Abstract
Bacteria can bypass the blood-brain barrier (BBB) transcellularly, paracellularly and/or in infected phagocytes, suggesting the possibility of employment of bacteria for combating central nervous system (CNS) diseases. However, the bacteria-based drug delivery vehicle crossing the BBB is still vacant up to present. Herein, we develop an innovative bacteria-based drug delivery system (dubbed Trojan bacteria) for glioblastoma (GBM) photothermal immunotherapy. Typically, Trojan bacteria are made of therapeutics internalized into bacteria (e.g., attenuated Salmonella typhimurium, Escherichia coli). The therapeutics are composed of glucose polymer (GP) (e.g., poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose])-conjugated and indocyanine green (ICG)-loaded silicon nanoparticles (GP-ICG-SiNPs). The GP-ICG-SiNPs can be selectively and robustly internalized into the bacterial intracellular volume through the bacteria-specific ATP-binding cassette (ABC) transporter. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected Trojan bacteria could take therapeutics together not only to bypass the BBB, but also to target and penetrate GBM tissues. Under 808 nm-laser irradiation, the photothermal effects (PTT) produced by ICG allow the destruction of Trojan bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens would promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual Trojan bacteria could be effectively eliminated from the body due to the distinct photothermal effects. We anticipate the proposed Trojan bacteria system would catalyze innovative therapies for various CNS diseases.
Peptide-Drug Conjugates across the Blood-Brain Barrier: Using Viral Protein Domains to Shuttle Small Drugs to the Central Nervous System