RNA-based Therapeutics

🧬 𝐑𝐍𝐀 might be the future of medicine, but it has a problem: 𝐝𝐞𝐥𝐢𝐯𝐞𝐫𝐲! Lipid nanoparticles make RNA drugs work, but they (mostly) go straight to the liver. Not great, if you want to treat anything else! So, what if we had a better vehicle? This paper introduces 𝐚𝐍𝐏𝐬: apolipoprotein-based nanoparticles, that deliver RNA drugs directly to immune cells. They are inspired by natural cholesterol particles, and are: 🎯 Great at targeting bone marrow and spleen 🧩 Versatile, delivering mRNA, siRNA and antisense oligos 💥 Effective, outperforming LNPs on most tasks! Here’s what the team did: 1. Built aNPs using apoA1, a natural cholesterol transporter 2. Optimized the formula using a 72-particle library 3. Screened for RNA encapsulation, delivery, and silencing 4. Validated top hits in mice, with real therapeutic targets The results? ✅ aNP18 delivered siRNA to the bone marrow, not liver ✅ Strong knockdown of target genes (like Lamp1) ✅ Reduced immunosuppressive tumor macrophages by silencing CCR2 ✅ No side effects, and more effective than LNPs! This opens new possibilities for: 💥 Cancer immunotherapy (targeting tumor-suppressive cells) 🛡️ Autoimmune and inflammatory diseases 🧬 Regenerative medicine via RNA reprogramming It’s an important step for RNA delivery, and a reminder to look to nature for solutions! PS: Get the full breakdown here! https://lnkd.in/et9F7MKy #RNAtherapeutics #nanomedicine #drugdelivery #biotech

Quite a nice (and updated) review -RNA therapeutics and LNPs for extrahepatic delivery LNPs have become a cornerstone in delivering RNA therapeutics, successfully used in mRNA vaccines and gene therapies. Despite their success, LNPs' tendency to preferentially accumulate in the liver remains a critical limitation. This liver tropism hinders their effectiveness in treating diseases in other organs, such as the lungs, brain, and pancreas. 🔬 Recent research has made significant strides in re-engineering LNPs to deliver RNA to organs beyond the liver. One approach is to adjust the composition of LNP formulations, either by adding a cationic lipid (like DOTAP) or replacing the ionizable lipid's ester linkers with amide linkers. These modifications change the physicochemical properties of LNPs, influencing the biomolecular corona that forms post-administration, which ultimately determines organ-specific targeting. For instance, lung-targeted LNPs can transfect up to 65% of endothelial cells and 40% of epithelial cells in the lungs, demonstrating a potential breakthrough for treating pulmonary diseases like cystic fibrosis and pulmonary fibrosis. Spleen-specific delivery has been achieved by incorporating anionic lipids, enabling the targeting of immune cells like macrophages and T cells, essential for in vivo immunotherapy applications. Meanwhile, LNPs designed for bone marrow delivery are showing promise in treating hematopoietic disorders like sickle cell disease. 🧠 Still, delivering RNA to the brain remains a considerable challenge (you know, the usual BBB). However, promising strategies, like adding neurotransmitter-derived lipids to LNP formulations, are showing early success in crossing this barrier, paving the way for treating neurological diseases. 🎯 As we look to the future, designing LNPs that can target specific cell types and improve safety profiles is paramount. Advances in overcoming physiological barriers, such as the BBB and tissue-specific targeting, will revolutionize how we approach gene therapies for previously untreatable conditions. From organ-selective LNPs to fine-tuned biomolecular coronas, the future of RNA delivery is more promising than ever. Learn more here: https://lnkd.in/ecQjkNaq #Nanomedicine #LipidNanoparticles #GeneTherapy #RNA #BiotechInnovation #TargetedDelivery #DrugDelivery

