Dongdong Wu

Orchestrating tissue regeneration in complex pathologies like post‐ischemic stroke requires materials that can precisely regulate multiple signaling pathways. A central challenge is engineering a single platform integrating mechanical, electrical, and biochemical cues to redirect these pathological networks. Here, we present a computation‐driven, multimodal hydrogel engineered to function as a programmable regulatory node. The system integrates a computationally screened de novo vasculogenic peptide scaffold and surface‐engineered, inflammation‐responsive conductive MXene nanosheets. This rational surface engineering solves the critical bottleneck of MXene instability, preserving colloidal stability for over 2 months and maintaining high conductivity (1.2 mS/cm) within the injectable system. In a mouse model of ischemic stroke, this targeted modulation reconstructed the neurovascular unit integrity, suppressed glial scarring, and promoted remyelination and synaptic repair. Crucially, the platform re‐established neural electrical signal transmission, leading to the recovery of neural function. Mechanistically, machine learning‐driven transcriptomics highlighted Akt2 as a candidate regulatory hub, while untargeted metabolomics, prompted by a striking hair yellowing phenotype, suggested metabolic remodeling involving the phospholipase D signaling pathway. Our findings demonstrate a promising data‐driven, bottom‐up rational design paradigm for advanced bioelectronic tissue repair materials.

Infected wound healing is hindered by a hostile microenvironment and limited active treatment options. While current hydrogels offer partial benefits, they struggle to simultaneously modulate the wound environment and physically close wounds. We design a smart hydrogel by integrating two peptide coiled-coil motifs: an antimicrobial tetramer and a stimuli-responsive dimer. Covalent polymerization of the antimicrobial tetramers, unfolded monopeptides derived from the coiled-coil dimer, and star-shaped polyethylene glycol (PEG) yields an intrinsically antimicrobial hydrogel in situ at the wound site. When treated by Zn2+, the monopeptides fold and assemble into coiled-coil dimers within the matrix, triggering rapid, controllable hydrogel contraction that actively pulls wound edges together. Both coiled-coils also endow the hydrogel with intrinsic antioxidant activity. Furthermore, these coiled-coils function as reversible, sacrificial noncovalent crosslinks that effectively dissipate mechanical energy, synergistically enhancing the hydrogel’s toughness and resistance to swelling. Collectively, this intrinsically multifunctional hydrogel accelerates infected wound healing without the need for dressing changes and through a coordinated cascade of actions: on-demand dynamic wound contraction, bacterial eradication, reactive oxygen species scavenging, inflammation suppression, and promotion of re-epithelialization. This integrated design represents a significant advance toward smart, bioactive dressings capable of actively orchestrating multiple phases of the wound healing process.

Myocardial infarction (MI) triggers a cascade of pathological processes characterized by oxidative stress and fibrotic scar formation, yet existing multi‐stage repair materials face challenges including complex compositions, uncontrollable degradation, and insufficient targeting specificity. This study develops the hydrogel system composed of chiral bioactive peptides (L/D gel@DPFR) by integrating chiral antioxidant peptide to enhance hydrogel stability and enable controlled degradation, while further incorporating cardiac fibroblast‐targeted peptide‐modified nanoparticles loaded with Repsox (a TGF‐β inhibitor). In vitro and in vivo experimental results demonstrate that D gel@DPFR exhibits a slower degradation rate than L gel@DPFR, enabling prolonged regulation of oxidative stress and apoptosis reduction, while facilitating orderly release of DPFR nanoparticles to effectively suppress type I and III collagen deposition and alleviate myocardial fibrosis. Overall, this study first elucidates the differential effects and mechanisms of multifunctional peptide hydrogels constructed based on a chiral bioactive peptide regulation strategy in myocardial repair. Compared to L gel@DPFR, D gel@DPFR establishes an effective “early antioxidant‐late antifibrotic” synergistic repair system for MI, demonstrating more favorable therapeutic effects in regulating the pathological microenvironment. These findings offer novel design strategies for multi‐stage coordinated repair peptide hydrogels targeting MI pathological conditions.

