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Along with the celebration of the new year, we celebrate many successes at Bioconjugate Chemistry. This includes additions and renewal of our editors, who play a critical role in service to our research community of authors, reviewers, and readers. As highlighted in our January 2023 editorial, (1) we sincerely thank Prof. Vince Rotello, who stepped down after a decade of success as Editor-in-Chief. We also extend a sincere thank you to Prof. Bradley Smith, who also stepped down after 10 years of service as Associate Editor for the journal. With great enthusiasm, we introduce the 2023 editorial team at Bioconjugate Chemistry, which includes five new additions to the editorial staff: Prof. Gonçalo Bernardes from the University of Cambridge, Prof. Peng Zou, from the Peking University, Mr. Nathan Quinn and Dr. Christina MacLaughlin from ACS Publications, and Prof. Theresa Reineke from the University of Minnesota. We also introduce and celebrate the team of four editors that are continuing in dedicated service to our community and ACS Publications: Prof. Zhifei Dai from Peking University, Prof. Jan van Hest from Eindhoven University of Technology, Prof. Erin Lavik from the University of Maryland Baltimore Country, and Prof. Gang Zheng from the University of Toronto. We wish our entire scientific community a happy, healthy, and productive 2023 and look forward to working with you all to disseminate many exciting advances in Bioconjugate Chemistry.

Family of levoglucosan-derived renewable networks via UV-initiated thiol–ene click chemistry with tailorable properties for 3D printing of hydrolytically degradable parts.

We demonstrate computational insight and radical ring opening polymerization of a fungi-derived thionolactone, thionoisochromanone (TIC), to create homo-, block-, and statistical copolymers under entirely free radical conditions.

Antisense oligonucleotides (ASOs) are an important emerging therapeutic; however, they struggle to enter cells without a delivery vehicle, such as a cationic polymer. To understand the role of polymer architecture for ASO delivery, five linear polymers and five diblock polymers (capable of self-assembly into micelles) were synthesized with varying cationic groups. After complexation of each polymer/micelle with ASO, it was found that less bulky cationic moieties transfected the ASO more effectively. Interestingly, however the ASO internalization trend was the opposite of the transfection trend for cationic moiety, indicating internalization is not the major factor in determining transfection efficiency for this series. Micelleplexes (micelle-ASO complexes) generally enable higher transfection efficacy as compared to polyplexes (linear polymer-ASO complexes). Additionally, the order of addition of cells and complexes was explored. Linear polyplexes showed better transfection efficiency in adhered cells, whereas micelleplexes delivered the ASO more efficiently when the cells and micelleplexes were added simultaneously. This phenomenon may be due to increased cell-complex interactions as micelleplexes have increased colloidal stability compared to polyplexes. These findings emphasize the importance of polymer composition and architecture in governing the cellular interactions necessary for transfection, thus allowing advancement in the design principles for nonviral nucleic acid delivery formulations.

The bacterial cell envelope provides a protective barrier that is challenging for small molecules and biomolecules to cross. Given the anionic nature of both Gram-positive and Gramnegative bacterial cell envelopes, negatively charged molecules are particularly difficult to deliver into these organisms. Many strategies have been employed to penetrate bacteria ranging from reagents such as cell-penetrating peptides, enzymes, and metal-chelating compounds, to physical perturbations. While cationic polymers are known antimicrobial agents, their ability to permeabilize bacterial cells without causing high levels of toxicity and cell lysis has not been demonstrated. Here, we evaluate the ability of four cationic polymers, two linear and two micellar (from self-assembled amphiphilic block copolymers), to facilitate the internalization of an anionic ATP-based chemical probe intoEscherichia coliandBacillus subtilis. Not only did we observe the permeabilization of these organisms, but also found that labeled cells were able to continue to grow and divide. In particular, the micelle-based polymers yielded effective internalization of the negatively charged chemical probe better than their linear analogues.

