Gallium
(Ga) compounds, as the source of Ga ions (Ga3+), have been
historically used as anti-inflammatories. Currently,
the widely accepted mechanisms of the anti-inflammatory effects for
Ga3+ are rationalized on the basis of their similarities
to ferric ions (Fe3+), which permits Ga3+ to
bind with Fe-binding proteins and subsequently disturbs the Fe homeostasis
in the immune cells. Here in contrast to the classic views, our study
presents the mechanisms of Ga as anti-inflammatory by delivering Ga
nanodroplets (GNDs) into lipopolysaccharide-induced macrophages and
exploring the processes. The GNDs show a selective inhibition of nitric
oxide (NO) production without affecting the accumulation of pro-inflammatory
mediators. This is explained by GNDs disrupting the synthesis of inducible
NO synthase in the activated macrophages by upregulating the levels
of eIF2α phosphorylation, without interfering with the Fe homeostasis.
The Fe3+ transferrin receptor-independent endocytosis of
GNDs by the cells prompts a fundamentally different mechanism as anti-inflammatories
in comparison to that imparted by Ga3+. This study reveals
the fundamental molecular basis of GND–macrophage interactions,
which may provide additional avenues for the use of Ga for anti-inflammatory
and future biomedical and pharmaceutical applications.
The CRISPR-Cas9 and related systems offer a unique genome editing tool allowing facile and efficient introduction of heritable and locus-specific sequence modifications in the genome.Despite its molecular precision, temporal and spatial control of gene editing with CRISPR-Cas9 system is very limited. We developed a light-sensitive liposome delivery system that offers a high degree of spatial and temporal control of gene editing with CRISPR/Cas9 system. We demonstrated its high transfection efficiency, by assessing the targeted knockout of eGFP gene in human HEK293 cells (52.8% knockout). We further validated our results at a single-cell resolution using an in vivo eGFP reporter system in zebrafish (77% knockout). To the best of our knowledge we reported the first proof-of-concept of spatio-temporal control of CRISPR/Cas9 by using lighttriggered liposomes in both in vitro and in vivo environment.
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