Size-tunable nanogels for cascaded release of metronidazole and chemotherapeutic agents to combat Fusobacterium nucleatum-infected colorectal cancer

Bacteria play important roles in tumor formation, growth and metastasis through downregulating immune response and initiating drug resistance. Herein, size-tunable nanogels (NGs) have been developed to address the existing size paradox in tumor accumulation, intratumoral penetration and intracellular release of therapeutics for the treatment of Fusobacterium nucleatum (F. nucleatum)-infected colorectal cancer. Zinc-imidazolate frameworks with doxorubicin (DOX) loading and folate grafting (f-ZIFD) were mixed with metronidazole (MET) and encapsulated in NGs through thiol-ene click crosslinking of sulfhydryl hyaluronan, sulfhydryl alginate and 4-arm poly(ethylene glycol) acrylate. Hyaluronidase-initiated matrix degradation causes NG swelling to release sufficient MET and maintains a large size for an extended time period, and the gradually discharged f-ZIFD nanoparticles (NPs) from NGs exhibit acid-responsive intracellular release of DOX after folate-mediated internalization into tumor cells. The encapsulation into NGs significantly enhances the bioavailability and increases half-lives of MET and DOX by around 20 times. In the F. nucleatum-infected tumor model, the extended retention of swollen NGs and the efficient tumor infiltration and cellular uptake of the discharged f-ZIFD NPs cause 6 times higher DOX levels in tumors than that of free DOX administration. F. nucleatum promotes tumor cell proliferation and tumor growth, and the cascaded releases of MET and f-ZIFD NPs eliminate F. nucleatum to effectively inhibit tumor growth with a significant extension of animal survival. Thus, the hyaluronidase-mediated NG expansion and dual-responsive cascaded drug release have overcome challenges in the release regimen and size paradox of drug delivery carriers to combat bacteria-infected cancer.