Light-Activated siRNA Endosomal Release (LASER) by Porphyrin Lipid Nanoparticles
In: ACS Nano, Jg. 17 (2023-03-14), Heft 5, S. 4688-4703
serialPeriodical
Zugriff:
Lipid nanoparticles (LNPs) have achieved clinical success in delivering small interfering RNAs (siRNAs) for targeted gene therapy. However, endosomal escape of siRNA into the cytosol remains a fundamental challenge for LNPs. Herein, we report a strategy termed light-activated siRNA endosomal release (LASER) to address this challenge. We established a porphyrin-LNP by incorporating porphyrin-lipids into the clinically approved Onpattro formulation. The porphyrin-LNP maintained the physical properties of an LNP and generated reactive oxygen species (ROS) when irradiated with near-infrared (NIR) light. Using confocal microscopy, we revealed that porphyrin-lipids within the LNP translocate to endosomal membranes during endocytosis. The translocated porphyrin-lipids generated ROS under light irradiation and enabled LASER through endosomal membranes disruption as observed through GAL-9 recruitment and transmission electron microscopy (TEM). By establishing a quantitative confocal imaging method, we confirmed that porphyrin-LNPs can increase siRNA endosomal escape efficiency by up to 2-fold via LASER and further enhance luciferase target knockdown by 4-fold more in luciferase-transfected prostate cancer cells. Finally, we formulated porphyrin-LNPs encapsulated with gold nanoparticles (GNP) and visualized the LASER effect within prostate tumors via TEM, confirming the light-activated endosomal membrane disruption and subsequent GNP release into cytosols in vivo. Overall, porphyrin-LNPs and the LASER approach enhanced siRNA endosomal escape and significantly improved knockdown efficacy. We believe the versatility of this technology could be applied to various LNP-based RNA therapeutics.
Titel: |
Light-Activated siRNA Endosomal Release (LASER) by Porphyrin Lipid Nanoparticles
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Autor/in / Beteiligte Person: | Mo, Yulin ; Cheng, Miffy H. Y. ; D’Elia, Andrew ; Doran, Katie ; Ding, Lili ; Chen, Juan ; Cullis, Pieter R. ; Zheng, Gang |
Zeitschrift: | ACS Nano, Jg. 17 (2023-03-14), Heft 5, S. 4688-4703 |
Veröffentlichung: | 2023 |
Medientyp: | serialPeriodical |
ISSN: | 1936-0851 (print) ; 1936-086X (print) |
DOI: | 10.1021/acsnano.2c10936 |
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