Engineered CAR-T-Derived Exosomes Co-Delivering miR-145 and Cytotoxic Proteins for Targeted Solid Tumour Therapy

Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated remarkable efficacy in haematologic malignancies but remains constrained in solid tumours due to limited tumour penetration, immunosuppressive microenvironments and the risk of cytokine release syndrome (CRS). Here, we develop a bioactive, cell-free therapeutic platform by engineering exosomes derived from B7-H3-targeted CAR-T cells and loading them with miR-145 (Name this exosome as exo-CT-145). The exosomes retain CAR-specific surface markers and cytotoxic payloads (perforin and granzyme), MiR-145 is expressed at low levels in various tumours and can inhibit the occurrence and development of tumours through multiple pathways. Exo-CT-145 significantly inhibited proliferation, migration, and Epithelial Mesenchymal Transition (EMT) of oesophageal squamous cell carcinoma (ESCC) cells and induced apoptosis in vitro. In vivo, exo-CT-145 demonstrated tumour-targeted accumulation, caspase-3 activation, EMT reversal, angiogenesis suppression and remodeling the tumor microenviroment while no detectable CRS or systemic toxicity. This study proposes a synergistic nanotherapeutic paradigm integrating antigen-specific killing and gene regulatory modulation, offering a promising direction for solid tumour treatment with improved safety and efficacy.