Micellar nanoparticles inhibit the postoperative inflammation, recurrence and pulmonary metastasis of 4T1 breast cancer by blocking NF-κB pathway and promoting MDSCs depletion

The progression of breast cancer can stimulate the production of myeloid-derived suppressor cells (MDSCs). These cells with significant immunosuppressive activity play a key role in promoting the formation of pulmonary inflammatory and immunosuppressive microenvironment, namely pre-metastatic niche (PMN). Surgical resection of tumors often leads to strong inflammatory reactions, and the produced circulating tumor cells (CTCs) can implant into PMN to promote the recurrence and pulmonary metastasis of breast cancer. Therefore, we developed a hyaluronic acid (HA)-coated chitosan oligosaccharide-all-trans-retinoic-acid (COS-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) (HA@CA/DOX NPs). The hydrophilic segment COS and hydrophobic segment ATRA both blocked NF-κB inflammatory signaling pathway in 4T1 tumor cells and MDSCs and alleviated the inflammation after resection. Besides, ATRA also significantly depleted MDSCs in lungs and tumors, thereby regulating the inflammatory and immunosuppressive microenvironment and inhibiting the formation of PMN. HA coated on the surface of nanoparticles shielded the excessive positive charge and achieved tumor targeting through CD44 on the surface of tumor cells. This drug delivery system combined with anti-inflammation and chemotherapy significantly inhibited the postoperative recurrence and pulmonary metastasis of breast cancer.