Glycopolymer microarrays offer a powerful route to probe glycan-protein interactions, but existing "grafting-to" approaches require presynthesized polymers and provide limited control over surface density and multivalent...Glycopolymer microarrays offer a powerful route to probe glycan-protein interactions, but existing "grafting-to" approaches require presynthesized polymers and provide limited control over surface density and multivalent presentation. Here we introduce a surface-initiated photoinduced electron-transfer RAFT (SI-PET-RAFT) platform that enables the in situ growth of well-defined glycopolymers directly on solid substrates under mild, oxygen-tolerant conditions. Using a combinatorial library of glycopolymers, we mapped the binding preferences of live HepG2, RAW264.7, and HeLa cells, revealing distinct and composition-dependent glycan-recognition signatures driven by multivalent effects. Guided by these insights, we designed thermoresponsive glycopolymer brushes on 96-well plates that mediate selective HepG2 adhesion at 37 °C and rapid, nondestructive release at 4 °C. This integrated workflow links high-throughput glycopolymer screening to the rational engineering of functional biointerfaces, offering broad opportunities in diagnostics, cell sorting, and glycan-targeted biomaterial design.
Biomacromolecules
· 2026 Apr · PMID 41917693
·
Full text
Semaglutide is a therapeutically important lipopeptide that comprises a lipidated peptide with a glucagon-like peptide-1 (GLP-1) sequence, and may be prone to aggregation. We show that semaglutide in low pH 2.4 solutions...Semaglutide is a therapeutically important lipopeptide that comprises a lipidated peptide with a glucagon-like peptide-1 (GLP-1) sequence, and may be prone to aggregation. We show that semaglutide in low pH 2.4 solutions forms β-sheet fibrils, in contrast to the oligomeric and micellar structures formed at higher pH. Based on cryo-TEM images showing twisted fibrils and the modeling of SAXS data (and with knowledge from fiber XRD) and molecular dynamics simulations, a model for the β-sheet structure is proposed, which comprises curved β-strands arranged in an antiparallel fashion around a core that comprises the lipidated lysine residue. This structure results from the patterning of the charged, polar, hydrophobic, and lipidated residues. Remarkably, it is possible to form a glass from the base form of semaglutide with crotonic acid, an organic salt capable of hydrogen bonding. Semaglutide glasses may have applications in biomedicine or therapeutics (for example, as slow-release depots).
This study demonstrates a "polymer dipole engineering" strategy to achieve ultrasensitive and ion-specific modulation of the lower critical solution temperature (LCST) in thermoresponsive polymers. Guided by this strateg...This study demonstrates a "polymer dipole engineering" strategy to achieve ultrasensitive and ion-specific modulation of the lower critical solution temperature (LCST) in thermoresponsive polymers. Guided by this strategy, we synthesized poly[2-(ethylsulfonyl)ethyl acrylamide] (PESEAm) featuring a highly dipolar sulfone group in its repeat unit. PESEAm exhibits an LCST-type phase transition, driven by the disruption of sulfone-water hydrogen bonds upon heating. Remarkably, the polymer demonstrates an ultrasensitive and linear response to both NaSCN and NaSO, enabling precise tuning of its cloud point across a broad temperature range from 10 to 90 °C. The slopes of the cloud point-concentration plots reach 647 °C M for NaSCN and -562 °C M for NaSO, representing the highest sensitivity ever reported for nonionic polymers. This exceptional sensitivity originates from the highly dipolar sulfone group, which engages in strong ion-dipole interactions with SCN to sharply elevate the cloud point. In the case of NaSO, polarization of the hydrogen-bonded water works in synergy with enhanced interchain dipole-dipole interactions to lower the LCST. The dipole engineering strategy demonstrated here provides a rational design route to thermoresponsive polymers with ultrasensitive and broadly tunable phase transitions, offering new insight into the development of ion-responsive and thermoresponsive polymers.
Triggered degradation activated by external stimuli in natural environments is desirable for water-soluble polymers (WSPs), such as poly(ethylene glycol) (PEG), as they often accumulate in natural environments and are di...Triggered degradation activated by external stimuli in natural environments is desirable for water-soluble polymers (WSPs), such as poly(ethylene glycol) (PEG), as they often accumulate in natural environments and are difficult to capture or recycle. To incorporate this function, coordination polymers are attractive due to their reversible linkages. We report the synthesis of PEG end-capped with alginate oligosaccharides (AOS), which, when linked with divalent calcium ions (PEG-AOS-Ca), exhibited higher viscosity (3.8 × 10 Pa·s) compared to the original polymer (PEG-AOS, 1.9 × 10 Pa·s), demonstrating their utility as a viscosity modifier. In addition, PEG-AOS-Ca degraded back to the original PEG-AOS through ion exchange by monovalent sodium ions, mimicking the conditions in the natural environment. This new degradable WSP with competitive viscosity to high molar mass PEG solutions during its use period exhibits triggered degradation behavior in high sodium environments and informs the design of future degradable WSPs.
