Understanding the Potential of Antibody-Drug Conjugates Functionalized Engineered Exosomes in Hepatocellular Carcinoma Therapy: A Comprehensive Narrative Review.

BACKGROUND: Exosomes are naturally secreted nanovesicles with high biocompatibility, low immunogenicity, and the ability to traverse biological barriers, making them attractive theragnostic carriers. When engineered to present tumor-specific antibodies and to deliver antibody-drug conjugates (ADCs), they may enhance selective targeting of hepatocellular carcinoma (HCC). METHODS: This narrative review synthesizes the multidisciplinary field of exosome bioengineering, ADCs, and HCC diagnosis and therapy, covering topics from click chemistry to translational challenges. A comprehensive search of PubMed, Web of Science, and Scopus (1991-2026) identified relevant studies on exosome-based targeted delivery, and diagnosis and therapeutics in HCC. Included studies focused on engineered exosomes, ADCs, and tumor-specific targeting, with rigorous characterization and relevance to HCC diagnosis and therapy. The review aims to provide a conceptual synthesis, highlighting translational progress and future directions in engineered exosome-based cancer diagnosis and therapy. RESULTS: The exosomal lipid bilayer protects encapsulated therapeutic cargo from premature degradation in circulation, while antibody display confers high-affinity recognition of HCC cells. A dual-targeting paradigm leveraging both the exosome's inherent tropism and antibody specificity supports increased intra-tumoral delivery and reduced off-target exposure relative to conventional modalities. Co-loading of imaging probes can enable integrated theragnostics, facilitating visualization of biodistribution, target engagement, and treatment response. However, as clinical data remains limited, these anticipated advantages in the human therapy should be established by thorough experimentation and clinical trials. CONCLUSION: ADC-functionalized exosomes (immuno-exosomes) can offer a suitable platform for precise HCC targeting with the potential to improve therapeutic index and enable real-time response monitoring. Translational progress will depend on robust, scalable manufacturing, rigorous characterization of purity and potency, and comprehensive evaluation of safety, pharmacokinetics, and efficacy in preclinical models and clinical studies.