A new class of mRNA drugs targets poison exons Companies are targeting poison exons embedded in mRNA transcripts as a strategy to restore wild-type protein abundance and cell fitness in severe pediatric epilepsy and other genetic diseases. In an early study testing a new class of therapeutic targeting toxic or poison exons, people with Dravet’s syndrome, a severe genetic form of epilepsy, showed improvements that were unexpected and substantial. STK-001, an antisense agent developed by Stoke Therapeutics, dramatically cut the number of seizures in patients who, before starting on the investigational treatment, were experiencing a median of seventeen episodes daily. These may be early trial results for STK-001, but for the wider field they are noteworthy for suggesting that strategies aimed at poison exons can indeed upregulate protein expression to counter deficits due to genetic mutations. Other companies are searching for similar antidotes to poisoned transcripts to treat other unsolved genetically driven conditions. Poison exons are small exons with premature stop codons that, if present, ‘poison’ an mRNA transcript and tag it for the scrap heap. Such mRNA poisoning is an evolutionarily conserved form of self-regulation critical in all eukaryotes. When included in an mRNA transcript, these poison exons influence alternative splicing, leading to its degradation via the nonsense-mediated decay pathway. Not only does this mechanism help remove faulty mRNA molecules from the transcriptome, but tagging ‘toxic’ RNA for disposal helps cells shape protein abundance in different tissues. Companies have found utility in drugging these ultraconserved elements to regulate transcription and tweak protein production in the cell. Drugs directed at poison exons can, depending on the biological context, boost a beneficial protein or suppress a harmful one. https://lnkd.in/eY_Y8KSs

I am pleased to share that our long-term collaborative research with Kyowa Kirin and Associate Professor Yasuaki Kimura at Nagoya University has been published in Nature Communications. In this work, we report the development of a fully chemically synthesized mRNA that exhibits over 100-fold higher translational output compared to canonical IVT mRNA, together with remarkably prolonged protein expression lasting more than 48 hours in cells—performance levels previously unattainable with enzymatically transcribed mRNA. Our study provides several key advances: First, by leveraging complete chemical synthesis, we established a platform enabling precise, position-specific introduction of ribose modifications within the open reading frame (ORF). This approach allowed us to systematically evaluate structural–activity relationships that were inaccessible with conventional IVT-based methods. Notably, we discovered that 2'-fluoro modification at the first nucleoside of each codon markedly stabilizes mRNA without impairing translation, overturning the long-standing assumption that ribose modification in ORFs is universally detrimental. Second, we found that extensive chemical modifications in the 5'-UTR can activate cap-independent translation with high efficiency. This enables robust protein synthesis even in the absence of a 5' cap structure—an important conceptual advance for the design of next-generation mRNA therapeutics. Third, by optimally combining ORF modifications with refined chemical designs at both the 5'-UTR and poly(A) tail, our chemically synthesized mRNA achieved higher and longer-lasting protein expression than state-of-the-art capped IVT mRNA (m1Ψ + extended poly(A)). In particular, the fully optimized construct (NK041) sustained high protein production for 24–48 hours and ultimately exhibited 6–16-fold higher expression than the best-performing IVT counterpart at later time points. These results demonstrate that rational chemical modification—made possible only through total chemical synthesis—provides a powerful and generalizable strategy for enhancing the stability and translational capacity of mRNA. We anticipate that this platform will contribute to future advances in cancer vaccines, protein replacement therapies, and regenerative medicine. This achievement would not have been possible without the dedicated efforts of our collaborators at Kyowa Kirin and the long-standing partnership with Associate Professor Kimura. I extend my sincere gratitude to all team members involved. Publication: Position-specific ORF nucleoside-ribose modifications enabled by complete chemical synthesis enhance mRNA stability and translation Nature Communications (2025) https://lnkd.in/gQqpHqNw

⭐NAR Breakthrough! ⭐ Two back-to-back studies from Dr. Gabriele Varani’s group at University of Washington deliver a striking advance in RNA-targeted therapeutics. The work lead by Ramireddy Ravikanth Reddy (RRR) reveals that the FDA-approved CDK4/6 inhibitor Palbociclib binds the HIV Trans-Activation Response (TAR) RNA with low nanomolar affinity and remarkable specificity - a level of precision long thought difficult to achieve for small, structurally simple RNA elements. Key insights: 🔬 A 13-nucleotide TAR motif forms the basis of an exquisitely specific interaction—disrupted by even single nucleotide changes. 💊 Palbociclib blocks recruitment of the super elongation complex (SEC) at low nanomolar concentrations, directly impacting viral transcription. 🧬 Structural studies uncover an unexpected induced-fit mechanism, where RNA refolding creates a deep binding pocket, enabling both high-affinity binding and functional inhibition. These findings challenge a long-standing paradigm: that small RNA stem-loops like TAR are “undruggable” due to the lack of defined pockets. Instead, they demonstrate that RNA structural plasticity can be harnessed to create druggable conformations. This work not only expands the therapeutic potential of RNA targeting but also highlights how repurposed small molecules can unlock entirely new mechanisms of action. A compelling step forward for RNA biology, antiviral strategies, and drug discovery. 📖 Explore the studies to learn more here: https://lnkd.in/eqXEBqMq https://lnkd.in/eWU-Jy3X #NARBreakthrough #RNABiology #DrugDiscovery #RNAtherapeutics #HIVResearch #StructuralBiology #ChemicalBiology #Transcription #Epigenetics