The development of biomimetic lubricants with superior lubrication, anti-inflammatory activity, and biocompatibility is urgently needed for the treatment of osteoarthritis (OA). Inspired by the architecture of biological...The development of biomimetic lubricants with superior lubrication, anti-inflammatory activity, and biocompatibility is urgently needed for the treatment of osteoarthritis (OA). Inspired by the architecture of biological lubricin and the exceptional lubrication of synovial joints, we designed a protein-based brush polymer by employing proteins as intrinsic macromolecular backbones. Specifically, we synthesized a biomimetic bottlebrush polymer, mHSA--PMPC, in which a denatured human serum albumin (HSA) backbone was grafted with zwitterionic poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC) brushes. The resulting drug-free biomaterial exhibits an ultralow coefficient of friction (μ < 0.01) and remains stable over 2000 friction cycles in aqueous and physiological media, primarily due to hydration lubrication of the PMPC side chains. In vitro evaluations confirmed that mHSA--PMPC exhibits high biocompatibility and significant anti-inflammatory properties. Overall, the biomimetic mHSA--PMPC bottlebrush polymer integrates well-defined molecular architecture with multifunctional biological performance, representing a promising drug-free strategy for potential OA treatment.
Biomacromolecules
· 2026 Apr · PMID 41906278
·
Full text
Molecular heterogeneity in lignin remains poorly understood due to the lack of analytics robust enough to determine the precise structure of individual molecules in isolated lignin samples. Recently, we showed that MALDI...Molecular heterogeneity in lignin remains poorly understood due to the lack of analytics robust enough to determine the precise structure of individual molecules in isolated lignin samples. Recently, we showed that MALDI-TOF MS analysis, combined with a range of NMR techniques, facilitated comprehensive structural studies of oligomer populations present in milled wood lignin from spruce, without prior fractionation. Here, the developed methodology is applied to study populations in milled wood lignin from birch. We report a dominance of linear aryl ether homo-oligomers subdivided into three categories: oligomers exclusively of sinapyl units, oligomers exclusively of guaiacyl units, and oligomers with both guaiacyl and sinapyl units. Linkage progressions in oligomeric structures with the other common interunits are also elucidated. Unlike previous reports, the study enabled the determination of molecule-specific syringyl/guaiacyl ratios. All of the elucidated oligomers contain enone or enal groups at the aliphatic end and phenolic hydroxyls on the other, highlighting homolytic cleavage reactions that occur during lignin procurement. Overall, the study provides a comprehensive framework for an atomistic understanding, offering significant potential for both fundamental and applied research.
DNA exhibits programmable self-assembly through complementary hydrogen bonding between nucleobases introduced to sugar-phosphate backbones in defined sequences, inspiring the development of synthetic analogs with nucleob...DNA exhibits programmable self-assembly through complementary hydrogen bonding between nucleobases introduced to sugar-phosphate backbones in defined sequences, inspiring the development of synthetic analogs with nucleobases as recognition motifs. However, most nucleobase-containing polymers lack defined monomer sequences or molecular uniformity, limiting their biomimetic precision. In this work, we synthesized sequence-defined polymers bearing adenine and thymine units via a Passerini iterative exponential growth strategy. Butoxycarbonyl (Boc)-protected nucleobase-functionalized isocyanides were employed to construct poly(hydroxybutyrate) bearing butyl- and bp-thymine side chains and poly(hydroxybutyrate) with butyl- and bp-adenine side chains with uniform molecular weights. After Boc deprotection, NMR analyses revealed complementary adenine-thymine hydrogen bonding, showing characteristic downfield shifts in a 1:1 mixture, an association constant of 320 M obtained by NMR titration, and thermoreversible behavior in variable-temperature NMR experiments. Furthermore, adenine and thymine were incorporated into a single polymer backbone, demonstrating the method's ability to encode programmable hydrogen-bonding motifs into uniform synthetic macromolecules.
