Nanoengineering of Exosomal Surfaces for Precision Targeting and Payload Delivery at the Molecular Level

Exosomes, nano-sized extracellular vesicles secreted by almost all cell types, have emerged as biologically compatible vehicles for targeted drug delivery, gene therapy, and molecular diagnostics. Their innate ability to traverse biological barriers and deliver diverse cargoes with minimal immunogenicity has catalyzed intense interest in their therapeutic exploitation. However, the intrinsic heterogeneity and limited targeting specificity of native exosomes necessitate advanced engineering strategies to fulfill their clinical potential. This review focuses on the molecular-level nanoengineering of exosomal surfaces to enhance specificity, loading efficiency, and release control of therapeutic payloads. We systematically examine current methodologies, including genetic modification of parental cells, covalent and non-covalent surface conjugation, lipid insertion, click chemistry, and hybrid vesicle fusion. We further detail the quantitative performance of targeting ligands-such as peptides, aptamers, nanobodies, and glycans-in relation to receptor affinity, conjugation efficiency, and biological outcomes. Payload loading techniques, both endogenous and exogenous, are critically analyzed based on loading yield and membrane preservation. Additionally, we highlight disease-specific applications in oncology, neurology, cardiology, and immunotherapy, supported by preclinical and translational case studies. Emerging technologies such as microfluidics, synthetic biology, artificial intelligence-guided modeling, and multi-omics are discussed as integral components of the next generation of precision exosome platforms. Finally, we address key challenges related to scalability, regulatory frameworks, and standardization. This review provides a comprehensive and quantitative framework to guide the design of molecularly engineered exosomes for future translational and clinical success.