Tissue engineering seeks effective strategies to integrate cells into scaffolds while preserving spatial organization and stability. Conventional approaches based on extracellular matrix molecules or adhesion peptides often provide weak and nonspecific attachments, limiting robust assembly of complex cellular architectures. Here, we investigate biorthogonal click chemistry to address these limitations. By enabling covalent cell-biomaterial bonding through strain-promoted azide-alkyne cycloaddition (SPAAC), we achieved stable cell-scaffold integration. As a proof of concept, we engineered artificial Bands of Büngner-like scaffolds by functionalizing silk microfibers with cyclooctyne groups and metabolically engineering Schwann cells to present azide functionalities. Over 15 days in vitro, these biohybrid scaffolds supported directed neurite outgrowth, preserved metabolic activity, and increased nerve growth factor levels at early time points. Our results support click chemistry as a robust strategy for assembling stable cell-laden scaffolds while preserving biological function, potentially enabling the tailored design of complex cellular architectures and microenvironments for tissue engineering applications.

Complex coacervates are widely used as model systems for studying biomolecular condensate formation, yet how intracellular crowding influences coacervation mechanisms remains unclear. Here, we investigate a model protein-polymer coacervate system in dilute and crowded environments to elucidate its formation mechanism. In dilute solutions, protein-polymer complexes gradually grow into larger assemblies as their net charge approaches neutrality. Under crowded conditions, excluded-volume effects force polymer chains into highly coiled conformations, creating a dense polymer network before the protein is introduced. Protein incorporation into this network relieves conformational tension and triggers the formation of protein-polymer networks that act as scaffolds for coacervates, bypassing the gradual charge-driven assembly seen under dilute conditions. Despite this mechanistic difference, crowders are found to be excluded from the dense phase, yielding comparable mesoscale structures under both conditions. Overall, this work suggests how condensates may adapt their assembly mechanisms within complex cellular environments.

Preventing tumor recurrence while promoting bone regeneration remains a major challenge for osteosarcoma implants after limb-salvage surgery. Herein, we developed a DNA molecular robot (DMR) that converts tumor microenvironment (TME) and near-infrared (NIR) stimuli into integrin-mediated mechanical forces, generating microtubule-targeting activity without drugs. The DNA-polypeptide chimera contains RGD peptides for integrin anchoring and allosteric DNA switches with tunable piconewton sensitivity. Under acidic TME and NIR irradiation, DMR modulates microtubule dynamics, suppresses adhesion protein expression through the FAK-Src pathway, and disrupts mitotic spindle formation. Consequently, DMR selectively eliminates osteosarcoma cells, reducing tumor volume by 81.5%, while simultaneously enhancing bone regeneration with a 2.1-fold increase in trabecular thickness. By transducing integrin-mediated forces into intracellular microtubule regulation, DMR provides a nonpharmacological strategy for dual-functional implants with synergistic antitumor and osteogenic activities.

Osteoarthritis (OA) is a degenerative joint disease characterized by the failure of cartilage lubrication and persistent inflammation induced by friction-generated debris. Therefore, an effective OA treatment strategy should simultaneously enhance joint long-term lubrication and suppress inflammation. Toward this goal, we developed durable Lipo/PADM microgels via multiple cross-linking to integrate sustained lubrication with matrix metalloproteinase (MMP)-responsive dexamethasone release. The microgels maintained a low coefficient of friction of 0.029, remaining 24.3% lower than PBS after 8 weeks of in vitro degradation. In the MMP-rich OA microenvironment, ester-bond cleavage enabled sustained, on-demand drug release, reaching 70% within 14 days. Lipo/PADM microgels restored type II collagen expression, suppressed MMP-13 in bone marrow mesenchymal stem cells, and alleviated the OA-associated catabolic microenvironment. Intra-articular administration significantly reduced cartilage degeneration and delayed OA progression. These poly(glutamic acid)-based microgels offer a promising OA therapy through durable lubrication, responsive drug delivery, and prolonged intra-articular retention.

Poor distribution is often a limiting factor when using affinity targeted treatments. High affinity creates a barrier to transport because proteins cannot diffuse throughout the tissue while bound to the cell surface. Lowering the affinity can help with transport throughout a tumor but can also result in a loss of total delivery and specificity for the target. In this research, we used point mutations to create affibodies with a range of different affinities for epidermal growth factor receptor (EGFR) and measured their penetration through tumor spheroids. Mutants in the range of ∼7-12 nM KD were able to distribute more evenly throughout 3D tumor spheroids without losing total accumulation or receptor specificity. Lower affinity mutants showed both low target specificity and accumulation in 3D tumor spheroids. This work shows the effects of affinity on distribution and how slightly reducing binding affinity can improve transport.