Noncoding RNA-based Therapeutics Noncoding RNA (ncRNA) therapeutics is a rapidly growing area of biotechnology that focuses on the therapeutic potential of RNA molecules that do not encode proteins but play key regulatory roles in gene expression. These noncoding RNAs include microRNAs (miRNAs), long noncoding RNAs (lncRNAs), small interfering RNAs (siRNAs), and other ncRNAs that affect cellular processes. (1) MicroRNAs (miRNAs): miRNAs are short, approximately 22 nucleotides long, and regulate post-transcriptional gene expression by binding to complementary sequences on messenger RNA (mRNA). This binding typically results in mRNA degradation or translational inhibition. Therapeutically, miRNAs can be targeted to inhibit their function using antagonists or mimic their activity using miRNA mimics to restore normal gene regulation. miRNA-based therapeutics are being used to treat a variety of diseases, including cancer, cardiovascular disease, and viral infections. (2) Long noncoding RNAs (lncRNAs): lncRNAs are more than 200 nucleotides long and are involved in a variety of cellular functions, including chromatin remodeling, transcriptional regulation, and splicing. lncRNA therapeutics can modulate these functions, providing potential treatments for cancer, neurological diseases, and metabolic diseases. Strategies include using antisense oligonucleotides (ASOs) to bind and alter lncRNA activity or using small molecules that can alter lncRNA interactions. (3) Small interfering RNA (siRNA): siRNAs are double-stranded RNA molecules that induce RNA interference (RNAi), leading to degradation of specific mRNAs, thereby silencing gene expression. siRNA therapeutics are designed to target and degrade mRNAs of disease-causing genes. This approach has been successfully used in treatments such as Patisiran, an siRNA drug for the treatment of hereditary transthyretin-mediated amyloidosis. (4) Aptamers: Aptamers are short, structured RNA or DNA molecules that, like antibodies, can bind to specific targets with high affinity. They can inhibit or modulate the activity of targets, including proteins, small molecules, and even cells. Aptamers have therapeutic potential in areas as diverse as oncology, ophthalmology, and coagulation disorders. Overall, ncRNA therapeutics have great potential in treating a variety of diseases by targeting regulatory RNAs that control gene expression, providing a new approach to precision medicine. References [1] Melanie Winkle et al., Nature Reviews Drug Discovery 2021 (https://lnkd.in/etPHSVuA) [2] Kinga Nemeth et al., Nature Reviews Genetics 2023 (https://lnkd.in/et6aETaP) [3] Daniel Fernandez-Diaz et al., Frontiers in Genetics 2022 (https://lnkd.in/eUfG4ARE)

RNA therapeutics is having a moment. Not hype. Real data. Real approvals. Real money. 🏥 First, the clinic: → Moderna's personalized cancer vaccine hit 5-year follow-up data. 49% sustained reduction in melanoma recurrence when combined with Keytruda. That's durability. Phase 3 pending. → Ionis got EU approval for DAWNZERA in hereditary angioedema—94% reduction in attack rates. Another ASO going commercial. → Arrowhead dropped obesity data that moved markets. ARO-INHBE combined with Zepbound doubled weight loss versus Zepbound alone (9.4% vs 4.8% at 16 weeks). RNAi is coming for cardiometabolic. → Ractigen dosed first patient in Phase 2 for SOD1-mutated ALS with an siRNA. The neurological space is opening up. 💵 Now, show me the money: → Arrowhead raised $825M - convertible notes plus equity. That's a war chest for their pipeline expansion beyond liver. → Corsera Health emerged with $80M Series A for once-annual siRNA cardiovascular therapies. Alnylam founder John Maraganore is a co-founder. When that name shows up, pay attention. → Ribo Life Sciences IPO'd on Hong Kong at $230M. Another China siRNA player going public. → Comanche Biopharma secured $40M for siRNA in preeclampsia. The modality keeps finding new targets. 🤝 The deals: → BioNTech + Bristol Myers Squibb: up to $7.6B in milestones for pumitamig. mRNA platforms are still attracting big pharma. → Soufflé Therapeutics + Bayer: collaboration on heart-targeted siRNA for dilated cardiomyopathy. Tissue-specific delivery is the new battleground. 👇 What does it all mean? Three patterns worth noting: 1️⃣ Beyond liver. Arrowhead's obesity data, Ractigen's ALS program, Soufflé's cardiac targeting...delivery is unlocking new tissues. 2️⃣ The durability question is being answered. Moderna's 5-year cancer vaccine data and Ionis' chronic disease approvals show these aren't one-time treatments. 3️⃣ Cardio is the next frontier...maybe. Arrowhead, Corsera, Novartis' pelacarsen - seems like the cardiovascular race is heating up. The mRNA vaccine moment proved the modality worked. Now we're seeing what else it can do.

