De Novo-Designed Peptide-Engineered Multimodal Platform for Post-Ischemic Stroke Tissue Repair.

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.