Dual cancer stem cell manipulation to enhance phototherapy against tumor progression and metastasis.

Targeting breast cancer stem cells (BCSCs) therapy is a prospective strategy to eliminate tumors owing to the BCSCs-governed drug resistance, tumor progression and metastasis. BCSCs are intrinsically in a disequilibrium state with favorable ability of self-renewal rather than differentiation, resulting in inability of complete tumor eradication. Besides the original BCSCs, epithelial-mesenchymal transition (EMT) process can further facilitate BCSCs regeneration, accompanied by tumor progression and metastasis. Herein, we, for the first time, engineered a photodynamic nanoplatform to manipulate BCSCs against tumor progression and metastasis by not only remolding the disequilibrium state but also blocking the EMT process. The HP@PP was constructed by haloperidol (HP)-incorporated polyethyleneimine-polyhistidine (PP) micelles, which was further integrated with low molecular weight heparin (LMWH)-chlorin e6 (Ce6) conjugate (LC) to form HP@PP/LC nanoparticles (NPs). For HP@PP/LC NPs, the protonation of PP in tumor tissues precisely targeted HP to BCSCs for remolding the disequilibrium state via promoting BCSCs differentiation into tumor cells. Simultaneously, LC conjugate targeted to tumors for exerting EMT blocking ability with LMWH, as well as exerting photodynamic clearance of tumor cells with Ce6 component. Therefore, our nanoplatform provides an emerging strategy for manipulating BCSCs against tumor progression and metastasis, demonstrating a promising photodynamic platform against tumors.