Transforming how plastics are made, unmade, and remade through innovative research and diverse partnerships that together foster environmental stewardship is critically important to a sustainable future. Designing, preparing, and implementing polymers derived from renewable resources for a wide range of advanced applications that promote future economic development, energy efficiency, and environmental sustainability are all central to these efforts. In this

We demonstrate the facile synthesis and characterization of stereoregular polysaccharides from the biomass-derived platform molecule levoglucosan via metal-triflate mediated cationic-ring opening polymerization.

The incorporation of renewable feedstocks into polymer backbones is of great importance in modern polymer science. We report the synthesis of 1,3-diyne polymers derived from the bispropargyl ethers of isosorbide, isomannide, and isoidide. The dialkyne monomers can be polymerized through an adaptation of the Glaser-Hay coupling using a nickel(II) cocatalyst. These well-defined diyne polymers bear an iodoalkyne end group, afforded through an unanticipated reductive elimination pathway, and display glass transition temperatures (

Cationic polymer vehicles have emerged as promising platforms for nucleic acid delivery because of their scalability, biocompatibility, and chemical versatility. Advancements in synthetic polymer chemistry allow us to precisely tune chemical functionality with various macromolecular architectures to increase the efficacy of nonviral-based gene delivery. Herein, we demonstrate the first cationic bottlebrush polymer-mediated pDNA delivery by comparing unimolecular, synthetically defined bottlebrush polymers to their linear building blocks. We successfully synthesized poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA) bottlebrushes through ring-opening metathesis polymerization to afford four bottlebrush polymers with systematic increases in backbone degree of polymerization (

Responsive polymers with properties designed to interact with their surrounding environment are enabling “smart” design features for custom biomaterials. Numerous applications are being innovated, ranging from diagnostics and imaging to tissue engineering and drug delivery. Herein, I feature a collection of research articles published in ACS Macro Letters that highlight an array of innovative chemical attributes such as pH-triggered hydrolytic degradation, reduction-based release, photomodulation, glucose responsiveness, thermal sensitivity, and membrane permeating peptides. The chemical, physical, mechanical, and morphological properties of polymeric structures can be custom tailored to enhance numerous features such as biological delivery, pharmaceutical potency and safety, disease diagnosis, and antigen/biomaker detection.

The advent of genome editing has transformed the therapeutic landscape for several debilitating diseases, and the clinical outlook for gene therapeutics has never been more promising. The therapeutic potential of nucleic acids has been limited by a reliance on engineered viral vectors for delivery. Chemically defined polymers can remediate technological, regulatory, and clinical challenges associated with viral modes of gene delivery. Because of their scalability, versatility, and exquisite tunability, polymers are ideal biomaterial platforms for delivering nucleic acid payloads efficiently while minimizing immune response and cellular toxicity. While polymeric gene delivery has progressed significantly in the past four decades, clinical translation of polymeric vehicles faces several formidable challenges. The aim of our Account is to illustrate diverse concepts in designing polymeric vectors towards meeting therapeutic goals of in vivo and ex vivo gene therapy. Here, we highlight several classes of polymers employed in gene delivery and summarize the recent work on understanding the contributions of chemical and architectural design parameters. We touch upon characterization methods used to visualize and understand events transpiring at the interfaces between polymer, nucleic acids, and the physiological environment. We conclude that interdisciplinary approaches and methodologies motivated by fundamental questions are key to designing high-performing polymeric vehicles for gene therapy.

The development of tunable and degradable crosslinked-polyanhydride networks from renewably derived itaconic anhydrides and multifunctional thiols is presented. Itaconic acid was initially converted to ethyl itaconic anhydride and isoamyl itaconic anhydride via a two-step synthetic procedure on hundred-gram scale with minimal purification. Dinorbornene-functionalized derivatives were prepared via cycloaddition chemistry, and photoinitiated thiol–ene polymerization reactions were explored using commercially available tetra- and hexa-functional thiols, all using solvent-free syntheses. The thiol–ene reaction kinetics of different monomer compositions were characterized by real-time Fourier transform infrared (RT-FTIR) spectroscopy, with the norbornene functionalized derivatives exhibiting the highest reactivity towards thiol–ene photopolymerizations. The thermal and mechanical characteristics of the thermosets were analyzed and the viscoelastic behavior was investigated by dynamic mechanical analysis to understand the influence of the ester functionality and choice of crosslinker on the material properties. The anhydride backbone was found to be susceptible to controlled degradation under physiologically-(phosphate-buffered saline) and environmentally-relevant (artificial seawater) testing conditions over a period of 60 days at 50 °C. This work demonstrates that itaconic acid may be a useful feedstock in the generation of degradable polyanhydride networks via thiol–ene photopolymerization.

