Core–Shell Nanosystems for Self-Activated Drug–Gene Combinations against Triple-Negative Breast Cancer

Abstract

The combination of gene therapy with chemotherapeutics provides an efficacious strategy for enhanced tumor therapy. RNA-cleaving DNAzyme has been recognized as a promising gene-silencing tool, while its combination with chemotherapeutic drugs has been limited by the lack of an effective codelivery system to allow sufficient intracellular DNAzyme activation, which requires specific metal ions as a cofactor. Here, a self-activatable DNAzyme/drug core–shell codelivery system is fabricated to combat triple-negative breast cancer (TNBC). The hydrophobic chemotherapeutic, rapamycin (RAP), is self-assembled into the pure drug nanocore, and the metal–organic framework (MOF) shell based on coordination between Mn2+ and tannic acid (TA) is coated on the surface to coload an autophagy-inhibiting DNAzyme. The nanosystem efficiently delivers the payloads into tumor cells, and upon endocytosis, the MOF shell is disintegrated to release the therapeutics in response to an acidic endo/lysosome environment and intracellular glutathione (GSH). Notably, the coreleased Mn2+ serves as the cofactor of DNAzyme for effective self-activation, which suppresses the expression of Beclin 1 protein, the key initiator of autophagy, resulting in a significantly strengthened antitumor effect of RAP. Using tumor-bearing mouse models, the nanosystem could passively accumulate into the tumor tissue, impose potent gene-silencing efficacy, and thus sensitize chemotherapy to inhibit tumor growth upon intravenous administration, providing opportunities for combined gene-drug TNBC therapy.

In Situ Modulating DNAzyme Activity and Internalization Behavior with Acid-Initiated Reconfigurable DNA Nanodevice for Activatable Theranostic

“…Distinctive tumor microenvironment (TME), including elevated glutathione level, low extracellular pH (pH e ), hypoxia et al, provides an alternative opportunity to improve specificity of cancer theranostics . By integrating TME-responsive element with DNAzyme-delivery system, the resulting nanomedicine is able to turn on its therapeutic activity upon occurrence of stimuluses. ,− Nevertheless, the activation of DNAzyme in current studies always rely on glutathione-triggered release of manganese ion (Mn 2+ ), essential cofactor of DNAzyme. ,,, Indeed, excess Mn 2+ can impair neurological function, thus posing potential safety risk . As such, developing precise and safety DNAzyme based theranostics is still in need.…”

CMBs carrying PTX and CRISPR/Cas9 targeting C‑erbB‑2 plasmids interfere with endometrial cancer cells

“…At the same drug concentration, compared with the PTX group, the anti-tumor effect of CMBs following release of PTX was improved. Combination therapy is expected to overcome the limitations of traditional treatments that rely on only one therapy, including the adverse reactions and toxic effects caused by ineffective increase of drug doses, off-target effects of gene editing and the effects of drugs or surgery on normal tissue and organs ( 43 , 44 ). Gene therapy combining chemotherapeutic agents and genetic material has become a promising combination therapy strategy due to its synergistic effect and ability to decrease chemotherapeutic dose without affecting anti-tumor activity ( 45 ).…”

Combinational application of metal–organic frameworks‐based nanozyme and nucleic acid delivery in cancer therapy

“…The MOF shell could degrade in the acidic environment of the lysosome and release Mn 2+ and the DNAzyme into the cytoplasm, with Mn 2+ acting as a cofactor for the DNAzyme. The DNAzyme suppressed the expression of beclin‐1, a key initiator of autophagy, and elicited a synergistic anti‐tumor effect with RAP (Liu et al, 2020).…”