Up
to 99% of systemically administered nanoparticles are cleared
through the liver. Within the liver, most nanoparticles are thought
to be sequestered by macrophages (Kupffer cells), although significant
nanoparticle interactions with other hepatic cells have also been
observed. To achieve effective cell-specific targeting of drugs through
nanoparticle encapsulation, improved mechanistic understanding of
nanoparticle–liver interactions is required. Here, we show
the caudal vein of the embryonic zebrafish (Danio rerio) can be used as a model for assessing nanoparticle interactions
with mammalian liver sinusoidal (or scavenger) endothelial cells (SECs)
and macrophages. We observe that anionic nanoparticles are primarily
taken up by SECs and identify an essential requirement for the scavenger
receptor, stabilin-2 (stab2) in
this process. Importantly, nanoparticle–SEC interactions can
be blocked by dextran sulfate, a competitive inhibitor of stab2 and other scavenger receptors. Finally, we exploit
nanoparticle–SEC interactions to demonstrate targeted intracellular
drug delivery resulting in the selective deletion of a single blood
vessel in the zebrafish embryo. Together, we propose stab2 inhibition or targeting as a general approach for modifying nanoparticle–liver
interactions of a wide range of nanomedicines.
Despite tremendous efforts to develop stimuli-responsive enzyme delivery systems, their efficacy has been mostly limited to in vitro applications. Here we introduce, by using an approach of combining biomolecules with artificial compartments, a biomimetic strategy to create artificial organelles (AOs) as cellular implants, with endogenous stimuli-triggered enzymatic activity. AOs are produced by inserting protein gates in the membrane of polymersomes containing horseradish peroxidase enzymes selected as a model for natures own enzymes involved in the redox homoeostasis. The inserted protein gates are engineered by attaching molecular caps to genetically modified channel porins in order to induce redox-responsive control of the molecular flow through the membrane. AOs preserve their structure and are activated by intracellular glutathione levels in vitro. Importantly, our biomimetic AOs are functional in vivo in zebrafish embryos, which demonstrates the feasibility of using AOs as cellular implants in living organisms. This opens new perspectives for patient-oriented protein therapy.
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