Glaucoma, a leading cause of irreversible blindness, is commonly treated with topical eye drops that reduce intraocular pressure (IOP), but their efficacy is limited by rapid precorneal clearance. To address this, we developed a dynamic hydrogel (CSFP) via Schiff base bonding between carboxymethyl chitosan (CMCS) and 4-formylphenylboronic acid (FPBA) as an advanced delivery vehicle for brimonidine (BRI) and timolol (TIM), two common IOP-lowering agents. The mechanical properties were tunable by adjusting CMCS and FPBA concentrations. The optimized hydrogel exhibited a storage modulus of ∼38.8 Pa (at 1 Hz, 1% strain), excellent self-healing ability, and shear-thinning behavior, facilitating easy administration and resistance to blink-induced clearance. It also achieved near 100% transmittance and a refractive index of 1.339, ensuring optical clarity. Notably, the incorporated phenylboronic acid (PBA) groups enabled selective binding to sialic acid residues on ocular mucins via dynamic phenylboronic ester bonding, prolonging precorneal retention beyond 30 min compared to less than 5 min for the solution control. In a magnetic bead-induced ocular hypertensive rat model, CSFP hydrogel loaded with either BRI or TIM induced greater and long-lasting IOP reduction than the free drug solutions. This work highlights the potential of mucoadhesive dynamic covalent hydrogels for advanced ocular drug delivery.

Dual-antibiotic loaded poly(ethylene glycol) (PEG)-based hydrogels were developed as antimicrobial wound dressings combining covalent and physical antibiotic incorporation. Hydrogels were prepared through amino-yne click conjugation of gentamicin sulfate (Gs) and thiol-yne cross-linking, followed by ciprofloxacin (CPX) loading via swelling-diffusion. The materials exhibited tunable gelation time, swelling capacity, and drug release profiles depending on thiol content. A dual-release mechanism was achieved, consisting of an initial burst release of CPX followed by a sustained, pH-responsive release of conjugated Gs through acid cleavage of β-aminoacrylate linkages. The hydrogels showed effective wide spectrum antibacterial activity against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, while cytotoxicity studies confirmed cytocompatibility at bactericidal concentrations. The results support the potential of these hydrogels as safe and effective dual-antibiotic wound dressings, allowing for the immediate elimination of invading bacteria after wounding (burst release), while maintaining long-term antibiotic release to minimize reinfection risk.

Mechanical loading coupled with moisture sorption causes mechano-sorptive creep in wood, but its molecular origin remains unclear. Here, DMA, in situ tensile FTIR, SAXS/WAXS, and MD/GCMC simulations were combined to examine molecular and nanostructural changes in wood cell walls during sorption under tensile stress. Adsorption under stress produced a higher moisture content than stress-free adsorption, whereas viscoelastic creep at constant relative humidity caused no additional uptake. The enhancement was most evident when the loading was approximately parallel to cellulose microfibrils. FTIR revealed changes in cellulose hydroxyl environments consistent with increased accessibility, while SAXS/WAXS showed enlarged interfibrillar distances with nearly unchanged crystalline lattice spacings. Simulations further indicated reduced polymer-polymer hydrogen bonding, greater solvent-accessible surface area, and pore opening during simultaneous adsorption and loading. Together, these findings link tensile-stress-induced cellulose hydroxyl accessibility to enhanced moisture sorption in the wood cell walls.

Liquid-liquid phase separation is central to nucleic acid organization in cells, yet the role of DNA secondary structures in phase separation is largely underexplored. Using confocal fluorescence microscopy, we investigated phase separation of i-motif (iM)-forming sequences in the presence of poly-l-lysine under varying pHs. iMs are four-stranded DNA structures formed in cytosine-rich sequences, often enriched in oncogenes and telomeres. At acidic pH, fully folded iMs suppressed droplet formation, indicating that structural stiffness inhibits phase separation. Near the transition pH, partially folded iMs formed gel-like droplets with high contact angles. At basic pH, unfolded iMs exhibited fluid-like droplets with lower contact angles. Disrupting the iM secondary structure via cytosine deamination restored liquid-like droplets at transitional pH, confirming the role of structure. In contrast, stable G-quadruplex structures consistently formed high-contact-angle droplets. These findings highlight the DNA secondary structure as a key determinant of biomolecular condensate formation, morphology, and dynamics, with potential implications for gene expression.

Polyelectrolyte complex micelles (PCMs) are promising nucleic acid nanocarriers; however, nucleic acids are usually treated as generic polyanions, leaving the impact of nucleotide sequence and partially hybridized structures unclear. Here, we systematically tune DNA stiffness in PCMs using (i) single-stranded sequences with varied purine contents and (ii) hybridization structures in the form of hairpins, single-tailed duplexes, and double-tailed duplexes. Small-angle X-ray scattering, electron microscopy, and dynamic light scattering reveal a strong bending penalty imposed by increasing DNA stiffness that drives a transition from spherical to less-curved cylindrical or worm-like PCMs with ordered cores. Increasing the purine content produces gradual morphological changes, whereas hybridized constructs show sharper transitions. We further link the availability of base-stacking sites to the cylindrical PCM length and see that longer rigid DNA results in higher stiffness of cylindrical PCMs. The results establish relationships connecting the DNA sequence, structure, and polymer length to PCM morphology.

