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Interfacial Assembly of Bacterial Microcompartment Shell Proteins in Aqueous Multiphase Systems
Compartments are a fundamental feature of life, based variously on lipid membranes, protein shells, or biopolymer phase separation. Here, this combines self-assembling bacterial microcompartment (BMC) shell proteins and liquid-liquid phase separation (LLPS) to develop new forms of compartmentalization. It is found that BMC shell proteins assemble at the liquid-liquid interfaces between either 1) the dextran-rich droplets and PEG-rich continuous phase of a poly(ethyleneglycol)(PEG)/dextran aqueous two-phase system, or 2) the polypeptide-rich coacervate droplets and continuous dilute phase of a polylysine/polyaspartate complex coacervate system. Interfacial protein assemblies in the coacervate system are sensitive to the ratio of cationic to anionic polypeptides, consistent with electrostatically-driven assembly. In both systems, interfacial protein assembly competes with aggregation, with protein concentration and polycation availability impacting coating. These two LLPS systems are then combined to form a three-phase system wherein coacervate droplets are contained within dextran-rich phase droplets. Interfacial localization of BMC hexameric shell proteins is tunable in a three-phase system by changing the polyelectrolyte charge ratio. The tens-of-micron scale BMC shell protein-coated droplets introduced here can accommodate bioactive cargo such as enzymes or RNA and represent a new synthetic cell strategy for organizing biomimetic functionality
Vitamin B6 Tethered Endosomal pH Responsive Lipid Nanoparticles for Triggered Intracellular Release of Doxorubicin
This study reports the development
of Vitamin B6 (VitB6) modified
pH sensitive charge reversal nanoparticles for efficient intracellular
delivery of Doxorubicin (DOX). Herein, VitB6 was conjugated to stearic
acid, and the nanoparticles of the lipid were formulated by solvent
injection method (DOX-B6-SA-NP). Because of the p<i>K</i><sub>a</sub> (5.6) of VitB6, DOX-B6-SA-NP showed positive charge
and enhanced release of DOX at pH 5. Confocal microscopy illustrated
that DOX-B6-SA-NP treatment kept higher DOX accumulation inside the
cells than conventional pH insensitive lipid nanoparticles (DOX-SA-NP).
The cationic charge of nanoparticles subsequently facilitated the
endosomal escape and promoted the nuclear accumulation of DOX. Furthermore,
in vitro cytotoxicity, apoptosis, cell cycle arrest, and mitochondrial
membrane depolarization studies supported the enhanced efficacy of
DOX-B6-SA-NP in comparison to free DOX and DOX-SA-NP. Intravenous
pharmacokinetics and biodistribution investigations indicated that
pH sensitive nanoparticles can significantly prolong the blood circulation
time of DOX in biological system and increase the drug accumulation
to tumor site. Consequent to this, DOX-B6-SA-NP also exhibited much
enhanced therapeutic efficacy and lower toxicity in tumor-bearing
rats compared to free DOX. The reduction in toxicity was confirmed
by histological and survival analysis. In conclusion, these results
suggest that the VitB6 modified charge reversal nanoparticles can
be a novel platform for the successful delivery of anticancer drugs