Dual-modal F/H MRI probes often suffer from hydrophobic aggregation caused by high fluorine content, limiting their solubility and imaging performance. Herein, a water-soluble dual-modal probe (PFCP-Gd) was developed by...Dual-modal F/H MRI probes often suffer from hydrophobic aggregation caused by high fluorine content, limiting their solubility and imaging performance. Herein, a water-soluble dual-modal probe (PFCP-Gd) was developed by grafting fluorinated phosphocholine zwitterions and Gd chelates onto a UV-responsive polymer via RAFT polymerization and ring-opening reactions. The design enables UV-triggered paramagnetic relaxation enhancement (PRE) modulation, allowing for activatable F/H MRI contrast. Upon UV irradiation, PFCP-Gd exhibited a significantly enhanced F signal with a relaxation time of 23 ms and a signal-to-noise ratio of 11.34 at 12 mM F. The probe also showed good biocompatibility and an efficient cellular uptake. This work provides a strategy for constructing water-soluble, activatable fluorinated MRI probes for dual-mode imaging.
Sathyavageeswaran A, Izzo M, Sabadini JB
… +3 more, Habeeba U, Belden J, Perry SL
Biomacromolecules
· 2026 Apr · PMID 41887206
·
Full text
Protein encapsulation holds considerable promise for applications spanning the food, pharmaceuticals, biocatalysis, and personal care industries. Complex coacervation─an associative liquid-liquid phase separation (LLPS)...Protein encapsulation holds considerable promise for applications spanning the food, pharmaceuticals, biocatalysis, and personal care industries. Complex coacervation─an associative liquid-liquid phase separation (LLPS) process─has recently emerged as an effective strategy for achieving high protein loading while maintaining protein structure and function. In this work, we systematically investigate the influence of the coacervate-forming peptide charge density, charge patterning, and hydrophobicity on the partitioning of two model proteins: hen egg white lysozyme (HEWL) and bovine serum albumin (BSA). Using a rationally designed library of synthetic polypeptides, we demonstrate that protein uptake is highly sensitive to both the sequence features and hydrophobicity of the peptides, as well as the surface charge characteristics of the protein cargo. In particular, the localized charge patches on HEWL were sensitive to peptide charge density and patterning, while the hydrophobic character of BSA resulted in preferential partitioning into more hydrophobic coacervates. These findings highlight the critical role of spatial charge distribution and sequence composition in governing protein-coacervate interactions, offering new design principles for tailoring coacervate systems for bioencapsulation and related applications.
Li SG, Gillett LP, Kuo KM
… +7 more, Lim SM, Mohanty KT, Kuo YT, Wang Q, Easley AD, Lutkenhaus JL, Wooley KL
Biomacromolecules
· 2026 Apr · PMID 41885353
·
Full text
Mussel-inspired, catechol-functionalized polypeptides were synthesized from natural feedstocks and investigated as redox-active organic electrode materials, to combine electrochemical performance with sustainability and...Mussel-inspired, catechol-functionalized polypeptides were synthesized from natural feedstocks and investigated as redox-active organic electrode materials, to combine electrochemical performance with sustainability and cytocompatibility. Postpolymerization grafting of dopamine onto pre-established poly(α-l-glutamic acid)s resulted in low conjugation, giving poor aqueous solubility and failing to function electrochemically in initial solution-state studies. Therefore, a direct strategy was adopted, whereby the redox-active catechol functionality was embedded into the monomer, followed by ring-opening polymerization to afford a polypeptide bearing a catechol group at each repeat unit. In the solid state, WAXS revealed short-range order, thermogravimetric analysis (TGA) and microscale combustion calorimetry (MCC) indicated thermal stability and low flammability, and electrochemical evaluation demonstrated a quasi-reversible catechol/-quinone aqueous redox process. The composite thin film electrochemical signal intensity was significantly greater for this poly(l-DOPA) than for the original catechol-grafted poly(α-l-glutamic acid). Cell-viability assays further support these catechol-functionalized polypeptides as viable components in sustainable and safe energy storage media.
