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

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Chimeric antigen receptor T cell (CAR-T) therapy shows efficacy in blood cancers but faces challenges in solid tumors, including poor penetration and toxicity.
• Solid tumors present immunosuppressive microenvironments and risks like cytokine release syndrome (CRS), limiting CAR-T efficacy and safety.

Purpose of the Study:

• To develop a novel cell-free therapeutic platform using engineered exosomes derived from CAR-T cells.
• To enhance anti-tumor activity and safety by loading exosomes with miR-145, creating exo-CT-145.

Main Methods:

• Engineering exosomes from B7-H3-targeted CAR-T cells, incorporating cytotoxic payloads (perforin, granzyme) and miR-145.
• Evaluating exo-CT-145 efficacy in vitro against oesophageal squamous cell carcinoma (ESCC) and in vivo tumor models.

Main Results:

• Exo-CT-145 demonstrated significant inhibition of ESCC cell proliferation, migration, and epithelial-mesenchymal transition (EMT), inducing apoptosis.
• In vivo studies showed targeted tumor accumulation, apoptosis induction, EMT reversal, and suppressed angiogenesis with no detectable CRS or systemic toxicity.

Conclusions:

• Exo-CT-145 represents a synergistic nanotherapeutic approach combining antigen-specific killing and gene modulation for solid tumors.
• This cell-free platform offers a promising strategy for improved efficacy and safety in treating solid tumors, overcoming CAR-T limitations.