Astragalus-derived nano-agonist potentiates chemotherapy by reducing tumor-suppressive macrophages

Platinum-based chemotherapy only achieves a short-term success in the treatment of triple-negative breast cancer (TNBC), which is attributed to immunosuppressive macrophages post-chemotherapy. Herein, inspired by the plant immune defense mechanism, we demonstrate that edible astragalus-derived exosome-like nanoparticles (ADNPs) exhibit conspicuous efficacy in reprogramming M1-like tumor-associated macrophages (TAMs) through the activation of TLR2 signaling. The docking between released formononetin and TLR2 plays a key role during the cell internalization process. As a result, ADNPs in combination with Cisplatin (termed ADNP-Cis) greatly inhibit TNBC murine tumor progression and metastasis. Besides, ADNPs alleviate the peripheral blood toxicity caused by cisplatin treatment, and show lower toxicity compared with other TLR2 agonists previously reported. Taken together, this safe and robust ADNP-Cis therapy offers fresh insights into the management of TNBC chemotherapy.