Cole CC, Kreutzberger MAB, Klein K
… +13 more, Cahue KA, Pogostin BH, Farsheed AC, Swain JWR, Bui TH, Dey A, Makhoul JT, Dubackic M, Pal A, Olsson U, Šarić A, Egelman EH, Hartgerink JD
Biomacromolecules
· 2026 Apr · PMID 41885220
·
Full text
The collagen triple helix assembles hierarchically into bundled oligomers, solvated networks, and fibers. Synthetic peptide assemblies, driven by supramolecular interactions, can form single triple helices through intrah...The collagen triple helix assembles hierarchically into bundled oligomers, solvated networks, and fibers. Synthetic peptide assemblies, driven by supramolecular interactions, can form single triple helices through intrahelical amino acid pairs; however, the principles guiding interhelical associations into higher-order structures remain unclear. Here, we incorporate cation-π and electrostatic charge pairs to probe interhelical interactions and elucidate the mechanisms driving triple helix assembly into fibrils, nanotubes, and nanosheets. Introducing cation-π pairs into a fibrillating collagen mimetic resulted in D-periodic fibrils with pH-sensitive gelation. By alternating the presentation of electrostatic and cation-π pairs, the assembly of another D-periodic fibril featuring inner and outer triple-helical layers was resolved by cryo electron microscopy to a resolution of 8 Å. At physiological pH, antiparallel association of these triple helices leads to the formation of nanotubes. The packing behavior of triple helices correlates with the interhelical interactions, where parallel associations favor fibril formation and antiparallel interactions drive nanotube and nanosheet assembly. These self-assembling triple-helical peptides demonstrate how packing of higher-order structures can be tailored with supramolecular interactions and establish the relationship of different hierarchical collagen-mimetic assemblies as pH-dependent.
In this work, we explore the use of porphyrin/fluorene assemblies as luminescent photosensitizers (PSs) for two-photon photodynamic therapy in biological media. In this context, we systematically investigated a series of...In this work, we explore the use of porphyrin/fluorene assemblies as luminescent photosensitizers (PSs) for two-photon photodynamic therapy in biological media. In this context, we systematically investigated a series of star-shaped hydrophobic porphyrins bearing four arms composed of either a single fluorenyl unit or two fluorenyls linked by triple or double bonds. These fluorenyl-porphyrins, previously identified as efficient fluorescent two-photon PSs in organic solvents, were encapsulated at various loadings in poly(benzyl malate)-based polymeric nanoparticles (NPs). Notably, promising PDT activity was observed in aqueous media for formulations with high PS loading (25 wt %), confirming this encapsulation strategy as an accessible and cost-effective approach for porphyrin biocompatibilization. Despite their strong confinement within the nanoparticles, the encapsulated porphyrins retained significant luminescent properties suitable for bioimaging, supporting the theranostic potential of these nanosystems.
Developing redispersible nanocellulose products is crucial for their industrial applications. However, challenges persist in developing convenient and efficient processes. This study presents a green strategy using dynam...Developing redispersible nanocellulose products is crucial for their industrial applications. However, challenges persist in developing convenient and efficient processes. This study presents a green strategy using dynamic covalent chemistry to tune the hydrogen-bonding network of cellulose nanocrystals (CNCs). CNCs were combined with sodium lipoate (SL) in an aqueous solution and dried to form composite films. SL incorporation effectively prevents CNC aggregation via electrostatic repulsion and steric hindrance, transforming the CNC skeleton structure from a "bundle-to-bundle" structure to a uniform, horizontally stacked architecture. The composite films exhibited enhanced transparency, surface smoothness, and tunable mechanical properties. Upon water immersion, SL depolymerized and separated with 100% recovery. The remaining CNC skeleton readily redispersed into individual nanocrystals via sonication, achieving near-complete recovery even with 15% SL. This simple, water-based process tailors CNC film performance and enables complete closed-loop recycling, offering sustainability and simplicity for advanced applications.
Polyethylene glycol (PEG) is used to graft liposomes with different densities to enhance their colloidal stability or blood circulation time, such as 0.3 mol % for commercial Onivyde and 5 mol % for DOXIL. However, the i...Polyethylene glycol (PEG) is used to graft liposomes with different densities to enhance their colloidal stability or blood circulation time, such as 0.3 mol % for commercial Onivyde and 5 mol % for DOXIL. However, the influence of PEG density on the mechanism of the accelerated blood clearance (ABC) of PEGylated liposomes remains unclear. In this study, we comparatively investigate the ABC phenomenon of liposomes modified with 0.3% and 5% molar ratios of PEG, and found that they displayed completely different mechanisms induced by anti-PEG antibodies. The ABC of liposomes grafted with 0.3 mol % PEG was induced by high-affinity anti-PEG antibodies, whereas the ABC of liposomes grafted with 5 mol % PEG was caused by both high and low-affinity anti-PEG antibodies. Free PEG can bind to high-affinity anti-PEG antibodies but not to low-affinity antibodies. Therefore, preinjecting a low dose of PEG completely inhibits the ABC of 0.3 mol % PEGylated liposomes while only partially decreasing the ABC of 5 mol % PEGylated liposomes in the PEG-immunized rats. These results suggest that the interfacial PEG density determines the mechanism of the ABC phenomenon of PEGylated liposomes, and the ABC of Onivyde can be readily inhibited by removing high-affinity anti-PEG antibodies in blood through preinjection of a low dose of PEG.