🧬 𝗔𝗜 𝗶𝘀 𝗥𝗲𝗱𝗲𝗳𝗶𝗻𝗶𝗻𝗴 𝘁𝗵𝗲 𝗙𝘂𝘁𝘂𝗿𝗲 𝗼𝗳 𝗡𝘂𝗰𝗹𝗲𝗶𝗰 𝗔𝗰𝗶𝗱 𝗧𝗵𝗲𝗿𝗮𝗽𝗲𝘂𝘁𝗶𝗰𝘀 🤖 Small nucleic acid-based drugs—such as 𝗔𝗦𝗢𝘀, 𝘀𝗶𝗥𝗡𝗔𝘀, 𝗮𝗽𝘁𝗮𝗺𝗲𝗿𝘀, 𝗮𝗻𝗱 𝗺𝗶𝗥𝗡𝗔𝘀—are unlocking previously undruggable targets by modulating gene expression with exquisite precision. Yet their clinical translation remains hindered by challenges like instability, off-target effects, and delivery complexity. 🚧 This review delivers a systematic and critical synthesis of how 𝗮𝗿𝘁𝗶𝗳𝗶𝗰𝗶𝗮𝗹 𝗶𝗻𝘁𝗲𝗹𝗹𝗶𝗴𝗲𝗻𝗰𝗲 is accelerating progress in this field—shifting the design paradigm from trial-and-error to data-driven optimization. ⚙️📊 🔍 From structure-based heuristics to advanced machine learning and graph neural networks, new platforms are emerging that: • Predict hybridization efficacy and off-target risks • Recommend tailored chemical modifications (e.g., PS, LNA, 2’-OMe) • Optimize delivery via lipid nanoparticles, CPPs, or polymeric carriers Platforms such as 𝗔𝗦𝗢𝗽𝘁𝗶𝗺𝗶𝘇𝗲𝗿, 𝗲𝗦𝗸𝗶𝗽-𝗙𝗶𝗻𝗱𝗲𝗿, 𝗘𝗡𝘀𝗶𝗥𝗡𝗔, 𝗮𝗻𝗱 𝗔𝗽𝘁𝗮𝗗𝗶𝗳𝗳 demonstrate how AI can streamline therapeutic design, from exon skipping to aptamer affinity enhancement—reducing development cycles and improving safety. 📉🧪 However, data scarcity, lack of standardization, and translational gaps persist. The field is now calling for: 📚 FAIR-compliant datasets 🔄 Better in vivo–validated models 🧠 Integration of multi-modal features (sequence, structure, epigenomics) 🎯 𝗞𝗲𝘆 𝗧𝗮𝗸𝗲-𝗔𝘄𝗮𝘆𝘀: • 🧬 Small nucleic acid drugs are redefining gene-targeted therapies • 🤖 AI enables predictive design and optimization of efficacy, specificity, and chemical architecture • 💊 Delivery remains a major bottleneck, but nonviral systems are rapidly evolving • 📉 AI reduces reliance on empirical screening, but success depends on high-quality data and biological validation • 🔄 A multidisciplinary ecosystem is essential for translation into safer, smarter medicines #AIinDrugDiscovery #OligonucleotideTherapeutics #siRNA #ASO #Aptamers #MedicinalChemistry #PharmaInnovation #ComputationalBiology #RNAtherapeutics #Bioinformatics  Pietro Delre, Carmen Cerchia & Antonio Lavecchia University of Naples Federico II

