Biomedical Technology · Published 2026-04-15 · DOI 10.1016/j.bmt.2026.100137
Background: Breast cancer remains a critical unmet clinical challenge due to its aggressive metastasis behavior and limited treatment options. Topoisomerase inhibitors are widely available clinically but fail to address the compensatory upregulation of alternative isoforms in metastatic breast cancer. Techonology: We engineered redox-responsive, carrier-free nanoassemblies (POD-2S-CPT NPs, PSC NPs) by co-assembling camptothecin (CPT, Topo I inhibitor) and podophyllotoxin (POD, Topo II inhibitor) linked via a disulfide bond. This design achieved high drug loading and leveraged the tumor microenvironment (TME), specifically elevated glutathione (GSH), for targeted drug release and maximized the synergistic therapeutic effect of Topo I/II inhibition. Results: The PSC NPs demonstrated GSH-responsive drug release and selective cytotoxicity against MCF-7 cells. Mechanistically, they induced necroptosis via concurrent nuclear Topo I/II inhibition, mitigating compensatory resistance. In vivo, PSC NPs exhibited potent antitumor efficacy and significantly suppressed lung metastasis, without significant systemic toxicity. RNA-seq analysis revealed concurrent downregulation of the CXCL1/5-S100A8/9 axis in treated tumors, suggesting potential immunomodulatory effects alongside direct DNA damage. This self-assembled, redox-responsive nanoplatform enabled synergistic dual Topo I/II inhibition within the TME. It demonstrated potent anti-tumor and anti-metastatic activity with a favorable safety profile, presenting a promising potential strategy for metastatic breast cancer therapy.
Abstract from DOAJ. Public domain (CC0 1.0).
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