Multifunctional Engineering of Exosomes for Precision Therapeutics: Strategies for Targeted Delivery, Barrier Evasion, and Clinical Translation

Exosomes (EXM), cell-secreted nanoscale vesicles, are now used as promising tools for therapeutic protein, nucleic acid, and small molecule delivery. However, various challenges, such as rapid immune system clearance, ineffective cargo loading, and reduced targeting specificity, hold them back from being clinically translated. Recent breakthroughs in EXM engineering have made them excellent biomolecule delivery tools. This review critically explores state-of-the-art strategies to maximize cargo incorporation, reengineer EXM surfaces, and create synthetic EXM mimetics. We present important engineering methods, such as genetic manipulation to increase cargo encapsulation, functionalization with targeting ligands, and designing synthetic vesicle structures. We further discuss the therapeutic uses of engineered EXM for different applications, such as cancer treatment, gene therapy, and regenerative medicine, highlighting their potential to evade biological barriers like the blood–brain barrier. Challenges in manufacturing, quality control, and regulatory concerns of translating engineered EXM into clinical therapies are also discussed. We emphasized the upcoming trends that would facilitate improving EXM-based delivery platforms, such as the creation of multifunctional engineered EXM and the incorporation of artificial intelligence for tailored drug delivery. This review stresses the revolutionary value of EXM engineering in establishing next-generation targeted therapeutics, unveiling new fronts for precision medicine and personalized health.