We report here the synthesis and polymerization of a novel disubstituted valerolactone, β-acetoxy-δ-methylvalerolactone, derived from the renewable feedstock triacetic acid lactone (TAL). The bulk polymerization proceeds to 45% equilibrium monomer conversion at room temperature using diphenyl phosphate as the organic catalyst. The resultant amorphous material displays a glass transition temperature of 25 °C. The ring opening polymerization (ROP) behavior of the disubstituted valerolactone was examined, and the enthalpy () and entropy *() of polymerization were calculated to be −25 ± 2 kJ mol−1 and −81 ± 5 mol−1 K−1, respectively. The polymerization kinetics were also measured and compared to those of other substituted valerolactones reported in the literature. This report is the first to demonstrate the successful ROP of a disubstituted valerolactone as well as the first to establish the ROP of a derivative of TAL.

3D printing is an essential tool for rapid prototyping in a variety of sectors such as automotive and public health. The 3D printing market is booming, and it is projected that it will continue to thrive in the coming years. Unfortunately, this rapid growth has led to an alarming increase in the amount of 3D printed plastic waste. 3D printing processes such as stereolithography (SLA) and digital light projection (DLP) in particular generally produce petroleum-based thermosets that are further worsening the plastic pollution problem. To mitigate this 3D printed plastic waste, sustainable alternatives to current 3D printing materials must be developed. The present review provides a comprehensive overview of the sustainable advances in SLA/DLP 3D printing to date and offers a perspective on future directions to improve sustainability in this field. The entire life cycle of 3D printed parts has been assessed by considering the feedstock selection and the end-of-use of the material. The feedstock selection section details how renewable feedstocks (from lignocellulosic biomass, oils, and animal products) or waste feedstocks (e.g., waste cooking oil) have been used to develop SLA/DLP resins. The end-of-use section describes how materials can be reprocessed (e.g. thermoplastic materials or covalent adaptable networks) or degraded (through enzymatic or acid/base hydrolysis of sensitive linkages) after end-of-use. In addition, studies that have employed green chemistry principles in their resin synthesis and/or have shown their sustainable 3D printed parts to have mechanical properties comparable to commercial materials have been highlighted. This review also investigates how aspects of sustainability such as recycling for feedstock/end-of-use or biodegradation of 3D printed parts in natural environments can be incorporated as future research directions in SLA/DLP.

The ability to design liver-targeted polymers for nucleic acid delivery vehicles is plagued with difficulties ranging from polymer-mediated cellular toxicity to challenges in synthesizing monomers that enable facile cell-specific polymeric gene delivery vehicles. Herein is presented an improved synthetic route to a N-acetyl-D-galactosamine (GalNAc)-derived monomer (two steps, 91% overall yield) and its incorporation into a library of nine diblock co-polymers with 2-aminoethylmethacrylamide (AEMA) and two end-group functionalized AEMA homopolymers. These polymers were complexed with plasmid DNA (pDNA) into polyplexes and evaluated for the toxicity, uptake and transfection efficiency against cultured hepatocytes (HepG2) at N/P ratios of 2.5, 5, and 10. All polyplexes showed a range of cell survivability between 60–90%, an improvement over JetPEI, a commercial transfection reagent, when dosed at standard concentrations. Although GalNAc block length does not play a significant role in cellular uptake of Cy-5 labeled pDNA, it has a heavy influence on the transfection efficiency of luciferase-encoded pDNA where longer GalNAc block lengths give rise to higher transfection efficiencies. Overall, this work demonstrates a greatly improved route to GalNAc monomer synthesis, which that can be incorporated into polymers that target hepatocytes.

