Light-Activated Core–Shell Nanoparticles for Spatiotemporally Specific Treatment of Metastatic Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) tumors are heterogeneous, with mesenchymal-like cells at their core and fast proliferating cells on the periphery. It is desirable and beneficial to treat TNBC cells of different phenotypes with the most appropriate drugs. Here, we report a 78 nm, chlorin e6-, docetaxel-, and anti-Twist siRNA-containing polymeric nanoparticle (CDTN) with spatiotemporally specific activity when irradiated by light. Under conditions mimicking superficial tumor tissue with sufficient light input, TNBC cells are mainly killed by the photodynamic therapy (PDT) function of CDTNs. In contrast, under conditions mimicking deep tumor tissue with weak light input, PDT potentiates chemotherapy (CT) and gene therapy (GT) by facilitating the endolysosomal escape of CDTNs. Compared with free drugs, CDTNs improve the intratumoral exposure of docetaxel and anti-Twist siRNA by 2.5- and 2-fold, respectively. When combined with laser irradiation applied at the time of maximal intratumoral accumulation, the CDTNs significantly inhibit the growth of primary tumors and their lung metastasis (both >80%) by killing the peripheral cells, mainly through PDT and prohibiting the growth and metastasis of deep cells through PDT as enhanced CT and GT. On the contrary, dual-modality nanomedicine lacking CT, GT, or PDT showed fast primary tumor growth, poor metastasis control, or both, respectively. This study reveals the spatiotemporally specific mechanism of CDTNs in treating metastatic TNBC and highlights the importance of combined therapy in treating TNBC.