RNA therapy combined with innovative delivery technology to stop psoriasis from being "cow"

Psoriasis (Psoriasis) is a chronic inflammatory skin disease that causes redness, itching and scaly knots that plague 125 million people worldwide.
small molecule drugs like steroids can penetrate the skin to treat the disease, but they can cause skin irritation and thinning, and their efficacy decreases over time.
Antibodies targeting specific inflammatory molecules associated with psoriasis have been developed, but since they cannot be delivered through the skin, they are generally given by injection, which undoubtedly limits the patient's acceptance of them and may also have systemic side effects.
researchers at Harvard University's Wyss Institute for Bio-Inspired Engineering and John A. Paulson's School of Engineering and Applied Sciences have successfully implemented skin delivery of small interfering RNA (siRNA) therapy in psoriasis model mice using a combination of ionic liquids (ionic liquids, IL).
this innovative treatment avoids the limitations of existing therapies and significantly reduces inflammatory cytokine levels and psoriasis symptoms without systemic side effects.
results were published July 22 in Science Advances.
photo source: Science Advances Synthesis SiRNA is a non-coding double-stranded RNA molecule that "silently" the gene by destroying RNA transcripts of the target gene.
this ability also makes them very attractive candidates for treating diseases without changing the DNA in a patient's cells.
, however, because RNA is a hydrophobic polymer, it is difficult to pass through the hydrophobic membranes of cells, and their medical application is hampered.
new study, the Harvard team used a recently discovered ionic liquid (IL) to address the challenge.
IL is essentially salty and liquid at room temperature.
based on early studies of IL's interactions with lipids, the researchers had a hunch that IL could stabilize siRNA and improve its ability to penetrate lipid cell membranes, achieving local gene silencing.
researchers first built a library of different IL and then tested their combinations to determine which had the physical and chemical properties they wanted.
they studied a mixture of CAGE (choline and balsamic acid) and CAPA (choline and phenylic acid), which helps the relevant siRNA molecules maintain their structural integrity and increase the permeability of siRNA in the skin of healthy mice.
when "naked" siRNA is applied to mouse skin, it has poor absorption capacity (medium).
the cage-CAPA ionic liquid makes it easier to penetrate the skin (right).
(Photo Source: Science Advances) When the CAGE-CAPA mixture was applied to the skin of living mice as a viscous external liquid, the researchers did not observe inflammation or irritation, indicating that the mixture was non-toxic.
because IL is a fairly new material, it is challenging to predict its interaction with "goods" that need to be delivered.
then conducted molecular dynamics simulations to simulate and understand how CAGE-CAPA solutions interact with siRNA and cell membranes at the molecular level.
results show that the component ions of the IL-siRNA complex have strong chemical interaction with the RNA base pair, and predict that the compound has excellent stability.
the model also shows that because ions in IL can be tightly stacked together to form aggregates, enhancing the complex's ability to destroy cell membranes and allow siRNA to enter, resulting in higher cell membrane permeability.
molecular dynamics simulations show that different types of ions (red, blue, purple) and siRNA atoms (white) in CAGE-CAPA ionic liquids interact strongly to help maintain their structure.
(Photo: Science Advances) identified an effective delivery tool, which the researchers combined with a siRNA (NFKBIZ siRNA) designed to silence the NFKBIZ gene.
the NFKBIZ gene is associated with an increase in many inflammatory molecules associated with psoriasis.
they applied the CAGE-CAPA mixture with siRNA to the skin of mice with psoriasis-like disease for 4 days, and then compared the mice to the IL-control siRNA group, the IL separate group, and the un treated mice.
treatment of IL-NFKBIZ siRNA significantly reduced skin thickening, redness and scales in model mice compared to other experimental groups.
, NFKBIZ and other psoriasis-related gene products in mouse skin cells were significantly reduced.
this is the first evidence that IL-siRNA complex can induce therapeutic effects at the molecular and visually visible levels through the silent target gene in the body after local drugation.
B) used IL-NFKBIZsiRNA for local treatment of psoriasis mice and compared them with untreated and applied IL groups.
C) psoriasis can cause inflammation when induced in mouse skin (left).
when treated with an ionic fluid free of siRNA, inflammation worsens (medium).
when treated with an IL-siRNA complex, inflammation is reduced (right).
(Photo Source: Science Advances) Overall, the study developed a mesothetic drug IL platform that delivers RNA to the skin, combined with RNA therapy to effectively silence key signaling targets for psoriasis.
-optimized IL formula does not show toxicity and can be reused.
the platform is easy to zoom in and adjust and works with a variety of therapeutic molecules, including DNA and antibodies.
it can also be delivered through the skin to treat other skin diseases, including eczema, and improve long-term efficacy by targeting genes that mediat multiple disease path path paths.
, author of the paper, said:
The treatment of skin diseases with external emulsions has been around for hundreds of years, but the skin is a very effective barrier to most substances, which limits their efficacy.
to build a 'bridge' to this barrier and deliver nucleic acid therapy directly to skin cells is a huge step forward in the search for targeted and effective therapies.
" Reference: 1 sbhirup Mandal et al. Treatment of psoriasis with NFKBIZ siRNA using topical ionic liquid developments. Science Advances (2020) 2 s Get under the skin of psoriasis (Source: Harvard University Wyss Institute of Bio-Inspired Engineering)