This manuscript describes chain-folding-regulated hierarchical self-assembly of an amphiphilic polyurethane (P1), exhibiting superior surface functional group display and biological activity compared to an analogous amphiphilic block copolymer (P3) or a rigid polyurethane (P2) that is deprived of chain folding. In P1, intrachain hydrogen bonding directs the formation of a pleated structure that hierarchically assembles into hollow capsules. A glucose oxidase-peroxidase assay confirmed that this unique assembly of P1 allows displaying ∼50% glucose moieties on the outer surface, which significantly outperforms amphiphilic block copolymers. This renders outstanding multivalent binding with the lectin concanavalin A, as is evident by a very high association constant (∼105 M-1) and spontaneous glycocluster effect. In contrast, P2 or P3 fails to exhibit any notable glycocluster effect under identical conditions. Furthermore, P1, unlike P2 or P3, induced clustering of Staphylococcus aureus by targeting bacterial carbohydrate transporters, deactivated the bacteria, and prevented internalization into mammalian cells.

Noninvasive transdermal drug delivery (TDD) offers sustained therapeutic release but is hindered by the stratum corneum (SC) barrier. Herein, we report ultrasmall polymeric micelles (PMs) embedded in poly(vinyl alcohol) hydrogels for the passive TDD of rosiglitazone (RGT) to treat Type 2 diabetes mellitus (T2DM). We synthesized amphiphilic brush copolymers with varied hydrophobic cores (linear alkanes, benzene, borneol) to tune SC interactions and ensure colloidal stability. Ex vivo murine skin studies demonstrated that PM variants with C10 alkane and benzene cores achieved 10.56% and 19.84% cumulative permeation at 24 h, respectively, via dual paracellular/intracellular routes. In vivo, PM hydrogels delivered steady plasma accumulation. In a T2DM model, transdermal RGT reduced blood glucose by 30% over 12 days without observable skin or organ toxicity. This nanoplatform enables noninvasive systemic delivery, offering a robust alternative to oral administration for sustained glycemic control.

Silk fibroin (SF) is ideal for aerogel fibers owing to its abundance, biodegradability, biocompatibility, and structural tunability, yet pristine SF aerogel fibers have insufficient performance for practical use. Here, a dual cross-linking strategy combining enzymatic cross-linking and Zn2+ coordination was used, leveraging their noncompetitive inhibition to produce SF aerogel fibers featuring low density, high strength, and outstanding thermal insulation. SF concentration governs the pore architecture formed by enzymatic cross-linking. Zn2+ ions complex with SF molecular chains, creating a more intricate three-dimensional network alongside the covalent bonds from enzymatic cross-linking. At 0.1 M Zn2+, the dual-cross-linked SF aerogel fibers achieve a maximum toughness of ∼0.31 MJ m-3 and optimal thermal insulation with ∼2.9 °C. Woven fabrics outperform commercial nylon, cotton and wool in thermal insulation. Superior performance arises from air-trapping pores suppressing conduction/convection and infrared-reflective pore walls reducing radiative loss. This work provides a guideline for designing biomass aerogel fibers.

A persistent challenge in the development of biobased materials is to balance sustainability with robust mechanical properties and specific functionalities. In this context, the present study provides a structure-guided functionalization strategy that offers a viable route toward this goal by integrating the introduction of functional groups into biobased feedstocks with precise control over polymer architecture. Specifically, a novel fluorinated biobased bisphenol monomer was synthesized. Its high steric bulk and fluorinated nature effectively reduce the material's dielectric constant and enhance hydrophobicity, thereby broadening the functional application scope of biobased polymers. Furthermore, by designing a terpolymer system incorporating rigid, semirigid, and flexible segments, a substantial increase in toughness was achieved without significantly compromising thermal stability. The resulting material exhibits a tensile strength of 51.5 MPa, an elongation at break of 75%, a low dielectric constant of 2.48 at 1 MHz, and a water contact angle of 90°. This work demonstrates that combining sterically demanding fluorinated monomers with a synergistic rigid-flexible architecture provides an effective pathway for functionalizing biobased materials and toughening high-performance polymers.

Zr-based metal-organic frameworks (MOFs) are promising nanomedicine platforms, but their rapid degradation in phosphate-rich biological environments remains a critical barrier to clinical translation. Here, incorporating MnOx into the porphyrinic Zr-MOF PCN-224 modulates the coordination environment of Zr6 clusters, suppressing phosphate-induced linker displacement and extending structural integrity under physiological conditions. The optimized 1:1 MnOx@PCN-224 formulation resists phosphate-triggered disassembly and porphyrin release in phosphate-buffered saline (PBS). MnOx also acts as a catalase mimic, converting endogenous H2O2 into O2 to relieve tumor hypoxia and potentiate sonodynamic therapy (SDT). Under high-intensity focused ultrasound (HIFU) irradiation, stabilized porphyrin linkers generate enhanced 1O2 levels. Functionalization with GST-EGFR as a preadsorbed targeting protein corona enables tumor-specific delivery, and the resulting nanoplatform suppresses tumor growth in a 4T1 breast tumor model. This coordination-driven strategy transforms the inherent lability of Zr-MOFs into a designable parameter for engineering biointerface stability for in vivo therapeutic applications.