Polymerization reaction media can have a profound effect on the physical properties of the resultant polymer. This phenomenon is showcased in a new experiment for the organic chemistry and polymer science teaching laboratories wherein the radical copolymerization of biobased β-myrcene and dibutyl itaconate is performed using a nonhazardous aqueous emulsion solvent and compared to a bulk reaction. Both procedures demonstrate multiple green chemistry principles and application to sustainable polymer synthesis. The emulsion copolymerization produces a tacky, elastomeric cross-linked material, capable of swelling to many times its original volume in organic solvents, setting the stage for the exploration of the relationship between solvent polarity and swelling capacity. Conversely, the polymerization of β-myrcene and dibutyl itaconate in the bulk yields a viscous non-cross-linked polymer whose 1H NMR spectrum is suitable for student analysis and estimation of polymer number-average molar mass (Mn), monomer conversion, and copolymer composition. This inexpensive experiment models the use of renewable feedstocks, the effect of reaction medium on polymer architecture, the unique properties of cross-linked organogels, and the quantitative analysis of polymer structure using 1H NMR spectroscopy.

Significance Polymer-based vehicles that controllably deliver therapeutic nucleic acids to cells show great potential to develop safe and effective gene therapies. Realizing this potential, however, is limited by the lack of understanding of how polymers unpackage their cargo. We developed a quinine-containing polymer that shows exceptional gene delivery activity. A key aspect of this platform is that the quinine serves as a reporter for DNA binding using Raman spectroscopy. This allows us to track cargo release inside the cell using Raman chemical imaging. We find that proteins dominate the unpackaging of DNA encapsulated by these quinine polymers inside cells. This trackable delivery system should be broadly applicable to study nucleic acid delivery mechanisms and to be used for clinical therapy applications., Polymeric vehicles that efficiently package and controllably release nucleic acids enable the development of safer and more efficacious strategies in genetic and polynucleotide therapies. Developing delivery platforms that endogenously monitor the molecular interactions, which facilitate binding and release of nucleic acids in cells, would aid in the rational design of more effective vectors for clinical applications. Here, we report the facile synthesis of a copolymer containing quinine and 2-hydroxyethyl acrylate that effectively compacts plasmid DNA (pDNA) through electrostatic binding and intercalation. This polymer system poly(quinine-co-HEA) packages pDNA and shows exceptional cellular internalization, transgene expression, and low cytotoxicity compared to commercial controls for several human cell lines, including HeLa, HEK 293T, K562, and keratinocytes (N/TERTs). Using quinine as an endogenous reporter for pDNA intercalation, Raman imaging revealed that proteins inside cells facilitate the unpackaging of polymer–DNA complexes (polyplexes) and the release of their cargo. Our work showcases the ability of this quinine copolymer reporter to not only facilitate effective gene delivery but also enable diagnostic monitoring of polymer–pDNA binding interactions on the molecular scale via Raman imaging. The use of Raman chemical imaging in the field of gene delivery yields unprecedented insight into the unpackaging behavior of polyplexes in cells and provides a methodology to assess and design more efficient delivery vehicles for gene-based therapies.

We investigate the use of in situ enzyme degassing to facilitate the open-to-air reversible addition–fragmentation chain transfer (RAFT) polymerization of hydroxyethyl acrylate (HEA) in a wide range of complex aqueous solvents, including, beer, wine, liquor, and fermentation broth. This enzyme-assisted polymerization procedure is impressively robust, and poly(HEA) was attained with good control over molecular weight and a narrow dispersity in nearly all of the solvents tested. Kinetics experiments on HEA polymerization in whisky and spectroscopic analysis of the purified polymers suggest high end-group fidelity, as does the successful chain extension of a poly(HEA) macro chain transfer agent with narrow dispersity. These results suggest enzyme-assisted RAFT may be a powerful and underutilized tool for high-throughput screening and materials discovery and may simplify the synthesis of well-defined polymers in complex conditions.

