Inflammation Cascade-Directed Therapy by Biomimetic Polydopamine Nanosystem for Long-Term Management of Ischemic Stroke.

Rationale: Although reperfusion has been established as the main strategy for stroke treatment, it frequently causes irreversible secondary injury with dynamic pathological changes. The ischemic microenvironment in the brain continues to deteriorate after reperfusion, resulting in progressive expansion of the injured area and subsequent neuronal death. Therefore, it is urgent to find a therapeutic strategy for long-term management of ischemic stroke at post-reperfusion stages. Methods: In this study, we designed an inflammation cascade-directed therapy using a biomimetic polydopamine nanosystem (MPP-B@MM). The synthesis of the nanosystem was confirmed by transmission electron microscopy, scanning electron microscopy, dynamic laser scattering, proton nuclear magnetic resonance, and so forth. The capability of blood-brain barrier crossing was investigated by cellular study with fluorescence imaging. Meanwhile, reactive oxygen species assay, apoptosis detection, and flow cytometry were employed to evaluate intracellular anti-apoptotic effects of the nanosystem. For in vivo evaluation, a middle cerebral artery occlusion model was established. Anti-stroke efficacy and mechanism of action of the nanosystem were assessed through multiple analytical methods, including behavioral tests, immunohistochemical staining, mRNA sequencing, and blood biochemical analysis. Results: In vitro experiments demonstrated that MPP-B@MM exhibited superior cellular uptake and blood-brain barrier crossing, significantly attenuated mitochondrial damage, and rescued injured neurons. Comprehensive in vivo studies, spanning both acute and chronic phases, confirmed the superior long-term therapeutic performance of the nanosystem. Importantly, mRNA sequencing and pharmacological intervention experiments demonstrated that Homx1 served as the predominant molecular target for acidosis-responsive drug release. Conclusions: This tailored nanosystem demonstrated acute neuroprotective effects during the initial phase of ischemic stroke. As inflammation progressed, the acidosis-responsive motif in the nanosystem could serve as an on-demand therapeutic method, spatiotemporally increasing neurotrophic factor expression at the stroke lesion, which significantly contributed to brain recovery.