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- Title
GRP75-driven, cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca<sup>2+</sup> nanoparticles underlies distinct gene therapy effect in ovarian cancer.
- Authors
Su, Linjia; Sun, Zhe; Qi, Fangzheng; Su, Huishan; Qian, Luomeng; Li, Jing; Zuo, Liang; Huang, Jinhai; Yu, Zhilin; Li, Jinping; Chen, Zhinan; Zhang, Sihe
- Abstract
Practice of tumor-targeted suicide gene therapy is hampered by unsafe and low efficient delivery of plasmid DNA (pDNA). Using HIV-Tat-derived peptide (Tat) to non-covalently form Tat/pDNA complexes advances the delivery performance. However, this innovative approach is still limited by intracellular delivery efficiency and cell-cycle status. In this study, Tat/pDNA complexes were further condensed into smaller, nontoxic nanoparticles by Ca2+ addition. Formulated Tat/pDNA-Ca2+ nanoparticles mainly use macropinocytosis for intercellular delivery, and their macropinocytic uptake was persisted in mitosis (M-) phase and highly activated in DNA synthesis (S-) phase of cell-cycle. Over-expression or phosphorylation of a mitochondrial chaperone, 75-kDa glucose-regulated protein (GRP75), promoted monopolar spindle kinase 1 (MPS1)-controlled centrosome duplication and cell-cycle progress, but also driven cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca2+ nanoparticles. Further in vivo molecular imaging based on DF (Fluc-eGFP)-TF (RFP-Rluc-HSV-ttk) system showed that Tat/pDNA-Ca2+ nanoparticles exhibited highly suicide gene therapy efficiency in mouse model xenografted with human ovarian cancer. Furthermore, arresting cell-cycle at S-phase markedly enhanced delivery performance of Tat/pDNA-Ca2+ nanoparticles, whereas targeting GRP75 reduced their macropinocytic delivery. More importantly, in vivo targeting GRP75 combined with cell-cycle or macropinocytosis inhibitors exhibited distinct suicide gene therapy efficiency. In summary, our data highlight that mitochondrial chaperone GRP75 moonlights as a biphasic driver underlying cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca2+ nanoparticles in ovarian cancer.
- Subjects
GENE therapy; OVARIES; PINOCYTOSIS; OVARIAN cancer; TREATMENT effectiveness; GLUCOSE-regulated proteins
- Publication
Journal of Nanobiotechnology, 2022, Vol 20, Issue 1, p1
- ISSN
1477-3155
- Publication type
Article
- DOI
10.1186/s12951-022-01530-6