Exosomes as Biomimetic Nanoplatforms for Synergistic Targeted Chemotherapy and Photothermal Treatment of Breast...

Breast cancer remains the most common cancer in women worldwide, with approximately 2.3 million new cases and 685,000 deaths annually (WHO, 2024). Triple-negative breast cancer (TNBC), the most aggressive subtype, has < 15% 5-year survival in metastatic cases, while conventional therapies are hampered by off-target toxicity, multidrug resistance, and poor tumor accumulation (< 0.7% injected dose per gram of tumor (ID/g)). We present engineered exosomes as next-generation Trojan horses for TNBC: NIR-activatable photothermal agents (polydopamine, BPQDs, or ICG) are integrated into the membrane and chemotherapeutics or nucleic acids (doxorubicin, paclitaxel, siKRAS, siPD-L1, miR-145) encapsulated in the lumen. This "smart" platform exploits exosomes' natural tumor-homing and immune-evasive properties; a single low-power 808 nm laser pulse triggers mild hyperthermia (42°C-45°C), immunogenic cell death, and burst payload release, converting "cold" TNBC into "hot" tumors. In orthotopic and metastatic 4T1/MDA-MB-231 models, one intravenous dose plus 5-min irradiation achieved a substantial tumor reduction in preclinical models, significant metastasis inhibition in murine models, long-term memory immunity, and 15%-18% IDg tumor accumulation with negligible toxicity. Major challenges-donor heterogeneity, low yields, rapid clearance, regulatory gaps, and limited NIR-II probes-are being overcome via single-cell omics, advanced bioreactors, CD47/PEGylation engineering, rigorous CMC standards, and PbS quantum dot loading. Future directions include AI/CRISPR-optimized design, NIR-II platforms, checkpoint inhibitor synergy, with early-stage clinical translation of photothermal and immunomodulatory exosome-based therapeutics currently underway, highlighting their potential to advance precision oncology. "However, challenges including scalability, batch variability, and regulatory standardization remain significant barriers to clinical translation."