Precise regulation of the collagen molecular aggregation behavior is an indispensable prerequisite for constructing functional collagen-based biomaterials. This study innovatively proposes a sustainable strategy to tune...Precise regulation of the collagen molecular aggregation behavior is an indispensable prerequisite for constructing functional collagen-based biomaterials. This study innovatively proposes a sustainable strategy to tune collagen molecular aggregation behavior using oxidized sodium alginate (OSA) as a cross-linker within a biphasic acetic acid/1-ethyl-3-methylimidazolium acetate solvent system. Such a polar solvent environment effectively shields electrostatic interactions between OSA and collagen, resulting in a homogeneous cross-linked network. The results indicated that the critical aggregation concentration of collagen was 1.70 mg/mL in the AA/[EMIM][Ac] solvent system and revealed a [NH]/[CHO] ratio-governed aggregation transition. Beyond the threshold ratio of 1:20, OSA exhibited optimal cross-linking efficiency, thereby driving the formation of large-sized collagen aggregates. Finally, molecular docking simulations of the binding interactions between collagen and OSA were conducted to validate the experimental findings. This work affords a practical methodology for developing high-performance OSA-mediated collagen-based biomaterials while achieving the biological resources transformation and valorization.
Kinaci E, Salazar SA, Palmese GR
… +1 more, Stanzione JF
Biomacromolecules
· 2026 Apr · PMID 41873607
·
Full text
This study focuses on the synthesis of an oligomeric diepoxy resin (EVAC) derived from two diverse biomass sources, cashew nutshell liquid and lignin, and its evaluation as a major component in an anticorrosion surface c...This study focuses on the synthesis of an oligomeric diepoxy resin (EVAC) derived from two diverse biomass sources, cashew nutshell liquid and lignin, and its evaluation as a major component in an anticorrosion surface coating. EVAC structural verifications were performed via spectroscopic and chromatographic methods. EVAC was mixed with diglycidyl ether of bisphenol A (EPON-828) at varying ratios and cured with 5,5'-methylene difurfurylamine (DFDA) and diethylmethylbenzenediamine (Epikure W). Thermally cured blends containing DFDA demonstrated improved moduli and char yields relative to those containing Epikure W. Although the replacement of EVAC with EPON-828 resulted in a reduction in the glass transition temperature and the strength, desired hydrophobicity, flexibility, and adhesion for coatings applications were imparted. Additionally, biobased DFDA demonstrated improved coatings and corrosion performance relative to Epikure W without significantly affecting network performance. Markedly, EVAC/DFDA-based formulations demonstrated high gloss, substrate compatibility, adhesion (5B), impact resistance (>160 lb.-ft), and durability characteristics.
da Silva FFA, Dos Santos SN, Pedrosa LF
… +9 more, Rodrigues VG, Pereira JX, Pereira JPM, Gushiken Junior DS, Rosales TKO, Dias LAP, Spencer PJ, Fabi JP, Bernardes ES
Biomacromolecules
· 2026 Apr · PMID 41873039
·
Full text
This study employed molecular imaging to evaluate MCP (PectaSol-C, modified citrus pectin, a complex polysaccharide with antitumor potential) absorption and pharmacokinetics following oral and intravenous (IV) administra...This study employed molecular imaging to evaluate MCP (PectaSol-C, modified citrus pectin, a complex polysaccharide with antitumor potential) absorption and pharmacokinetics following oral and intravenous (IV) administration. MCP was radiolabeled with technetium-99m (Tc) ([Tc]MCP), allowing precise in vivo tracking. Imaging and biodistribution analyzes revealed low tumor uptake of IV [Tc]MCP, with predominant renal and hepatobiliary clearance. Within tumors, MCP was detected at low levels and did not bind to viable cells. Consistent with these findings, IV administration produced only modest antitumor effects (∼50% tumor growth reduction) in SKOV-3 (ovarian), MKN45 (gastric), and 4T1 (breast) grafts, whereas oral administration was ineffective due to extremely poor absorption (bioavailability <0.01%). Notably, faster clearance of [Tc]MCP in galectin-3 (Gal-3) knockout mice suggests a role for Gal-3 in systemic retention or an indirect contribution to antitumor activity. These findings provide new insights into MCP pharmacological profile, highlight the limitations of oral delivery, and underscore the need for improved delivery strategies to enhance the therapeutic potential of pectin-based cancer treatments.
