Engineering exosomes for Alzheimer's disease: Multi-target therapeutic strategies from pathogenesis to clinical translation

Abstract

The complex pathogenesis of Alzheimer's disease (AD), combined with the presence of the blood‒brain barrier (BBB), severely limits the effectiveness of conventional therapeutic approaches. Engineered exosomes—nanoscale extracellular vesicles of natural origin—have emerged as a promising platform for innovative AD therapy due to their excellent biocompatibility, low immunogenicity and intrinsic ability to cross the BBB. This review provides a systematic overview of the synthetic and structural biological characteristics of exosomes, with a focus on their functionalisation through physical, chemical and genetic modifications. These approaches enable the targeted loading of therapeutic cargo and the conjugation of brain-targeting peptides, thereby facilitating precise delivery to specific brain regions and offering a multi-target therapeutic strategy for AD. We further examine the potential of engineered exosomes in modulating core AD pathological pathways, including amyloid-beta deposition, tau hyperphosphorylation, neuroinflammation and synaptic dysfunction, and highlight their utility as an integrated delivery system for the co-delivery of multiple therapeutic agents to achieve synergistic therapeutic effects. Finally, key challenges in clinical translation are addressed, such as scalable production, standardised drug loading protocols and comprehensive assessment of safety and immunogenicity. Unlike previous reviews that primarily focus on general engineering techniques, this article emphasises a rational design strategy tailored for multi-target synergistic therapy and presents a comprehensive roadmap from basic research to clinical application, thereby providing both theoretical insights and practical guidance for the development of next-generation AD treatments.

Keywords

Alzheimer's disease / blood‒brain barrier / clinical translation / engineered exosomes / multi-target therapy / safety assessment / targeted delivery

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