Bacterial navigation for tumor targeting and photothermally-triggered bacterial ghost transformation for spatiotemporal drug release

Cancer chemotherapy is confronted with challenges regarding the effective delivery of chemotherapeutics into tumor cells after systemic administration. Herein, we propose a strategy to load drugs into probiotic E. coli Nissle 1917 (EcN) for self-guided navigation to tumor tissues and subsequently release the drugs with in situ transformation into bacterial ghosts (BGs). Chemotherapeutic agent 5-fluorouracil (FU) and macrophage phenotype regulator zoledronic acid (ZOL) are loaded into EcN through electroporation, followed by decoration of Au nanorods on the ECN surface to construct EcN_Z/F@Au. High loading levels of 5FU (8.8%) and ZOL (10.5%) are achieved as well as high retention rates of bacterial viability (87%) and motion velocity (88%). Under near infrared (NIR) illumination the photothermal effect of Au nanorods elevates the local temperature to induce the transformation of live EcN into BGs. The created transmembrane channels initiate the gradual drug release from BGs, thus representing the first attempt to control the drug release via a biological evolution. An intermittent NIR illumination causes stepwise increases in the BG formation and drug release, which could implement an external on-off control and spatiotemporal drug release. Self-guided motion of EcN promotes efficient extravasation across blood vessels and preferential accumulation of drugs in tumors. In addition to the chemotherapeutic effect of FU, the local release of ZOL from EcN_Z/F@Au enhances valid polarization of tumor-associated macrophages toward the M1 phenotype and an effective production of proinflammatory cytokines, leading to a synergistic efficacy on tumor growth inhibition. Thus, this study demonstrates a feasible strategy to integrate chemotherapy, immunotherapy, and photothermal effects in a concise manner for effective cancer treatment with few side effects. STATEMENT OF SIGNIFICANCE: Bacteria are capable to trace and colonize in hypoxic tumor tissues. Bacterial drug carriers indicate limitations in efficient drug loading and effective release modulation. Herein, we propose a strategy to load drugs into bacteria for self-guided delivery and subsequently release the drugs in tumors with in situ transformation into bacterial ghost (BGs). Drugs are loaded into live bacteria through electroporation and Au nanorods are decorated on the bacterial surface, wherein the photothermal effect, chemotherapy, and immunotherapy are integrated in a concise manner. NIR illmumination of Au nanorods elevates the local temparature, induces the BG tranformation, and activates the spatiotemporal drug release, representing the first attempt of release modulation via a biological evolution.

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