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Not AvailableConventional type I photoinitiators require high-energy ultraviolet (UV) light to generate radicals, whereas most visible-light systems rely on slower, oxygen-sensitive type II photosensitization pathways. We report boron-alkylated boron-dipyrromethenes (BODIPYs) as type I photoinitiators that operate efficiently under green-light-emitting diodes (LEDs) and ambient conditions. Replacing methyl with ethyl at the boron site accelerates photolysis, lowers the B–C bond dissociation energy, and suppresses oxygen sensitization. Consequently, the ethyl derivative doubles the polymerization rate and decreases oxygen inhibition times by over an order of magnitude. Relative to Ivocerin, a leading blue-light type I photoinitiator, the BODIPY system achieves a higher external quantum yield due to stronger absorption. Owing to these performance enhancements, the ethyl derivative enables rapid, ambient, green-light digital light processing (DLP) 3D printing of commercial acrylate resins, achieving 2.5 s exposures per 50 µm layer at 3 mW cm^−2. This oxygen-tolerant platform provides a practical, mild route for photocurable technologies. 

Dynamic covalent cross-links impart hydrogels with viscoelastic and self-healing properties, motivating applications as biomimetic cell scaffolds and injectable materials. The long bond lifetime results in complex rheological behavior including shear thickening. We hypothesized that this behavior applies broadly across dynamic covalent hydrogels and can be engineered through reaction rate constants. Thus, we synthesized multiarm poly(ethylene glycol) (PEG) hydrogels with conjugate addition, boronate ester, or terpyridine-zinc cross-links, which tune bond dissociation kinetics and hydrogel relaxation times over four orders of magnitude. All formulations exhibited shear thickening, with the onset dictated by the relaxation time. Although multiple mechanisms may underlie this behavior, chain stretching is hypothesized to contribute to shear thickening, as the cross-linking concentration remained constant under shear and networks with more defects correlated with increased shear thickening. These molecular and structural drivers of shear thickening apply across dilute dynamic covalent tetra-PEG hydrogels, clarifying their suitability for applications under shear. 

ABSTRACT Combination cancer therapies offer to minimize toxicity and alleviate patient burden, but a key challenge is independent control over the release of multiple therapeutics, especially in systems with chemotherapeutic drugs of similar size and structure. Due to MMP upregulation in cancer microenvironments, matrix metalloproteinase (MMP)‐degradable linkers are often exploited for targeted release; however, their short substrates exhibit overlap with multiple proteases, which confounds kinetic control. Here, a library of MMP‐responsive “peptomer” drug linkers was developed to control release on fast and slow timescales. Peptomers are hybrid molecules of peptides and non‐natural peptoids (N‐substituted glycines), which hinder proteolytic susceptibility. Systematic variation of peptoid substitutions within a pan‐MMP‐cleavable peptide sequence yielded distinct degradation kinetics to multiple MMPs. Two chemotherapeutics, doxorubicin and geldanamycin, were conjugated to peptomer linkers and incorporated into polyethylene glycol (PEG)‐based hydrogels for sequential delivery. Fluorogenic and mass spectrometry‐based assays demonstrated decoupled release of each drug in response to MMP‐2 and MMP‐9. In vitro studies using MDA‐MB‐231 and A549 cells showed that cell death rates correlated with the order of drug release. These findings highlight peptomers as modular, biocompatible linkers capable of kinetic control over multiple therapeutic agents, providing a versatile platform for improving the precision of combination drug delivery systems. 

