Smart exosomes: multimodal engineering strategies for logic-gated and stimuli-responsive precision theranostics

Exosomes are endogenous extracellular vesicles with exceptional biocompatibility and intrinsic targeting potential, yet their clinical translation is limited by functional heterogeneity, insufficient controllability, and lack of spatiotemporal precision. While numerous engineering strategies have been developed, most remain confined to single-function enhancement and fail to achieve coordinated, programmable therapeutic control. In this Review, we propose the concept of "smart exosomes" as a next-generation paradigm for exosome engineering, defined by multi-stimuli responsiveness, Boolean logic-gated signal processing, and multimodal theranostic integration. We summarize exosomal biomarkers across animal-, plant-, and microbial-derived vesicles and highlight their evolving roles from passive identifiers to active structural and functional interfaces for intelligent design. Natural exosome organotropism and surface molecular fingerprints are discussed as a biological foundation for precision targeting. We further review the major exosome engineering strategies, including genetic modification, chemical conjugation, physical manipulation, and exosome-nanocarrier hybridization, which together constitute a versatile engineering toolbox. A central focus is the integration of endogenous and exogenous cues-such as pH, redox status, enzymatic activity, and external physical stimuli-into logic-gated exosome systems capable of multi-input sensing and conditional activation. Importantly, we explicitly differentiate experimentally validated logic-gated exosome systems from hypothetical or extrapolated designs, and we discuss the key technological barriers to achieving true multi-input Boolean logic execution in vivo. Such designs enable programmable cargo release, imaging feedback, and precisely controlled therapeutic action. Finally, we discuss key translational challenges and outline future directions toward AI-assisted design, plant-derived exosome platforms, and cooperative multi-stimulus response systems. Collectively, this Review establishes a conceptual framework for programmable exosome-based precision theranostics.