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.
Development
of coatings with tailored surface properties that enhance
bone growth is crucial to enhancing the life span of load bearing
implants. Bioactive ceramic–polysaccharide hydrogel composite
materials are attractive for this application due to their chemical
similarity to human bone at the nanoscale. Equally important is the
creation of advanced coating processing techniques that can be easily
upscaled for mass manufacturing. Toward this aim, we developed an
electrochemical fabrication technique for the simple and rapid processing
of composite pectin hydrogels. This technique used polygalacturonic
acid (PGA) combined with anodic electrophoretic deposition (EPD) to
fabricate composite hydrogels, which contained bioactive particles
such as TiO2, hydroxyapatite, and bioactive glass. Another
key finding was the ability of PGA to facilitate rapid fabrication
of antibacterial coatings for infection prevention using the antibiotic
tetracycline. We proposed a mechanism of deposition and proved our
hypothesis using Fourier transform infrared spectroscopy. To evaluate
the suitability of our coatings for bone tissue repair, comprehensive
surface characterization was conducted, including scanning electron
microscopy, X-ray diffraction, water contact angle measurements, and
cell metabolism assays. Surface characterization results revealed
that our PGA composite films exhibit a desirable combination of surface
chemistry and morphology, which was achieved in one processing step.
Furthermore, PGA hydrogel coatings supported cell adhesion and proliferation,
demonstrating that our technique is an attractive strategy for rapid
surface modification of metallic implants.
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