Intracellular delivery of bacterial effectors for cancer therapy using biodegradable lipid nanoparticles
- PMID: 36919841
- DOI: 10.1039/d3bm00008g
Intracellular delivery of bacterial effectors for cancer therapy using biodegradable lipid nanoparticles
Abstract
Bacterial effector proteins are virulence factors that are secreted and mediate orthogonal post-translational modifications of proteins that are not found naturally in mammalian systems. They hold great promise for developing biotherapeutics by regulating malignant cell signaling in a specific and targeted manner. However, delivering bacterial effectors into disease cells poses a significant challenge to their therapeutic potential. In this study, we report on the design of a combinatorial library of bioreducible lipid nanoparticles containing disulfide bonds for highly efficient bacterial effector delivery and potential cancer therapy. A leading lipid, PPPDA-O16B, identified from the library, can encapsulate and deliver DNA plasmids into cells. The gene cargo is released in response to the reductive cellular environment that is upregulated in cancer cells, leading to enhanced gene delivery and protein expression efficiency. Furthermore, we demonstrate that PPPDA-O16B can deliver the bacterial effector protein, DUF5, to degrade mutant RAS and inactivate downstream MAPK signaling cascades to suppress cancer cell growth in vitro and in tumor-bearing mouse xenografts. This strategy of delivering bacterial effectors using biodegradable lipid nanoparticles can be expanded for cancer cell signaling regulation and antitumor studies.
Similar articles
-
Cationic Lipid-based Intracellular Delivery of Bacterial Effectors for Rewiring Malignant Cell Signaling.Angew Chem Int Ed Engl. 2020 Oct 5;59(41):18087-18094. doi: 10.1002/anie.202009572. Epub 2020 Aug 18. Angew Chem Int Ed Engl. 2020. PMID: 32671943
-
Fast and Efficient CRISPR/Cas9 Genome Editing In Vivo Enabled by Bioreducible Lipid and Messenger RNA Nanoparticles.Adv Mater. 2019 Aug;31(33):e1902575. doi: 10.1002/adma.201902575. Epub 2019 Jun 19. Adv Mater. 2019. PMID: 31215123 Free PMC article.
-
Enhanced intracellular siRNA delivery using bioreducible lipid-like nanoparticles.Adv Healthc Mater. 2014 Sep;3(9):1398-403. doi: 10.1002/adhm.201400039. Epub 2014 Feb 20. Adv Healthc Mater. 2014. PMID: 24574196
-
Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids, proteins, and drugs.Acta Pharm Sin B. 2022 Jun;12(6):2624-2639. doi: 10.1016/j.apsb.2022.04.013. Epub 2022 Apr 27. Acta Pharm Sin B. 2022. PMID: 35755280 Free PMC article. Review.
-
Developing Biodegradable Lipid Nanoparticles for Intracellular mRNA Delivery and Genome Editing.Acc Chem Res. 2021 Nov 2;54(21):4001-4011. doi: 10.1021/acs.accounts.1c00500. Epub 2021 Oct 20. Acc Chem Res. 2021. PMID: 34668716 Review.