, and mechanical properties. Atomic force microscopy-based mechanical measurements show peptoid nanotubes are highly stiff (Young’s Modulus ~13–17 GPa). We further demonstrate the precise incorporation of functional groups within nanotubes and their applications in water decontamination and cellular adhesion and uptake. These nanotubes provide a robust platform for developing biomimetic materials tailored to specific applications.

Bortezomib is a boronate proteasome inhibitor widely used as an efficient anticancer drug; however, the clinical use of bortezomib is hampered by its adverse effects such as hematotoxicity and peripheral neuropathy, and low efficacy on solid tumors due to unfavorable pharmacokinetics and poor penetration in the solid tumors. In this study, we developed a tripeptide ArgGlyAsp (RGD)-targeted dendrimer conjugated with catechol and poly(ethylene glycol) groups for the targeted delivery of bortezomib to metastatic bone tumors. Bortezomib was loaded on the dendrimer via a boronatecatechol linkage with pH-responsive property, which plays an essential role in the control of bortezomib loading and release. The nontargeted bortezomib nanomedicine showed minimal cytotoxicity at pH 7.4, but significantly increased anticancer activity when cyclic RGD (cRGD) moieties were anchored on the dendrimer surface. The ligand cRGD enabled efficient internalization of the bortezomib complex by breast cancer cells such as MDA-MB-231 cells. The targeted nanomedicine efficiently depressed the progression of metastatic bone tumors and significantly inhibited the tumor-associated osteolysis in a model of bone tumors. This study provided an insight into the development of nanomedicine for metastatic bone tumors.

The design and synthesis of biocompatible nanomaterials as cargoes for the intracellular delivery of therapeutic proteins or genes have attracted intense attention because of their potential for use in therapeutics. Despite the advances in this area, very few nanomaterials can be efficiently delivered to the cytosol. To address these challenges, crystalline nanoflower-like particles are designed and synthesized from fluorinated sequence-defined peptoids; the crystallinity and fluorination of these particles enable highly efficient cytosolic delivery with minimal cytotoxicity. A cytosol delivery rate of 80% has been achieved for the fluorinated peptoid nanoflowers. Furthermore, these nanocrystals can carry therapeutic genes, such as mRNA and effectively deliver the payload into the cytosol, demonstrating the universal delivery capability of the nanocrystals. The results indicate that self-assembly of crystalline nanomaterials from fluorinated peptoids paves a new way toward development of nanocargoes with efficient cytosolic gene delivery capability.

Fluorinated dendrimers have shown great promise in gene delivery due to their high transfection efficacy and low cytotoxicity, however, the structure-activity relationships of these polymers still remain unknown. Herein, we synthesized a library of fluorinated dendrimers with different dendrimer generations and fluorination degrees and investigated their behaviors in both DNA and siRNA delivery. The results show that fluorination significantly improves the transfection efficacy of G4-G7 polyamidoamine dendrimers in DNA and siRNA delivery. Fluorination on generation 5 dendrimer yields the most efficient polymers in gene delivery, and the transfection efficacy of fluorinated dendrimers depends on fluorination degree. All the fluorinated dendrimers cause minimal toxicity on the transfected cells at their optimal transfection conditions. This study provides a general and facile strategy to prepare high efficient and low cytotoxic gene carriers based on fluorinated polymers.Statement of SignificanceThe structure-activity relationships of fluorinated dendrimers in gene delivery is still unknown and the behavior of fluorinated dendrimers in siRNA delivery has not yet been investigated. Herein, we synthesized a library of fluorinated PAMAM dendrimers with different dendrimer generations and fluorination degrees and investigated their behaviors in both DNA and siRNA delivery. The results clearly indicate that fluorination significantly improves the transfection efficacy of dendrimers in both DNA and siRNA delivery without causing additional toxicity. G5 PAMAM dendrimer is best scaffold to synthesize fluorinated dendrimers and the transfection efficacy of fluorinated dendrimers depends on fluorination degree. This systematic study provides a general and facile strategy to prepare high efficient and low cytotoxic gene carriers based on fluorinated polymers. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The transfection of tumor necrosis factor-related apoptosis-inducing ligand gene by using fluorinated dendrimer is highly efficient and low toxic, resulting in efficient killing of cancer cells in vitro and suppressing tumor growth in vivo.