mRNA makes up roughly 40% of all approved RNA therapeutics. But it wasn't the first. Antisense oligonucleotides (ASOs) were, accounting for ~34% of approvals and paving the way for the quick COVID turnaround of the 2020s. When choosing how to drug a target, researchers have plenty of options: small molecules, antibodies, peptides, even engineered cells. So why spend billions building drugs made of RNA? It comes down to mechanism. Small molecules work well when there’s a defined pocket to bind, but around 80% of the human proteome lacks one. Antibodies are highly specific, but they can’t cross cell membranes and target only the 10–15% of proteins exposed on the surface or in circulation. That leaves most disease-relevant biology inside cells — upstream of proteins and out of reach. RNA therapeutics solve that problem by going one level deeper. Instead of trying to block a protein once it’s made, targeting RNA lets you increase the right transcript or silence the wrong one. The first approved RNA drug arrived in 1998: Fomivirsen, a short, single-stranded ASO that binds complementary mRNA and recruits RNase H to degrade it. It targeted a CMV transcript essential for viral replication and treated CMV retinitis in immunocompromised patients. The 21-nucleotide drug used a phosphorothioate backbone, improving nuclease resistance and stability, and was delivered by direct injection into the eye — no lipid nanoparticles required. That first generation of ASOs focused on silencing. But researchers soon realized antisense could do more — it could reshape how RNA is processed. The second wave built on that insight. A single pre-mRNA can code for multiple protein isoforms through alternative splicing, a process that cuts and stitches different transcript versions together. Scientists hypothesized they could guide the spliceosome to include or skip specific regions, restoring functional proteins that would otherwise be defective. Spinraza (2016) was the result — one of the most transformative RNA therapies to date. It targets spinal muscular atrophy (SMA), a leading genetic cause of infant death. A single nucleotide change in SMN2 causes the splicing machinery to skip a crucial exon, producing a non-functional protein. By binding specific regulatory motifs on pre-mRNA, Spinraza prevents this skipping, tricking the cell into including exon 7 and restoring protein function. But mechanism wasn’t the only innovation. RNA chemistry had evolved too. 2′-O-methoxyethyl (2′-MOE) modifications strengthened binding and extended stability from hours to days, while fully modified, non–RNase H-activating motifs enabled precise splicing modulation without degrading the transcript. To date, there are roughly 35 approved RNA therapeutics in the U.S.: 14 mRNA, 12 ASOs, 7 siRNA, and 2 aptamers. With the low-hanging fruit of small-molecule and protein drugs slowly picked clean, the next breakthroughs might just come further upstream — in the language of RNA.

🧬 Harnessing RNA Therapeutics to Advance Healthy Aging Aging is a systemic decline affecting many organs, increasing risks of diseases like Alzheimer’s, cardiovascular disorders, pulmonary fibrosis, sarcopenia, and immune dysfunction. A recent Nature Aging review by Shuying Chen et al. (link in the comments) highlights RNA therapeutics as a promising strategy to delay aging and improve healthspan. 🔍 Key insights from the review: 1️⃣ RNA as a versatile therapeutic modality: RNA enables both upregulation and downregulation of gene expression through diverse mechanisms, including: ✅ mRNA therapy and RNA activation (RNAa) ✅ RNA interference (RNAi) and antisense oligonucleotides (ASOs) ✅ Aptamers and CRISPR–Cas gene editing tools 2️⃣ Beyond traditional RNA types: ✅ The review highlights the growing importance of noncoding RNAs — including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), tRNAs, and small activating RNAs (saRNAs) — in regulating genome stability, epigenetic memory, inflammatory response, and cellular senescence. 3️⃣ Innovations in RNA chemistry and delivery: To overcome biological instability and immunogenicity, researchers are now: ✅ Applying chemical modifications (on cap, tail, backbone, and nucleotides) ✅ Designing circular and hybrid RNA forms ✅ Leveraging next-gen delivery systems, both viral and nonviral, to enable targeted, efficient in vivo delivery ⚠️ Challenges Ahead: Despite its promise, RNA therapy for aging still faces significant roadblocks: • Selecting the right targets and sequences • Ensuring delivery across multiple tissues and barriers • Navigating the complex pharmacokinetics in older populations • Reducing cost to improve clinical accessibility 🔬 In short: Addressing these challenges is key to unlocking the full potential of RNA therapeutics in healthy aging. With continued research and innovation, this future feels within reach. 🧩 We’re only at the beginning of understanding RNA’s potential in aging science. I’d love to hear your perspective — let’s start a conversation. — #RNAtherapeutics #NatureAging #HealthyAging #mRNA #RNAi #CRISPR #NoncodingRNA #GeneTherapy #LongevityBiotech #BiotechInnovation