仿生构建可降解 DNAzyme 纳米胶囊用于肺转移性乳腺癌的自给自足基因治疗,ACS Nano

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仿生构建可降解 DNAzyme 纳米胶囊用于肺转移性乳腺癌的自给自足基因治疗
ACS Nano ( IF 15.8 ) Pub Date : 2023-11-05 , DOI: 10.1021/acsnano.3c09581
Renting Jiang ₁ , Linhu Li ₁ , Ming Li ₁

Affiliation

乳腺癌肺转移是乳腺癌患者死亡的主要原因，但目前仍缺乏针对肺转移的有效治疗方法。在此，开发了一种可降解的仿生DNAzyme生物胶囊，其中将聚（乙烯亚胺）（PEI）-DNAzyme复合物封装在Mn ²⁺ /Zn ²⁺配位的肌醇六磷酸（IP6）胶囊中，并用cRGD靶向肽修饰以实现高效基因原发性和肺转移性乳腺肿瘤的治疗。^{这种 DNAzyme 生物胶囊在酸性溶酶体内可降解，导致 DNAzyme 和丰富的 Mn 2+} /Zn ²⁺的释放，用于催化裂解 EGR-1 mRNA。我们发现 PEI 促进释放的 DNAzyme 的溶酶体逃逸。体外和体内实验均表明，用 DNAzyme 生物胶囊处理后，EGR-1 和 Bcl-2 蛋白表达明显下调，从而诱导肿瘤细胞凋亡。我们进一步证实DNAzyme生物胶囊对原发性和肺转移性乳腺肿瘤具有有效的治疗功效，并显着抑制肺周围转移。这项研究为构建可降解的基于 DNAzyme 的平台提供了一种有前途的有效策略，该平台具有丰富的金属离子辅因子的自供能力，用于转移性乳腺癌的高效基因治疗。

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

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.

更新日期：2023-11-05

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