A Carrier-Free Nanomedicine Enables Apoptosis-Ferroptosis Synergistic Breast Cancer Therapy by Targeting Subcellular Organelles.

The heterogeneity of cancer cells disables the single-cell death patterns in subtypes of cells with different genotypes and phenotypes, such as refractory triple-negative breast cancer (TNBC). Therefore, the combination of multiple death modes, such as the proven cooperative apoptosis and ferroptosis, is expected to sensitize in treating TNBC. Herein, carrier-free theranostic ASP nanoparticles (NPs) were designed for wiping out TNBC by synergistic apoptosis and ferroptosis, which was self-assembled by aurantiamide acetate (Aa), scutebarbatine A (SA), and palmitin (P). Structurally, the rigid parent nucleus of SA and hydrophobic chain of P combined with the Aa to form an ordered nanostructure by noncovalent bonding forces. This self-assembly example applies to the design of nanomedicines based on more than two natural products. Notably, enhanced permeability and retention (EPR) effects and mitochondrial-lysosomal targeting empower ASP NPs to pinpoint tumor sites. Especially, Aa and P induced mitochondrial apoptosis of cancer cells, while SA and P inhibited TNBC by ferroptosis and upregulating p53. More interestingly, the combination of Aa, SA, and P enhanced the uptake of ASP NPs by cancer cell membranes. Overall, the three compounds synergize with each other to exert excellent anticancer effects.