A comprehensive approach to target exact molecular weights and chemical compositions for multimonomeric statistical copolymers using a new controlled statistics method with reversible addition-fragmentation chain transfer free-radical (RAFT) polymerization is presented. The system chosen to illustrate this procedure is an acrylic quarterpolymer consisting of methyl acrylate, 2-carboxyethyl acrylate, 2-hydroxypropyl acrylate, and 2-propylacetyl acrylate, modeling a well-known macromolecule utilized to deliver poorly water-soluble drugs (hydroxypropyl methylcellulose acetate succinate, HPMCAS). The relative reactivities at 70 °C between monomer pairs were measured and employed to predict the feed ratio necessary for synthesizing well-defined compositions based on the Walling-Briggs model. Application of Skeist's equations addressed compositional drift and anticipated the general monomer incorporation distribution as a function of conversion, which was verified experimentally. This new and simple paradigm combining both predictive models provides complementary synthetic and predictive tools for designing macromolecular chemical architectures with hierarchical control over spatially dependent structure-property relationships for complex applications such as oral drug delivery.

Herein, we demonstrate the reversible addition–fragmentation chain transfer (RAFT) synthesis of an adamantane-conjugated glycopolymer, poly(2-methacrylamido-2-deoxy glucopyranose) (Ad-pMAG), as a hydrophilic coating to promote colloidal stability of click cluster-pDNA complexes in biological media. The Ad-pMAG is assembled via noncovalent interactions through inclusion complex formation between adamantane (Ad) and the β-cyclodextrin (βCD) core of the click cluster/pDNA and then further assembled with plasmid DNA to form polyplexes. Ad-pMAG incorporation was favorable over Ad-poly(ethylene glycol) (Ad-PEG) due to the enhanced colloidal stability of the click cluster/pDNA polyplex under physiological salt conditions at high N/P ratios. Interestingly, the uptake and reporter gene expression with polyplexes coated with the Ad-pMAG was much lower in HeLa cells than that observed with two glioma cell lines (U87 and U251 cells) in vitro, possibly indicating some delivery specificity.

Using the glucose derivatives isosorbide and glucarodilactone along with a castor oil derivative, 10-undecenoyl chloride, two monomers were synthesized: glucarodilactone undecenoate (GDLU) and isosorbide undecenoate (IU). These monomers were polymerized via acyclic diene metathesis (ADMET) polymerization to yield two homopolymers, P(GDLU) and P(IU), and two copolymers, P1(GDLU-co-IU) and P2(GDLU-co-IU), of similar number-averaged molecular weight and relative composition (51 and 61 kDa, Đ = 1.8 and 1.4, 46:54 and 52:48 mol percent). Comparison of the physical properties and degradation behavior of these polymers revealed divergent characteristics arising from differences in the nature of the carbohydrate building blocks. P(IU) is more thermally stable and has a lower glass transition temperature (Td = 369 °C, Tg = −10 °C) than P(GDLU) (Td = 206 °C, Tg = 32 °C) and P1,2(GDLU-co-IU) (Td = 210 and 203 °C, Tg = 1 and 7 °C). While all of the polymers were stable in acidic and neutral aqueous conditions, the tw...

The quantity of free polymer in a polymer/DNA complex (polyplex) formulation critically impacts its gene transfection efficiency, cellular uptake, and toxicity. In this study, the compositions of three interpolyelectrolyte polyplex formulations were quantified by a facile NMR method. Using careful integration of a 1D 1H NMR spectrum with a broad spectral width, the quantities of unbound polymer and polyplexes in solution were determined. Linear polyethyleneimine (PEI) mixed with DNA at polymer amine to DNA phosphate molar ratio (N/P ratio) of 5 revealed an effective binding N/P ratio of 3.5 without excess free polymer. This result is in strong agreement with the stoichiometric number of PEI/DNA binding obtained by isothermal titration calorimetry. The noninvasive nature of this method allows broad application to a range of polyelectrolyte coacervates, opening new opportunities for understanding and optimizing polyelectrolyte complex formation and providing quantitation of complex formation in a single mea...