Intracellular siRNA release is a crucial step in efficient gene silencing mediated by cationic polymers. Here, we show an example of temperature change-induced intracellular siRNA release and silencing using a temperature-responsive polymer consisting of dendrimer, poly(N-isopropylacrylamide) and phenylboronic acid. The smart polymer can trigger the release of loaded siRNA in a controlled manner upon cooling the surrounding solution below its lower critical solution temperature. Gene silencing efficacy of the polymer was significantly increased by cool treatment after its cellular uptake. The polymer and the cool treatment cause minimal toxicity to the transfected cells. The results provide a facile and promising strategy to design stimuli-responsive polymers for efficient gene silencing.

Polyethylenimine (PEI) is one of the most promising polymeric gene vectors, however its applications are limited by serious cytotoxicity and moderate transfection efficacy. Fluorination is an efficient strategy to improve the transfection efficacy of cationic polymers while reducing their cytotoxicity. Here we grafted different fluoroalkyl chains to PEI via oxirane and anhydride reactions. The fluorinated PEIs show superior transfection efficacy on both 2D and 3D cell cultures to unmodified PEI. These fluorinated polymers allow efficient gene transfection at relatively low nitrogen to phosphorus ratios and thereby ensure low cytotoxicity on the transfected cells. Fluorinated PEIs prepared via the oxirane reaction are much more stable in aqueous solutions than the ones prepared by the anhydride reaction and show reproducible gene transfection during a period of 6 months. This study extends the applicable scope of fluorination on improving the transfection efficacy of polymers and generates a list of gene vectors for efficient 2D and 3D cell culture gene transfection.

A nanoparticle with a specific response to tumor extracellular acidity provides a new option in the design of tumor-targeted delivery systems. In this study, we report such a pH-responsive polymer which realizes an "off-on" release of bortezomib in tumor acidic microenvironments. A dendrimer surface is grafted with a neutral shell to reduce its cellular uptake, and its interior is functionalized with catechol moieties. An anticancer drug, bortezomib, is loaded within the dendrimer interior via a boronate-catechol interaction. The bortezomib-loaded dendrimer is non-toxic to a number of cells under physiological conditions, but kills most of the cells in slightly acidic microenvironments. In vivo studies further prove that the bortezomib-loaded dendrimer significantly inhibits tumor growth while causing minimal systemic toxicity to the animals. Since there are a number of potent anticancer drugs containing the boronate structure, the polymeric vector in this study provides a versatile scaffold to design pH-responsive drug carriers for chemotherapy.

Cationic dendrimers are widely used as gene vectors; however, these materials are usually associated with unsatisfied transfection efficiency and biocompatibility. In this study, we used an aliphatic hydrocarbon-cored polyamidoamine (PAMAM) dendrimer as an alternative to traditional cationic PAMAM dendrimers in the design of efficient gene vectors. Diaminododecane-cored generation 4 (C12G4) PAMAM dendrimer showed dramatically higher efficacy in luciferase and EGFP gene transfection than diaminoethane-cored generation 4 (C2G4) and diaminohexane-cored generation 4 (C6G4) PAMAM dendrimers. The viability of cells incubated with C12G4 at transfection concentrations is above 90%. The significantly improved gene transfection efficacy of C12G4 is attributed to the hydrophobic core of C12G4 which increases the cellular uptake of dendrimer/DNA polyplexes. Further modification of C12G4 with functional ligands such as arginine, 2,4-diamino-1,3,5-triazine, and fluorine compounds significantly increase its transfection efficiency on several cell lines. These results suggest that diaminododecane-cored dendrimers can be developed as a versatile scaffold in the design of efficient gene vectors.

The use of poly(propylenimine) (PPI) dendrimers as gene delivery vectors is limited by their low transfection efficacy and serious cytotoxicity. In this study, we prepare a series of efficient and low cytotoxic gene vectors based on PPI dendrimers using a facile fluorination strategy. Fluorinated G3, G4, and G5 PPI dendrimers show comparable or superior transfection efficacies to six representative transfection reagents such as Lipofectamine 2000, jetPEI, branched poly(ethyleneimine), SuperFect, PolyFect, as well as arginine-modified dendrimer on both HEK293 and HeLa cells. These fluorinated PPI dendrimers exhibit low cytotoxicity on the transfected cells because they achieve optimal transfection efficacy at extremely low nitrogen to phosphorus (N/P) ratios. In addition, the synthesized materials show high transfection efficacy on 3D multicellular spheroids. These results demonstrate that fluorination is a promising strategy to improve the transfection efficacy of PPI dendrimers while reducing the cytotoxicity of these cationic polymers.