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

Abstract

ABSTRACT 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.