Sequentially unlockable prodrug nanoparticles enable spatiotemporal coordination of chemotherapy and tumor microenvironment regulation for metastasis prevention in breast cancer

Chemotherapy remains the cornerstone in the clinical management of metastatic cancer, aiming at tumor cells. However, its therapeutic efficacy is significantly hampered by poor pharmacokinetics, non-specific biodistribution, off-target toxicity, and the pro-metastatic tumor microenvironment (TME). To address these challenges, we developed a sequentially responsive nanoplatform (SB@MHNP) that combines a hydroxycamptothecin (HCPT) prodrug with a TGF-β pathway inhibitor (SB525334, SB), stabilized through matrix metalloproteinase-9 (MMP-9)-sensitive peptide crosslinkers. Upon intravenous injection, SB@MHNP exhibits prolonged blood circulation due to its doubly stable structure and accumulates in the tumor site via the enhanced permeability and retention (EPR) effect. In the MMP-9-overexpressed TME, SB@MHNP loosens and swells to release SB, which inhibits the TGF-β signaling pathway and disrupts pro-metastatic TME formation. Subsequently, the remaining prodrug nanoparticles (HNP) collapse in the acidic intracellular environment, releasing pristine HCPT to inhibit DNA topoisomerase I, thereby exerting cytotoxic effects on tumor cells. In orthotopic breast tumor models with lung metastasis, SB@MHNP demonstrates potent primary tumor suppression and effective prevention of pulmonary metastases. This innovative nanoplatform offers a promising strategy for metastatic cancer therapy by orchestrating sequential TME modulation and tumor cell eradication.