Hasan MS, Seu MS, Lee J
… +3 more, Gothwal S, Dhasaiyan P, Ryu JH
Biomacromolecules
· 2026 Apr · PMID 41871185
·
Full text
The endoplasmic reticulum (ER) is essential for protein folding, lipid metabolism, calcium homeostasis, and cellular stress signaling. Cancer cells endure chronic ER stress from elevated metabolic demands and oxidative c...The endoplasmic reticulum (ER) is essential for protein folding, lipid metabolism, calcium homeostasis, and cellular stress signaling. Cancer cells endure chronic ER stress from elevated metabolic demands and oxidative conditions, adapting ER pathways to evade apoptosis, while promoting growth, survival, and drug resistance. This dysregulated ER state presents a strategic therapeutic target. Self-assembled nanomaterials provide precise ER localization, significantly enhancing treatment efficacy while reducing systemic toxicity. This review details recent advances in their design for ER-targeted cancer therapy, focusing on in situ assembly (stimulus-driven intracellular formation) and preassembled nanostructures constructed from peptides, polymers, and small molecules. Therapeutic applications encompass chemotherapy, photodynamic therapy, bioimaging, immunotherapy, and nanovaccines. Key challenges to clinical translation─including in vivo delivery efficiency, targeting specificity, and regulatory requirements─are thoroughly examined, alongside promising directions in programmable, multiorganelle-targeting, and bioresponsive nanomedicines. By integration of self-assembly principles with ER stress biology, these platforms establish a robust foundation for precise, patient-tailored cancer therapies.
White oak is favored over red oak for alcoholic-barrel cooperage because of its lignin-rich tyloses. To reveal how tyloses regulate diffusion and dimensional stability in oak wood, this study investigated the absorption...White oak is favored over red oak for alcoholic-barrel cooperage because of its lignin-rich tyloses. To reveal how tyloses regulate diffusion and dimensional stability in oak wood, this study investigated the absorption and swelling of white and red oak immersed in ethanol solutions (0-100%). Codiffusion revealed competitive interactions: water expedited ethanol motion, while ethanol hindered water diffusion by disrupting the cooperative hydrogen-bond network. Water mainly penetrated polysaccharides, whereas ethanol preferentially was associated with lignin. In white oak latewood, radial swelling decreased from 8.8% in water to 4.9% in ethanol. In red oak latewood, radial swelling was 6.9% in water and 5.0% in ethanol but reached 8.3% at 40% ethanol, indicating a distinct hyperswelling effect. Tyloses in white oak obstructed vessels, restricted solvent codiffusion, and suppressed the amplification of molecular softening into macroscopic hyperswelling. These findings provide insight into multicomponent diffusion and swelling regulation in hierarchically structured porous biomaterials.
Folkesson M, Wesseler JP, Pierucci C
… +4 more, Rader C, Weder C, Ianiro A, Berrocal JA
Biomacromolecules
· 2026 Apr · PMID 41861375
·
Full text
Stimuli-responsive nanocomposite hydrogels have garnered significant interest as alternatives to conventional hydrogels, enabling the engineering of stimuli-responsive behavior and network connectivity through compositio...Stimuli-responsive nanocomposite hydrogels have garnered significant interest as alternatives to conventional hydrogels, enabling the engineering of stimuli-responsive behavior and network connectivity through composition and architecture. Here, we report thermoresponsive, "one-component" nanocomposite hydrogels composed of copolymer-grafted cellulose nanocrystals (CNCs). Thermoresponsive polyacrylamides or poly(oligoethylene glycol acrylate) copolymers bearing terminal olefin side chains were the CNC surfaces using atom-transfer radical polymerization, yielding densely grafted hairy nanoparticles (HNPs). The HNPs were cross-linked via UV-mediated thiol-ene click chemistry to form hydrogels. The resulting networks exhibit reversible LCST-type swelling and deswelling, with thermoresponsive and mechanical behavior governed by graft chemistry, architecture, and solvation. Comparative experiments using CNC-free and physically mixed hydrogels show that, at the low CNC loadings employed here, mechanical properties are shaped predominantly by chain entanglement and solvation, rather than by reinforcement from the nanocrystals.