Stimuli-responsive nanozyme-hydrogel systems for ischemic stroke: toward spatiotemporal catalytic control of the neurovascular unit

Abstract

The development of ischemic stroke involves swiftly changing and spatially varied states, including oxidative burst, acidosis, hypoxia, endothelial dysfunction, blood-brain barrier disruption, neuroinflammation, and later tissue remodeling. This temporal structure is poorly matched by conventional single-dose neuroprotectants. Nanozyme-hydrogel systems that respond to stimuli provide a promising approach by integrating catalytic redox control with localized retention, lesion-adaptive mechanics, and release triggered by specific cues. This Mini Review critically examines the design logic of such systems for ischemic stroke. Initially, we categorize reactive oxygen and nitrogen species, low pH, hypoxia, thrombin, matrix metalloproteinases, and inflammatory signals as a pathological code for activating materials. Following this, we examine nanozyme catalytic modules, responsive hydrogel matrices, and integration approaches including encapsulation, anchoring, in situ assembly, and multi-input gating. Emphasis is on the phase-aligned management of the neurovascular unit, covering early reperfusion defense, endothelial stabilization, glial adjustment, angiogenesis, and neural reconfiguration. A key takeaway is that there is limited direct evidence of fully integrated nanozyme-hydrogel platforms specifically for stroke; the field largely relies on the intersection of advanced stroke nanozymes and responsive hydrogels. Consequently, we recommend translational benchmarks that emphasize phase-route alignment, exact catalytic activity, degradation tracking, production feasibility, and validation in various preclinical settings. Accordingly, this Mini Review is intended as a design framework for hypothesis generation and preclinical validation, rather than as evidence of clinical readiness.