Two renewable, structurally analogous monomers, isosorbide undecenoate (IU) and glucarodilactone undecenoate (GDLU) reacted with pentaerythritol tetrakis(3-mercaptopropionate) (PETT) via thiol-ene photopolymerization to form IU-PETT and GDLU-PETT thermosets. Despite their chemical similarity, uniaxial tensile testing showed that GDLU-PETT exhibited a strain-hardening behavior and is significantly tougher than IU-PETT. To understand this observation, in situ tensile testing and wide-angle X-ray scattering experiments (WAXS) were conducted. While the 2D WAXS patterns of IU-PETT displayed an isotropic halo during uniaxial deformation, they exhibited a change from an isotropic halo to a pair of scattering arcs for the GDLU-PETT samples. Density functional theory calculations further revealed that the GDLU alkyl chains are less angled than the IU alkyl chains. Based on these results, we postulate that the GDLU molecules can more easily order and align during uniaxial deformation, hence increasing intermolecular interactions between the GDLU molecules and contributing to the observed strain hardening behavior of their thermosets. This study exemplifies how molecules with subtle differences in their chemical structures can alter the structures and thermophysical properties of the resulting polymers in unpredictable ways.

Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver hydrophobic small molecule actives. To this end, we synthesized a poly(N-isopropylacrylamide...

We report the rapid, one-pot synthesis of functional polycarbonates derived from renewable alcohols (i.e., glucose tetraacetate, acetyl isosorbide, lauryl alcohol, and ethanol) and a cyclic carbonate bearing an imidazolecarboxylate. This tandem functionalization/ring-opening polymerization strategy can be performed on multigram scale and eliminates the need for rigorous purification and specialized equipment. A wide range of glass transition temperatures (

Exchange of deuterium (D) for hydrogen (H) on polyolefins enabled by heterogeneous catalysts is a versatile and relatively inexpensive technique to obtain matched pairs of isotopically labeled and ...

A method for the development of ABA triblock copolymers for high-performance pressure-sensitive adhesives from the biorenewable chemicals lauryl acrylate and triacetic acid lactone (TAL) is present...

The improvement of nonviral gene therapies relies to a large extent on understanding many fundamental physical and biological properties of these systems. This includes interactions of synthetic delivery systems with the cell and mechanisms of trafficking delivery vehicles, which remain poorly understood on both the extra- and intracellular levels. In this study, the mechanisms of cellular internalization and trafficking of polymer-based nanoparticle complexes consisting of polycations and nucleic acids, termed polyplexes, have been observed in detail at the cellular level. For the first time evidence has been obtained that filopodia, actin projections that radiate out from the surface of cells, serve as a route for the direct endocytosis of polyplexes. Confocal microscopy images demonstrated that filopodia on HeLa cells detect external polyplexes and extend into the extracellular milieu to internalize these particles. Polyplexes are observed to be internalized into membrane-bound vesicles (i.e., clathrin-coated pits and caveolae) directly within filopodial projections and are subsequently transported along actin to the main cell body for potential delivery of the nucleic acids to the nucleus. The kinetics and speed of polyplex trafficking have also been measured. The polyplex-loaded vesicles were also discovered to traffic between two cells within filopodial bridges. These findings provide novel insight into the early events of cellular contact with polyplexes through filopodial-based interactions in addition to endocytic vesicle trafficking-an important fundamental discovery to enable advancement of nonviral gene editing, nucleic acid therapies, and biomedical materials.

The solid state and fluxional behaviors in solution of complexes L2AlOBn and L7AlOBn (Bn = benzyl) supported by an analog of salen incorporating indolide arms connected via their 2- and 7-positions...

