Engineered Exosomal miRNAs for Post-Stroke Neural Repair: Mechanisms, Delivery Strategies, and Translational Challenges

Abstract

Abstract Functional neurological recovery after ischemic stroke remains a formidable challenge in neuroscience. Exosomes serve as pivotal mediators of intercellular communication, and the microRNAs (miRNAs) they carry, in particular, offer a promising “cell-free therapy” strategy for promoting neurological repair. This review systematically summarizes the multi-target mechanisms by which exosomal miRNAs regulate the neurovascular unit (NVU) and outlines technical strategies to enhance exosomal therapeutic efficacy through targeted modification and engineered cargo loading, with the aim of constructing a smart drug delivery system capable of precise navigation. Following the trajectory of “natural exosomes–engineered exosomes–clinical translation”, this review addresses the core scientific question of how to transform exosomal miRNAs from natural messenger molecules with basic reparative activity into an intelligent therapeutic system for precise targeted delivery. It further explores precision exosome treatment models based on the pathological staging of stroke progression, and integrates single-cell, spatial transcriptomic, and multi-omics technologies to decode the “miRNA–cell source–target cell–signaling pathway” regulatory axis, thereby identifying candidate miRNA combinations with translational potential. Finally, this review provides an in-depth analysis of the core challenges in translating such nanotherapeutic strategies from the bench to the bedside, including manufacturing standardization, quality control, and potency assessment, with the aim of providing a theoretical basis for advancing exosomal miRNA therapies from mechanistic studies to precision stroke treatment.