Abstract Human mesenchymal stromal cell (hMSC) manufacturing requires the production of large numbers of therapeutically potent cells. Licensing with soluble cytokines improves hMSC therapeutic potency by enhancing secretion of immunoactive factors but typically decreases proliferative ability. Soft hydrogels, however, have shown promise for boosting immunomodulatory potential, which may compensate for decreased proliferation. Here, hydrogels are cross‐linked with peptoids of different secondary structures to generate substrates of various bulk stiffnesses but fixed network connectivity. Secretions of interleukin 6, monocyte chemoattractive protein‐1, macrophage colony‐stimulating factor, and vascular endothelial growth factor are shown to depend on hydrogel stiffness in the presence of interferon gamma (IFN‐γ) supplementation, with soft substrates further improving secretion. The immunological function of these secreted cytokines is then investigated via coculture of hMSCs seeded on hydrogels with primary peripheral blood mononuclear cells (PBMCs) in the presence and absence of IFN‐γ. Cocultures with hMSCs seeded on softer hydrogels show decreased PBMC proliferation with IFN‐γ. To probe possible signaling pathways, immunofluorescent studies probe the nuclear factor kappa B pathway and demonstrate that IFN‐γ supplementation and softer hydrogel mechanics lead to higher activation of this pathway. Overall, these studies may allow for production of more efficacious therapeutic hMSCs in the presence of IFN‐γ. 

Depletion interactions are thought to significantly contribute to the organization of intracellular structures in the crowded cytosol. The strength of depletion interactions depends on physical parameters such as the depletant number density and the depletant size ratio. Cells are known to dynamically regulate these two parameters by varying the copy number of proteins of a wide distribution of sizes. However, mammalian cells are also known to keep the total protein mass density remarkably constant, to within 0.5% throughout the cell cycle. We thus ask how the strength of depletion interactions varies when the total depletant mass is held fixed, a.k.a. fixed-mass depletion. We answer this question via scaling arguments, as well as by studying depletion effects on networks of reconstituted semiflexible actin in silico and in vitro. We examine the maximum strength of the depletion interaction potential U∗ as a function of q, the size ratio between the depletant and the matter being depleted. We uncover a scaling relation U∗ ∼ qζ for two cases: fixed volume fraction φ and fixed mass density ρ. For fixed volume fraction, we report ζ < 0. For the fixed mass density case, we report ζ > 0, which suggests that the depletion interaction strength increases as the depletant size ratio is increased. To test this prediction, we prepared our filament networks at fixed mass concentrations with varying sizes of the depletant molecule poly(ethylene glycol) (PEG). We characterize the depletion interaction strength in our simulations via the mesh size. In experiments, we observe two distinct actin network morphologies, which we call weakly bundled and strongly bundled. We identify a mass concentration where different PEG depletant sizes lead to weakly bundled or strongly bundled morphologies. For these conditions, we find that the mesh size and intra-bundle spacing between filaments across the different morphologies do not show significant differences, while the dynamic light scattering relaxation time and storage modulus between the two states do show significant differences. Our results demonstrate the ability to tune actin network morphology and mechanics by controlling depletant size and give insights into depletion interaction mechanisms under the fixed-depletant-mass constraint relevant to living cells. 

The utility of active proteases as biomarkers is often limited by overlapping substrate specificity. Here, this feature is leveraged to develop a quantitative pattern-recognition sensing system driven by the degradation patterns of peptide–peptoid hybrid substrates to classify proteases and estimate their concentration by multivariate data analysis. 

Engineered living materials combine the advantages of biological and synthetic systems by leveraging genetic and metabolic programming to control material-wide properties. Here, we demonstrate that extracellular electron transfer (EET), a microbial respiration process, can serve as a tunable bridge between live cell metabolism and synthetic material properties. In this system, EET flux from Shewanella oneidensis to a copper catalyst controls hydrogel cross-linking via two distinct chemistries to form living synthetic polymer networks. We first demonstrate that synthetic biology-inspired design rules derived from fluorescence parameterization can be applied toward EET-based regulation of polymer network mechanics. We then program transcriptional Boolean logic gates to govern EET gene expression, which enables design of computational polymer networks that mechanically respond to combinations of molecular inputs. Finally, we control fibroblast morphology using EET as a bridge for programmed material properties. Our results demonstrate how rational genetic circuit design can emulate physiological behavior in engineered living materials.