Biomimetic Construction of Degradable DNAzyme-Loaded Nanocapsules for Self-Sufficient Gene Therapy of Pulmonary Metastatic Breast Cancer

Abstract

Pulmonary metastasis of breast cancer is the major cause of deaths of breast cancer patients, but the effective treatment of pulmonary metastases is still lacking at present. Herein, a degradable biomimetic DNAzyme biocapsule is developed with the poly­(ethylenimine) (PEI)-DNAzyme complex encapsulated in a Mn2+/Zn2+-coordinated inositol hexaphosphate (IP6) capsule modified with the cRGD targeting peptide for high-efficiency gene therapy of both primary and pulmonary metastatic breast tumors. This DNAzyme biocapsule is degradable inside acidic lysosomes, leading to the release of DNAzyme and abundant Mn2+/Zn2+ for catalytic cleavage of EGR-1 mRNA. We find that PEI promotes the lysosomal escape of the released DNAzyme. Both in vitro and in vivo experiments demonstrate the apparent downregulation of EGR-1 and Bcl-2 protein expression after treatment with the DNAzyme biocapsule, thereby inducing apoptotic death of tumor cells. We further verify that the DNAzyme biocapsule exhibits potent therapeutic efficacy against both primary and pulmonary metastatic breast tumors with significant inhibition of peri-pulmonary metastasis. This study provides a promising effective strategy for constructing degradable DNAzyme-based platforms with self-supply of abundant metal ion cofactors for high-efficiency gene therapy of metastatic breast cancer.

Nanotechnology for the theranostic opportunity of breast cancer lung metastasis: recent advancements and future challenges

“…Liu et al (2016) delivered Map3k1-amiRNA into 4T1 breast cancer cells using a miRNA-expressing lentiviral system and showed that MAP3K1 amiRNA attenuated tumor growth and lung metastasis of breast cancer cells in vivo nude mice model. Jiang et al (2023) have constructed DNAzyme nanocapsules, which encapsulate poly -LRB-ethylenimiPEI (PEI)-DNAzyme iMN2 MnZN2/Zn2 +coordinated inositol hexaphosphaIP6(IP6) capsule modified with cRGD targeting peptide, exhibits effective therapeutic efficacy against both primary and metastatic breast tumors inMCF-7CF-7 breast tumor-bearing mouse model. In this study, apoptosis was induced by downregulation of EGR-1 and BCL-2 protein expression.…”