Stimuli-Responsive Biomimetic Nanomedicines for Targeted Therapy in Ischemic Stroke: Design Principles, Preclinical Evidence and Translational Challenges.

Ischemic stroke (IS) is a complex cerebrovascular disease with multifactorial etiology and pathological mechanisms, characterized by high morbidity, disability, and mortality rates. Although mechanical thrombectomy, intravenous thrombolysis, and neuroprotective interventions have improved acute management, effective brain-targeted delivery remains limited by the blood-brain barrier, short therapeutic windows, heterogeneous ischemic lesions, and secondary injury after reperfusion. Biomimetic nanomedicines have emerged as promising platforms for IS therapy because they can inherit biological functions from cell membranes, extracellular vesicles, or endogenous ligands, thereby improving biocompatibility, immune evasion, circulation stability, and lesion targeting. However, their clinical translation is still constrained by biosafety and immunogenicity concerns, uncertain pharmacokinetics and reproducible large-scale manufacturing, quality control, and regulatory requirements. Moreover, the balance between drug-loading capacity and target release efficiency remains a key challenge. Excessive cargo loading may compromise nanocarrier stability, whereas insufficient loading may fail to achieve therapeutic efficacy. Therefore, rational nanocarrier design for IS should coordinate brain accumulation, stable systemic circulation, lesion-selective activation, efficient loading, and controllable release. In this review, we discuss how stimuli-responsive biomimetic nanomedicines exploit pathological cues such as reactive oxygen species, acidosis, enzymes, inflammatory mediators, or external stimuli for spatiotemporally controlled therapy and combined therapy. This review critically summarizes IS pathophysiology, major biomimetic nanocarrier types, and the design principles and response mechanisms of stimuli-responsive biomimetic systems. Finally, current limitations and future directions are discussed, with emphasis on biosafety evaluation, standardized characterization, scalable manufacturing, clinically relevant models, and rational integration of precision-responsive designs to accelerate translation.