Hyaluronic acid-modified biomimetic liposomes co-loaded with doxorubicin and melatonin for targeted inhibition of breast cancer proliferation and metastasis

The tumor microenvironment (TME) plays an important role in tumor development. In TME, cancer-associated fibroblasts (CAFs) and neutrophil extracellular traps (NETs) facilitate tumor proliferation, drug resistance, and metastasis. Anti-tumor strategies targeting CAFs and NETs might be effective therapeutic modalities to inhibit tumor growth, drug resistance, and metastasis. In this study, a platelet membrane-encapsulated hyaluronic acid (HA)-acid-modified biomimetic nano-delivery system co-loaded with doxorubicin (DOX) and melatonin (MT) was prepared. MCF-7 + MRC-5 co-culture cell model and 4 T1 + NIH-3 T3 co-implanted in situ breast cancer model were used to simulate the real breast cancer microenvironment. As expected, the HA-PLIP-based nanodelivery system enhanced drug internalization and inhibited drug efflux. The growth and proliferation of breast cancer cells were significantly inhibited. Histological analysis showed that DM/HA-PLIP significantly inhibited tumor growth, suppressed extracellular matrix (ECM) deposition reduced tumor neovascularization and alpha-SMA protein expression, and significantly reduced the number of metastatic nodules and NETs. In summary, DM/HAPLIP is expected to substantially improve the therapeutic efficacy of breast cancer by inhibiting the crosstalk of CAFs and NETs with tumor cells, which has a broad clinical application prospect.