Methylcellulose (MC) is a water-soluble cellulose derivative with a wide range of commercial applications. Upon heating, MC solutions reversibly form ∼15–20 nm diameter fibrils, which percolate int...

A linear, methacrylamide polymer affinity agent was explored to capture two mycotoxins, deoxynivalenol (DON) and ochratoxin A (OTA), for multiplex surface-enhanced Raman scattering (SERS) detection. These mycotoxins are naturally occurring small molecules from fungi that can be dangerous at low concentrations. SERS detection was completed for each polymer-toxin complex at concentrations relevant to current safety regulation by the FDA: 1 ppm for DON and 5 ppb for OTA. Visibly distinguishable vibrational modes were observed in the multiplex spectra that were attributed to each mycotoxin individually, thus, not requiring any additional chemometric analysis. Density functional theory (DFT) was used to model DON and OTA to accurately label the vibrational modes in the experimental spectra as well as provide insight on the binding between both targets and the affinity agent. Fully modeled vibrations of these toxins are novel contributions due to OTA never being modeled and only a few published vibrational modes of DON. DFT guides empirical observations regarding hydrogen bonding at multiple sites of each mycotoxin target molecule through the amine groups on the polymer, confirming the capabilities of a single polymer affinity agent to facilitate multiplex detection of a class of molecules through less-specific interactions than traditional affinity agents.

Recessive dystrophic epidermolysis bullosa (RDEB), an inherited disease featuring blistering wounds, causes constant inflammation that leads to the eventual development of an aggressive form of squamous cell carcinoma (RDEB SCC). The persistence of inflammatory chemokines such as MCP-1 and Il-8 in RDEB wounds may foster RDEB SCC carcinogenesis. We report the production of ternary composite nanofibers containing pullulan, chondroitin sulfate, and tannic acid as RDEB wound dressings. The swellable fibers are stable to hydration and absorb ∼500% their weight in water. The fibers remove ∼99% of MCP-1 from solution in

We report the facile synthesis and characterization of 1,6-α linked functional stereoregular polysaccharides from biomass-derived levoglucosan

The development of polymers that can replace engineered viral vectors in clinical gene therapy has proven elusive despite the vast portfolios of multifunctional polymers generated by advances in polymer synthesis. Functional delivery of payloads such as plasmids (pDNA) and ribonucleoproteins (RNP) to various cellular populations and tissue types requires design precision. Here, we systematically screen a combinatorially designed library of 43 well-defined polymers, ultimately identifying a lead polycationic vehicle (P38) for efficient pDNA delivery. Further, we demonstrate the versatility of P38 in co-delivering spCas9 RNP and pDNA payloads to mediate homology directed repair as well as in facilitating efficient pDNA delivery in ARPE-19 cells. P38 achieves nuclear import of pDNA and eludes lysosomal processing far more effectively than a structural analog that does not deliver pDNA as efficiently. To reveal the physicochemical drivers of P38's gene delivery performance, SHapley Additive exPlanations (SHAP) are computed for nine polyplex features, and a causal model is applied to evaluate the average treatment effect of the most important features selected by SHAP. Our machine learning interpretability and causal inference approach derives structure-function relationships underlying delivery efficiency, polyplex uptake, and cellular viability, and probes the overlap in polymer design criteria between RNP and pDNA payloads. Together, combinatorial polymer synthesis, parallelized biological screening, and machine learning establish that pDNA delivery demands careful tuning of polycation protonation equilibria while RNP payloads are delivered most efficaciously by polymers that deprotonate cooperatively via hydrophobic interactions. These payload-specific design guidelines will inform further design of bespoke polymers for specific therapeutic contexts.

Correction for ‘Sustainable advances in SLA/DLP 3D printing materials and processes’ by Erin M. Maines et al., Green Chem., 2021, 23, 6863–6897, DOI: 10.1039/D1GC01489G.

Gene editing with CRISPR/Cas9 is revolutionizing biotechnology and medical research, yet affordable, efficient, and tailorable delivery systems are urgently needed to advance translation. Herein, a...

