Dual-targeted poly(amino acid) nanoparticles deliver drug combinations on-site: an intracellular synergistic strategy to eliminate intracellular bacteria.

Multi-drug combinations are a common strategy for the treatment of intracellular bacterial infections. However, different internalized pathways and the accumulation of the composite drugs at different subcellular organelles very much reduce their efficacy. Herein, an intracellular synergistic strategy is proposed, which is realized by on-site delivery of a drug combination using a macrophage/intracellular bacterium-dual targeted drug delivery system (DDS). The DDS is fabricated by encapsulating vancomycin (Van) and curcumin (Cur) into poly(α-N-acryloyl-phenylalanine)-block-poly(β-N-acryloyl-D-aminoalanine-co-2-O-acetyl-α-D-mannosyloxy) nanoparticles, denoted by (Van + Cur)@F(AM) NPs. Mannose ligands on (Van + Cur)@F(AM) NPs trigger their specific internalization in macrophages, while aminoalanine moieties subsequently drive the NPs to target intracellular methicillin-resistant Staphylococcus aureus (MRSA). Thereafter, Van and Cur are durably released in a synergistic dose at the residence site of intracellular MRSA. Under this intracellular synergistic effect, (Van + Cur)@F(AM) NPs show superior elimination efficiency in vitro and in vivo compared to the control groups, including free Van, (Van + Cur), the DDS encapsulated Van and the DDSs separately-encapsulated Van and Cur. Furthermore, (Van + Cur)@F(AM) NPs significantly enhance the in vivo antibacterial capacity by modulating the immune response. Therefore, this dual-targeted DDS-assisted intracellular synergistic antibacterial strategy of drug combination is an effective therapeutic against intracellular bacteria.