<H4text="LNPs and their impact on modern medicine"id="text"/>
<p>LNPs are an advanced delivery system designed to transport therapeutic molecules like RNA, DNA or proteins into the cells. These nanoparticles are tiny spheres made of lipids that form a protective shell around the cargo. The size of LNs typically ranges from 50 to 200 nm in diameter, making them incredibly small - about 1,000 times thinner than a human hair <SupScrollLinklabel="1"/> . </p>
<p>LNPs are an advanced delivery system designed to transport therapeutic molecules like RNA, DNA or proteins into the cells. These nanoparticles are tiny spheres made of lipids that form a protective shell around the cargo. The size of LNPs typically ranges from 50 to 200 nm in diameter, making them incredibly small - about 1,000 times thinner than a human hair <SupScrollLinklabel="1"/> . </p>
<p>Overall, LNPs represent a significant advancement in drug delivery technology. LNPs offer exceptionally high drug-loading capacities, making them highly effective for delivering substantial amounts of therapeutic agents in a single dose. Their advanced design allows for the encapsulation of a large payload, which enhances the efficacy of treatments and reduces the frequency of administration <SupScrollLinklabel="3"/> . By encapsulating and protecting therapeutic agents like mRNA, LNPs enhance the stability, targeted delivery, and effectiveness of treatments. Their ability to be tailored for specific delivery needs, such as targeting particular organs or overcoming physiological barriers, makes them a powerful tool in modern medicine <SupScrollLinklabel="9"/> .</p>
<H4text="Protection of cargo"id="text"/>
<p> The primary function of LNPs is to shield the therapeutic agents they carry, such as mRNA, from degradation and facilitate their delivery into cells. mRNA is a critical component in many modern vaccines and therapies, but it is highly susceptible to breaking down before it can reach its target within cells. LNPs address this challenge by encapsulating the mRNA, thus protecting it from harmful enzymes, like RNases and environmental conditions <SupScrollLinklabel="2"/> . </p>
<H4text="Delivery assurance"id="text"/>
<p>LNPs come in various types tailored for different therapeutic needs. Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) enhance drug stability and solubility, while Liposomes, with their bilayer structure, are versatile for encapsulating both hydrophilic and hydrophobic drugs. Cationic LNPs are ideal for gene delivery due to their positive charge, whereas anionic and neutral LNPs offer reduced interaction and lower toxicity, respectively <SupScrollLinklabel="3"/> . </p>
<p>To enhance their effectiveness, LNPs are designed with specific components. For instance, the Nebulized Lung Delivery 1 (NLD1) nanoparticle, a particular type of LNP, includes a combination of lipids and polymers that stabilize the mRNA and allow it to be delivered efficiently. This formulation includes small lipid particles that encapsulate the mRNA and can maintain stability for several days under proper storage conditions <SupScrollLinklabel="2"/> . </p>
<H4text="Size impact of pulmonary LNPs"id="text"/>
In the context of pulmonary delivery, where the goal is to target the lungs, the size and properties of the LNPs are crucial. Particles smaller than 2 micrometers are particularly effective for reaching the alveolar regions of the lungs <SupScrollLinklabel="11"/> .
<p>To enhance their effectiveness, LNPs are designed with specific components. For instance, the Nebulized Lung Delivery 1 (NLD1) nanoparticle, a particular type of LNP, includes a combination of lipids and polymers that stabilize the mRNA and allow it to be delivered efficiently. This formulation includes small lipid particles that encapsulate the mRNA and can maintain stability for several days under proper storage conditions <SupScrollLinklabel="2"/> . </p>
<H4text="Role of surface modifications in targeting"id="text"/>
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<p>We have successfully demonstrated a <b>proof of concept</b> for our gene therapy approach targeting cystic fibrosis. In initial experiments, HEK cells carrying a 3-base deletion analogous to the <i>F508del</i> mutation were transfected with our prime editing complex. The results met our expectations, confirming the viability of our approach for precise gene correction. Based on these findings, we optimized the prime editing complex, leading to the creation of <i>PrimeGuide</i>, a more compact and efficient editing tool. </p>
<p>Central to our <b>delivery system</b> is <b>AirBuddy</b>, a lung-specific lipid nanoparticle designed to stabilize and protect the prime editing complex during transport to lung epithelial cells. <i>AirBuddy</i> ensures that the protein complex is delivered specifically to lung cells, enhancing the efficiency of the gene-editing process. By modifying the lipid nanoparticle with protective features, we achieved increased stability, ensuring effective delivery to the target cells. </p>
<p>We further optimized the prime editing fusion protein, <b>PrimeGuide</b>, to streamline its components, resulting in a smaller and more efficient prime editing complex. This improvement significantly enhances the precision of the gene editing process, reducing off-target effects and increasing the overall success of mutation correction. </p>
<p>In subsequent experiments, <b>HEK cells</b> carrying the CFTR <i>F508del</i> mutation were successfully <b>transfected</b> with the optimized prime editing complex. Our results indicated successful correction of the mutation, confirming the potential of our approach for treating cystic fibrosis. </p>
<p>In subsequent experiments, <b>HEK and lung (CFBE41o-)cells</b> carrying the CFTR <i>F508del</i> mutation were successfully <b>transfected</b> with the optimized prime editing complex. Our results indicated successful correction of the mutation, confirming the potential of our approach for treating cystic fibrosis. </p>
<p>Additionally, we explored <b>downstream applications</b>. Primary cell cultures were treated with lipid nanoparticles to introduce a reporter RNA. We also established 2D cultures transfected with YFP, a sodium-sensitive reporter protein, to assess ion channel functionality. Finally, in CFTR-deficient organoids, our system facilitated repair of the CFTR channel, evidenced by an increase in organoid volume upon treatment. This suggests successful functional restoration of CFTR activity. </p>