Amorphous solid dispersions of polymers and drugs have been shown to improve supersaturation maintenance of poorly water-soluble drugs. Herein, amorphous spray-dried dispersions (SDDs) of poly(acrylic acid)-polystyrene (PS

Methylcellulose (MC) is widely used as a rheology modifier because, upon heating in aqueous solutions, MC reversibly self-assembles into ∼7–10 nm radius fibrils that percolate into a network, resulting in physical gelation. Here, we have chemically cross-linked both MC solutions at room temperature and MC physical fibril gels at 80 °C and compared the swelling and shear modulus properties of both materials. To achieve this, hydroxyl moieties on MC (Mw ≈ 150 kDa) were substituted with allyl groups, with a degree of substitution of about one pendant carbon–carbon double bond per nine anhydroglucose repeat units. The allyl groups undergo cross-linking in the presence of a photoinitiator and UV light. Chemically cross-linking MC fibril gels (“xfib-MC”) at 80 °C results in opaque solid materials and locks in the fibril structure, which persists even on cooling back to room temperature. From small-angle X-ray scattering analysis, the fibril radius is larger at room temperature ∼20 nm and decreases to ∼10 nm at ...

Carbohydrate-derived monomers were synthesized, and thiol–ene photopolymerization was employed to produce thermoset films and fibers from the biobased dienes isosorbide 10-undecenoate (IU) and glucarodilactone 10-undecenoate (GDLU) and multifunctional thiols. The resulting materials, comprising up to 94% biorenewable content, were flexible and cross-linked and had mechanical and thermal properties that varied with IU and GDLU content (e.g., rubbery plateau storage moduli = 6.1 to 10.5 MPa at 40 °C above the glass transition temperature; glass transition temperatures = −9.9 to 27 °C by differential scanning calorimetry; degradation temperatures = 238 to 347 °C by thermogravimetric analysis). By combining electrospinning with in-situ UV irradiation and carefully controlling the monomer mixture viscoelasticity and orifice-to-collector flight time, we produced uniformly cured fibers directly from the monomer feed when the ene monomers contained either 100% GDLU or 50% GDLU/50% IU. The resulting GDLU-containin...

Cellular delivery of biomacromolecules is vital to medical research and therapeutic development. Cationic polymers are promising and affordable candidate vehicles for these precious payloads. However, the impact of polycation architecture and solution assembly on the biological mechanisms and efficacy of these vehicles has not been clearly defined. In this study, four polymers containing the same cationic poly(2-(dimethylamino)ethyl methacrylate) (D) block but placed in different architectures have been synthesized, characterized, and compared for cargo binding and biological performance. The D homopolymer and its diblock copolymer poly(ethylene glycol)-block-poly(2-(dimethylamino) ethyl methacrylate) (OD) readily encapsulate pDNA to form polyplexes. Two amphiphilic block polymer variants, poly(2-(dimethylamino)ethyl methacrylate)-block-poly(n-butyl methacrylate) (DB) and poly(ethylene glycol)-block-poly(2-(dimethylamino)ethyl methacrylate)-block-poly(n-butyl methacrylate) (ODB), self-assemble into micelles, which template pDNA winding around the cationic corona to form micelleplexes. Micelleplexes were found to have superior delivery efficiency compared to polyplexes and detailed physicochemical and biological characterizations were performed to pinpoint the mechanisms by testing hypotheses related to cellular internalization, intracellular trafficking, and pDNA unpackaging. For the first time, we find that the higher concentration of amines housed in micelleplexes stimulates both cellular internalization and potential endosomal escape, and the physical motif of pDNA winding into micelleplexes, reminiscent of DNA compaction by histones in chromatin, preserves the pDNA secondary structure in its native B form. This likely allows greater payload accessibility for protein expression with micelleplexes compared to polyplexes, which tightly condense pDNA and significantly distort its helicity. This work provides important guidance for the design of successful biomolecular delivery systems via optimizing the physicochemical properties.