Overcoming wet tissue adhesion remains a persistent challenge in biomedicine due to interference from blood and tissue fluids, yet there is strong demand for biosafe, robust, and multifunctional surgical bioadhesives. We present a supramolecular adhesive network that integrates peptide coiled-coils with polyethylene glycol (PEG). In this system, coiled-coil motifs, formed in situ through zinc ion chelation, spatially organize amphiphilic residues to enable tissue adhesion via van der Waals forces and electrostatic interactions. In its dehydrated state, the adhesive network is non-adhesive but rapidly activates strong adhesion upon contact with wet tissues by absorbing interfacial water. The dehydrated coiled-coil-PEG patch achieves hemostasis and sealing of gastric punctures in both rat and porcine models, as well as effective irregularly shaped wound repair. Its dynamic coiled-coil architecture confers ultrafast self-healing (6000% strain), strong cohesion, and full recyclability. By covalently incorporating bioactive peptides and physically encapsulating nanomaterials, the adhesive system becomes multifunctional. Demonstrated biosafety, biocompatibility, and scalable fabrication underscore its clinical and industrial potential in tissue regeneration, hemostasis, and bio-integrated wearables—ushering in a new paradigm for managing complex tissue interfaces.

We design stable, surface-modifiable peptide nanoparticles. Employing these nanoparticles as crosslinkers, we fabricate a PEG-based hybrid hydrogel with excellent antibacterial and anti-swelling properties, which effectively treats infected wounds.

Designing supramolecular hydrogels that simultaneously exhibit dynamic behavior and robust stability remains a fundamental challenge, as conventional strategies to enhance thermal and anti‐swelling properties often compromise injectability, self‐healing, and responsiveness. Here, a minimalist two‐component hydrogel system is reported, formed by crosslinking self‐assembled peptide nanoparticles with four‐arm polyethylene glycol (PEG) via click chemistry. The resulting hydrogel uniquely combines thermostability and anti‐swelling behavior with dynamic features such as shear‐thinning, injectability, and self‐healing. The hydrophobic effect driving nanoparticle formation imparts water‐repellency and thermal resilience, while the reversible supramolecular interactions enable structural adaptability. The hydrogel also demonstrates multi‐responsiveness, antibacterial activity, and cargo‐grafting capability. In vivo studies confirm its efficacy in accelerating the healing of infected wounds, with pronounced anti‐inflammatory and pro‐angiogenic effects. This work introduces a new design paradigm for multifunctional supramolecular hydrogels, transforming component simplicity into performance complexity.

Rigidity is a fundamental attribute of linear polymers that determines their functions and applications, and the modulation of polymer rigidity is thus attractive. However, tuning the rigidity of polymers after their formation without changing their chemical composition is challenging. Herein, pH‐responsive rigid homodimeric peptide coiled‐coils are used as transformable linkers to polymerize with rigid peptide bundles to yield rigid polymers, which can transform into a distinct semi‐flexible state upon the in situ unfolding of rigid dimeric linkers into flexible monomeric chains. The resultant semi‐flexible polymers exhibit unique thermally driven self‐crosslinking capabilities, enabling the spontaneous hydrogelation of highly concentrated polymer solutions. Elevated temperatures accelerate the gelation kinetics and enhance the hydrogel stiffness, demonstrating a rare thermal stiffening phenomenon in the peptide hydrogel. Additionally, semi‐flexible polymers promote cell proliferation and migration at certain concentrations. The thermally self‐crosslinkable semi‐flexible polymers can ideally synergize with thermoresponsive polyvinyl alcohol (PVA), facilitating the facile fabrication of a robust PVA membrane with an ultrahigh toughness of 303.6 MJ m ⁻³ and enhancing swelling resistance. Peptide‐based semi‐flexible polymers may offer a universal, effective, and biocompatible toughening strategy for biomedical applications.

Enhancing the toughness of hydrogels for biomedical applications remains a challenge, as many toughening approaches often sacrifice biocompatibility or in situ applicability, thereby restricting their broader utility in biomedical contexts. Inspired by the intervertebral disk, here, we introduce a biocompatible toughening strategy using peptide-based rigid nanorods (PRNs) as backbone supports within gelatin methacryloyl (GelMA) hydrogels. PRNs are short polymers with exceptional rigidity, capable of covalent cross-linking with GelMA molecules at both ends. Photocuring nanorod-supported GelMA (NSG) molecules yields NSG hydrogels, which demonstrate great improvements in compressive strength (1018%) and toughness (508%) compared to untreated GelMA hydrogels, alongside enhanced structural integrity and fatigue resistance. We further demonstrate that NSG hydrogels are ideal for in situ repair of damaged osteochondral tissues and are highly compatible with additive manufacturing, owing to their good biocompatibility and photocurable properties. This strategy provides a potential pathway for developing highly biocompatible and tough hydrogels, significantly expanding their potential for biomedical applications.